CA2029398A1 - Method and apparatus for the treatment of cancer - Google Patents
Method and apparatus for the treatment of cancerInfo
- Publication number
- CA2029398A1 CA2029398A1 CA002029398A CA2029398A CA2029398A1 CA 2029398 A1 CA2029398 A1 CA 2029398A1 CA 002029398 A CA002029398 A CA 002029398A CA 2029398 A CA2029398 A CA 2029398A CA 2029398 A1 CA2029398 A1 CA 2029398A1
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- Prior art keywords
- magnetic flux
- predetermined
- magnetic field
- field
- flux density
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N2/00—Magnetotherapy
- A61N2/02—Magnetotherapy using magnetic fields produced by coils, including single turn loops or electromagnets
Abstract
2,716-005 METHOD AND APPARATUS FOR THE TREATMENT OF CANCER
ABSTRACT OF THE DISCLOSURE
A method and apparatus for therapeutically treating cancer is provided. The apparatus includes a magnetic field generator for producing a controlled, fluctuating, directionally oriented magnetic field parallel to a predetermined axis projecting through a malignant neoplasm. In one aspect, a field detector measures the magnetic flux density along the predetermined axis. The applied magnetic field may comprise a full-wave rectified signal oscillated at predetermined frequencies to maintain a preselected ratio of frequency to the effective flux density, where the ratio regulates the growth characteristics of cancer cells of the neoplasm. This ratio is maintained by adjusting the frequency of the fluctuating magnetic field and/or by adjusting the intensity of the applied magnetic field after nulling out the local magnetic field at that region containing the neoplasm. In one aspect, a synergistic therapeutic cancer treatment is obtained by exposing cancer cells to the magnetic fields of the invention in the presence of a chemotherapeutic cancer agent.
ABSTRACT OF THE DISCLOSURE
A method and apparatus for therapeutically treating cancer is provided. The apparatus includes a magnetic field generator for producing a controlled, fluctuating, directionally oriented magnetic field parallel to a predetermined axis projecting through a malignant neoplasm. In one aspect, a field detector measures the magnetic flux density along the predetermined axis. The applied magnetic field may comprise a full-wave rectified signal oscillated at predetermined frequencies to maintain a preselected ratio of frequency to the effective flux density, where the ratio regulates the growth characteristics of cancer cells of the neoplasm. This ratio is maintained by adjusting the frequency of the fluctuating magnetic field and/or by adjusting the intensity of the applied magnetic field after nulling out the local magnetic field at that region containing the neoplasm. In one aspect, a synergistic therapeutic cancer treatment is obtained by exposing cancer cells to the magnetic fields of the invention in the presence of a chemotherapeutic cancer agent.
Description
~2~39~
r,2, 1 16-005 MET~OD AND APPARAll.~S FQR D~C~
ll~CIINICAL FIELD
The present invention relates generally to the treatment of cancer. More specifically, it provides in one aspect a method and apparatus by which a reduction in the proliferation rate of cancer cells is achieved through the use of fluctuating magnetic fields which are tuned to preselected frequencies. In the presence of a chemotherapeutic agent, target cancer cells are exposed to the therapeutic fields, producing a reduction in the proliferation of cancer cells greater than that of the chemotherapeutic agent alone. In another aspect, the present invention reduces malignancy by potentiating differentiation of the cells.
BAC~G~OUND OF T~ rNVENTION
Appro~imately one-fifth of all deaths in the United States are caused by cancer. An estimated $20 billion is spent annually in the United State~ in connection with the care and treatment of cancer patients. Although vast sums are spent on cancer research worldwide, little is known about the initiation and progression of this disease.
A~ will be appreciated by tho~e skilled in the art, cancer cells are relatively autonomou~ in that they fail to respond to normal biolo~ical signals that control cellular growth and metabolism in the living organism. Malignant tumors are characterized by their ability to metastasize. In metastasis, cancer cells spread through the organism ~2~ 2,716-005 producing tumors at sites remote from the point of origin. It is generally accepted that the number of cell membrane processes is inversely proportional to the probabilit~ of cell metastasis. Malignant neoplasms are generally classified as those arising from supportive tissues such as connective tissue, bone, cartilage or striated muscle (sarcomas) and those arising from epithelial tissue (carcinomas). In another type of cancer known as "leukemia," cancer cells circulate predominantly in the bloodstream. In general, leukemias originate in the lymphatic tissues and bone marrow where blood components are formed. After a neoplasm develops in an organism, it may progress from a benign form to a malignant form or from a low-level malignancy to a rapidly proliferating malignancy. Although millions of cells may metastasize from a primary tumor, it is known that only a few of these cells actually result in metastatic lesions at other sites.
While the behavior of cancer cells is unpredictable, it is generally acknowledged that early recognition of cancer is paramount to successful trestment. The most common modern-day method of treating cancer is surgical intervention. Both primary tumors and metastatic tumors may be surgically removed. It is also known that malignant tumor~, particularly lymphomas, leukemias and carcinomas can be treated by radiation therapy, for example by exposure to gamma rays and the like. More recently, advances have been made in the use of chemotherapeutic agents, often in conjunction with surgical and/or radiation treatment. It wlll be appreciated by those skilled in the art that rapidly progressing cancers have a high percentage of cells undergolng mitosis, i.e. a large growth fraction, and it is these cancers that are particularly susceptible to chemotherapy. More 62 716-0o5 ~ ~ 2 9 3 ~ ~
recently, immunotherapeutic techniques which utilize antibodies to which cytocidal agents are linked have met with limited success. However, the need for a more effective treatment for cancer is clearly evidenced by the large nu~ber of cancer deaths worldwide.
In United States Patent No. 4,622,952, entitled "Cancer Treatment Method," a method cf cancer treatment is described by whi~h the application of external electromagnetic energy allegedly achieves biophysical alterations including thermal changes, the stimulation of intracellular interferon production and the stimulation of intracellular prostaglandin production. The process includes the step of empirically tuning external electromagnetic energy to a "resonant" frequency which achieves a precise increment of heat rise within the cancer cell and which stimulate~ the intracellular production of interferon and/or prostaglandins. The present invention utilizes a group of resonant frequencies, not derived from heating consideration, but derived instead from a basic formula that acts to selectively control the transport of variou~ electrolyte ions into and out of cancer cells, in a manner refiulting in sub~tantially no measurable temperature increa~e within the cells.
In recent years, multi-disclplinary investigations of phy~iologicsl processes have provided evidence suggesting that electric and msgnetic fielts play an important role in cell and tissue behavior.
In United States Patent Number 4,818,697, entitled "Techniques for Enhancing the Permeability of Ions Through Membranes," which has been assigned to the assignee of the present invention and the disclosure of which is incorporated herein by reference, a method and apparatus are 20293~8 62,716-005 disclosed by which transmembrane movement of a preselected ion is magnetically regulated using a time-varying magnetic field The fluctuating magnetic field is preferably tuned to the cyclotron resonance energy absorption frequency of the preselected ion This important discovery brought to light the interplay of local magnetic fields and frequency dependence in ion transport mechanisms In United States Patent Application Serial Number 172,268, filed March 23, 1988, the disclosure of which is incorporated herein by reference, the inventors of the present invention disclose that cyclotron resonance can be used to control~ tissue development In United States Patent Application Serial Number 254,43R, entitled '~ethod and Apparatus for Controlling the Growtb of Non-Osseous, Non-Cartilaginous, Solid Connective Tissue," filed October 6, 1988, the di~closure of which is incorporatet herein by reference, the present inventor~ disclo~c a method of controlling the growth of non-osseous, non-cartilaglnou~ connective tissue which Dtilize~ cyclotron resonance frequencie~ In United~State~ P-tent Application Serial Number 295,164, entitled "TechQique- for Controlling O~teoporosi~ UsiDg Non-Invasive Magnetic Field~," filed January 9, 1989, the disclosure of which is incorpor-tet herein by reference, the prosent inventors disclo~e a thod of controlling osteoporosis using cyclotron resonance magnetic fi~lt~ In United State~ Patent Application Serial Number 343,017, fllet April 25, 1989, eneitled "Methods and Apparatus for Regulating Tran~membrane Ion Movement UtiIizing Selective Harmonic Frequencies and Simultaneou~ Multipl- Ion Regulation," the disclosure of which is incorporatot heroin by reference, the present inventor~ disclose a m-thot of utilizing therapeutic higher-harmonic frequencie~ and a method - -, , -2~2~
2,716-005 of simultaneously controlling the transport of multiple ions. In United States Patent Application Serial Number 3951247~ filed August 17~ 1989, entitled "Treatment for Stroke Victims," the present inventors describe a method and apparatus for magnetically treating stroke victims.
The present invention discloses a new and unique apparatus for non~invasive treatment of cancer which is directed at reducing the rate of growth of neoplasms through the action of a fluctuating magnetic field.
~ Q~Y OF T~E INV~NTION
In one aspect, the present invention provides an apparatus for decrea~ing the proliferation rate of cancer cells in the presence of 8 chemotherapeutic agent. That is, the conventional reduction in the number of cancer cells produced by exposing the cells to a chemotherapeutic agent is enhanced by the magnetic fields of the present invention. The inventive apparatus includes mean~ for generating an applied magnetic flux parallel to a predetermined axis and projecting through a predetermined space. The predetermined space i8 occupied by cancer cells or a tumor present in a living subject, preferably either man or animal, in the presence of a chemotherapeutic agent. It ~hould al80 be noted that the present invention may also be useful in the treatment of plant tumors. Means for measuring total magnetic flux ten6ity parallel to the predeterminet axis extending through the pretetermined fipace is provided 80 that the msgnetic flux density along the axis can be monitored. Means in association with the flux generating means is provided 60 that the applied magnetic flux can be : ' ,, 2~293~
2,716-005 oscillated. Finally, means for creating and maintaining a relationship between the rate of fluctuation of the magnetic flux and the intensity of the magnetic flux density is provided, where the predetermined relationship decreases the proliferation rate of the target cancer cells. In another aspect, this predetermined relationship is such that the number of cell membrane processes is increased to decrease metastatic potential.
In one embodiment, the means for applying a magnetic flux includes two opposed field coils arranged in Helmholtz configuration such that an applied magnetic field having known parameters along the predetermined axis can be generated between the coils. In another embodiment, a second pair of field coils are placed such that they generate an applied magnetic flux along an axis perpendicular to the predetermined axis defined by the first coil pair. In this same manner, a third pair of opposed coil~ can be utilized such that magnetic fields are applied by the three coil pairs along the x, y, z axes of a Carte~ian coordinate system. The second and third coil pairs are ~imilarly actuatet to provide a predetermined relationship between the frequency of the magnetic flux and the intensity of the magnetic flux ten~ity.
In another a6pect, a method for decreasing the proliferation of cancer cell~ is provided utilizing the apparatus of the present invention. Therein, a tumor comprising cancer cells in the presence of a chemotherapeutic agent in a living subject, either man or animal, is po~itioned ad~acent to the magnetic field generating means. A specific magnetic flux extending through the space in which the target cancer . ..: ::
62,716-OOS 2~29~
cells are positioned is generated parallel to a predetermined axis projecting through the cells. A relationship is then created between the frequency of the oscillating magnetic flux and the intensity of the magnetic flux density where the relationship decreases the proliferation rate of the target cancer cellæ, i.e. the number of cancer cells existing after a predetermined period is less than that with chemotherapy alone. In a preferred embodiment of the present invention, the magnetic flux generating means compriæes a pair of field coils as previously described. Also, in a preferred embodiment of the invention, the predetermined therapeutic relationship between the frequency of the magnetic flux permeating the cancer cells and the in~ensity of the magnetic flux is detenmined by the cyclotron resonance equation fc/B =
q/(2~m), where fc i8 the frequency in Hertz, B is the average value of the magnetic flux density in Tesla parallel to the predetermined axis, q/m has a value of from about 5 x 105 to about lOO x 106 Coulombs per kilogram and where B has a value of less than about l x 10-2 Tesla. In a particularly preferred embodiment, q/m i6 the charge-to-mass ratio of a preselected ion present in the cancer cells.
In still another aspect, a system for decreasing the proliferation of cancer cells iB provided which includes means for generatlng an spplied magnetic flux parallel to a predetermined axis and pro~ectlng through a predetermined space where the space is occupied by cancer cells of a living subject in the presence of a chemotherapeutic agent. In this particular configuration, the magnetic flux generating means lncludes at least two opposed field coils having an axis extending through ant parallel to the predetermined axis projecting through the predetermined space. Each of the field coils ha~ at least two - 2~2~39~
2,716-005 windings. One winding is designated an ac winding and the other is designated a dc winding. Means in association with the coils is provided for supplying a direct current to the dc winding and an alternating current to the ac winding. Means for measuring the ambient or local field existing in the predetermined space in the region of the cancer cells is also provided. Means in association with the flux generating means for controlling the direct current to the dc windings is supplied such that the dc windings may be activated to create a magnetic flux which reduces the ambient magnetic flux to substantially zero. A full-wave rectifier circuit and an oscillator are provided in as60ciation with the ac windings and the current supply means in order to produce an ac magnetic field component along the predetermined axis in the predetermined 6pace which has a preselected rms value, where the rms value deçreases the proliferation of cancer cells. In addition, the system may use a sinusoidal signal to the ac windings, offset by a constant bias current equal to the rms-value utilized when full-wave rectification is used.
The system may further include a second pair of oppo~ed field coils which define an axis extending through the region of the cancer cell~ which i~ perpendicular to the predetermined axi6 defined by the flr~t coil pair. Further, a third coil pair can be provided such that tho ~mbient flelt along the x, y, z axes of a Cartesian coordinate ~ystem is reduced to zero, with an applied field having the therapeutic non-zoro average value a6 provided by the pre~ent invention being generated along each of the axes.
With respect to the aforementioned system which includes ac windings and dc windings, there is provided by the present inven~ion a 2~2~39~
2,716-005 method for decreasing the proliferation of cancer cells which comprises the steps of generating an applied magnetic flux parallel to a predetermined axis which projects through a predetermined space, with the space being occupied by cancer cells in a living subject in the presence of a chemotherapeutic agent. The ambient field along the predetermined axis in the predetermined space is measured using a magnetic field sensor which is capable of measuring both static and time-varying magnetic fields. Utilizing the dc windings and a power supply, a magnetic flux is generated which reduces the ambient field to substantially zero along the axis. The ac windings are then used to generate an ac magnetic field having a component along the predetermined axis which has a non-zero average value that i~ effective in decreasing the proliferation rate of cancer cells.
In stlll another aspect, the present invention provides a method for the therapeutic treatment of cancer in which the proliferation rate of cancer cells i8 reduced by the fluctuating magnetic fielts provided by the present invention without the concurrent application of a chemotherapeutic a8ent.
Still further, treatment in accordance with the present invention i~ in one embodiment effective in stimulating the differentiation of cell processes, i.e., neurites to decrease the metastatic potent~al of the cells.
The aforementioned control of cancer cell growth is also achieved to varying extents in one embodiment of the present invention through the use of higher-harmonic tuning and multiple ion tuning is also provided.
, 2~2~8 62,716-005 ~ ^
BRIEF DES~IPTION OF T~E DRAWLNGS
Figure 1 diagrammatically illustrates one preferred placement of the apparatus of the present invention.
Figure 2 is a front elevational view of the treatment heads of the present invention in one embodiment.
Figure 3 is a graph which illustrates the magnetic flux density value (B) in the present invention.
Figure 4 is a block diagram of the functional elements of a preferred circuit for use in the present invention.
Figure 5 is a side elevational view in which the present invention i8 shown utilizing three pairs of coils.
Figure 6 is a perspective view of the present invention for use in systemic treatment of cancer.
~ igure 7 i~ a block diagram of the circuitry of one embodiment of the pre~ent invention for use in sy6temic treatment.
~SCRIPTIOW OF TRF PR~F~R~eD ~M~ODIMRNTS OF Tae INV~NTIQN
Referring now to Figure 1 of the drawings, cancer treatment apparatus 20 is shown in position on a subject' 8 leg 22. It is to be -- 2~293~
2,716-005 understood that both the apparatus and the method of the present invention are suitable for use in decreasing the proliferation rate of cancer cells in both animal and human subjects. As used herein, the term "cancer" shall have its customary meaning, although it is to be noted that the present invention may be useful in the treatment of non-cancerous neoplasms as well as cancerous neoplasms. The term "decreasing the proliferation" and "decreasing the proliferation rate"
shall mean that the number of cancer cells existing after a predetermined period of treatment in accordance with the present invention is less per unit volume than the number of cancer cells in a control without treatment in accordance with the present invention. The term "chemotherapeutic agent" shall mean one or more of the various anti-cancer treatment drugs, the identity and nature of which will be known by those of skill in the art. It i8 known that many of these agent~ produce a decrease in cancer cell proliferation rates. Thus, the target tissue which is to be affected is a region of cancer cells such a8 a malignant tumor. Although the present invention has been shown to be useful in decreasing the proliferation rate of neurobla~toma tumor cells in the presence of a chemotherapeutic agent, it i6 believed that thé present invention will be effective in the treatment of other cancer cell~, including carcinoma, leukemia, ~arcoma, lymphoma, melanoma, myeloma and the like.
A malignant neoplasm 24, shown here as a sarcoma in the ~ub~ect's thigh, is positioned in a pretetermined volume 26 between treatment heats 28 and 30 of cancer treatment apparatus 20. It is within this pretetermined space or volume that the therapeutic o~cillating magnetic field i8 generated. Hence, as will be appreciated, ,. . :
. . .
--` 2~9~8 2,716-005 there exist within space 26 cancer cells which are multiplying by mitotic division in the uncontrolled manner characteristic of cancers.
As with all cancer treatments, it is preferred that treatment be commenced immediately following detection of the condition. In this embodiment of the invention, a chemotherapeutic agent, for example cytosine arabinoside, is administered to the subject in the customary manner. The dosage will be consistent with the known effective dosage for the particular chemotherapeutic agent, although it is anticipated that a reduction in the standard dosage may be facilitated by the pre~ent invention. Accordingly, a cancer chemotherapeutic agent is administered to the patient either systemically or locally, for example through the use of cancer cell-specific antibodies to which chemotherapeutic agents are conjugated. The most preferred chemotherapeutic agents which are suitable in the practice of the present invention are those which demonstrate substantially enhanced therapeutic action in the treatment of cancer when administered in connection with selected frequencies of cyclotron resonance tuning as provided by the present invention over control applications of the chemotherapeutic a8ent without exposure to the magnetic fields of the present invention. This can be readily determined by in vitro or n vivo animal experiment~. Preferred chemotherapeutic agents believed to be u~eful in this respect include alkylating agents and nucleic acid analo8~-In order to better appreciate the configuration of treatmentheads 28 and 30 as provided by the present invention, reference is now made to Figure 2 of the drawings in which trestment heads 28 and 30 are shown a~ including housings 32 and 34 of a non-magnetic material such as 2~3~
2,716-005 plastic. ~ach housing 32, 34 encloses a field coil 36 and 38. At least one of the treatment heads encloses a magnetic field sensing device 40, such as a Hall-effect device, shown in Figure 2 enclosed within housing 32 of treatment head 28. The power source for driving the field coils is preferably external, but may be a battery or the like shown as power source 42 in treatment head 30. Straps 44 and 46 are provided by which cance~ treatment apparatus can be conveniently attached to the patient.
While field coils 36 and 38 are the preferred means by which an applied magnetic field i8 generated in the present invention, those skilled in the art will appreciate that other electromagnets or possibly permanent magnets may be adapted for u~e in the present invention, and any such use is intended to come within the scope of the present invention. Also, the radius of each field coil 36 and 38, as well as the turns of the windings, may vary in accordance with the principles of the present invention. In the most preferred arrangement, the geometry and relative position of treatment heads 28 and 30 during treatment are such that field coils 36 and 38 operate as Helmholtz coils. Hence, thofie skilled in the art will recognize that in the mo6t preferred arrangement, field coils 36 and 38 are su~stantially identical, f$eld-aiding, parallel coaxial coils separated by a distance equal to tha rsdius of each coil.
It will be appreciated that the malignant neoplasm to be affected will generally be subject to local magnetic influences. As u~ed hercin, the term "local magnetic field," "ambient magnetic field"
or the like shall be dcfined as the magnetic influences, including the earth's magnetic field or geomagnetic field, which create a local 2,716-005 magnetic flux that flows through the target tissue. "Magnetic flux density" shall be defined in the customary manner as the number of magnetic field lines per unit area through a section perpendicular to the direction of flux. Factors contributing to the local magnetic field in addition to the geomagnetic fi.eld may include localized regions of ferromagnetic materials or the like. In one embodiment of the present invention, field coils 36 and 38 are used to create an applied, fluctuating magnetic field which, when combined with the local magnetic field parallel to a predetermined axis extending longitudinally between treatment heads 28 and 30, produces a combined magnetic field or composite field having a componen~ along the axis which has a precisely controlled, predetermined ratio of frequency to average magnetic flux den6ity.
In one embodiment, and referring again to Figure 2 of the drawings, this relationship is created using microprocessor 48 which is in communication with electronics neces6ary to control the oscillation and intensity of the magnetic flux which permeates the target cells.
Also, leads 50 and 52 are shown by which the various components of cancer treatment apparatus 20 are interconnected, along with other such leadH which are not 6hown. Magnetic sensor or magnetometer 40 measures the total or composite magnetic flux which passes through the predetermined space between treatment heads 28 and 30 thus providing an accurate measurement of the magnetic field which permeates the malignant neopla8m 24. Predetermined axis 54 is shown in Figure 1 as extending between treatmcnt heads 28 and 30. It will be appreciated that the applied field generated using treatment head6 28 and 30 may be in either direction of predetermined axis 54 and that the local or ambient 3 ~ ~
2,716-005 magnetic field will also have a component along axis 54 which either augments or decreases the applied magnetic flux. The relatively low applied flux density in the precise, predetermined relationships of combined flux density and frequency provided by the present invention are to be maintained during treatment, notwithstanding the influence of the local magnetic field. This may be achieved in es~entially two preferred manners which will be explained more fully herein. Thus, magnetic field sensor 40 is provided to determine the level of the magnetic flux density of the local magnetic field.
The unexpected and superior result~ of the present invention are achieved by creating a fluctuating magnetic field having a magnetic flux density parallel to predetermined axi6 54, with the magnetic flux density alon~ axis 54 bein8 maintained at a predetermined ratio of the frequency of the fluctuations to the non-zero value of the magnetic flux density. In this embodiment, the magnetic flux density parallel to predetermined axis 54 has a non-zero time-average value. More specifically, as illustrated in Figure 3 of the drawings, the therapeutic magnetic field of the present invention can be thought of as a static field having refer~nce level A on which a fluctuating magnetic field is ~uperlmposed. It comprise~ a time-varying component which vario~ in amplitute but not direction and a steady reference value around which the time-varying component varies. Reference level A is the non-zero average value of the flux density (B). Therefore, it will be understood that the non-zero time-average, or net average value where the magnetic field is the combination of the local field and the applied field, along predetermined axis 54 is utilized since the magnitude B of the composite flux density changes at a predetermined rate due to 2 ~
2,716-005 oscillation or fluctuation of the applied magnetic flux. Thus, an average value is utilized which is a non-zero average value illustrated at point (c). This reflects that although the magnetic flux density along the axis is oscillating at a controlled rate, the field is regulated to ensure that the field is always unipolar; that is, the field is always in the same direction along predetermined axis 54.
As stated, it has been found that rather precise relationships of the flux density of the magnetic field to the frequency of the fluctuations are used in the present invention to provide therapeutic results. These ratios of frequency to composite flux density are found in accordance with the following equation:
fc/B = q/(2~m) where fc is the frequency of the combined magnetic field in Hertz, B is the net average value of the magnetic flux density of the magnetic field (the combined field where a local field component is present) parallel to predetenmined axis 54 in Tesla and q/m has a value of from about 5 x 105 to about 100 x 106 Coulombs per kilogram. B preferably has a value not in exceaa of about 1 x 10-2 Tesla. In order to increase the inhibition of cancer cells in the presence of a chemotherapeutic agent, the following frequency and associated combined magnetic flux density (B) are preferred:
fc (Hertz~ 8 (~esla) 16 20.9 X 10-6 at an ac amplitude, peak-to-peak of 40 microTesla.
-- 2~3!~
62,716-005 In use, malignant neoplasm 24 in the presence of a chemotherapeutic agent is then subjected to a fluctuating magnetic field as described herein for a period of time effective to inhibit the rate of growth of the neoplasm by decreasing the proliferation rate of cancer cells. While the length of time necessary for successful treatment may vary, it is anticipated that up to about 100 days of treatment will provide beneficial results. Longer treatment may be desirable in certain applications.
` In another embodiment of the present invention, values for q and m are determined with reference to a preselected ionic species. It will be known by those skilled in the art that the biochemical milieu of a malignant neoplasm comprises a mixture of various ions in the intracellular and intercellular fluids. These ions include potassium ions, magnesium ions, sodium ions, chloride ions, phosphate ions, sulfate ions, carbonate ions, bicarbonate ions and the like and various lons formed by the dissociation of amino acids, proteins, sugars, nucleotides and enzymes. By utilizing the values of charge and mass for a preselected ion in the equation set forth above, which will be recognized by those skilled in the art as the cyclotron resonance relationship solved for fc/B, ratios of frequency to magnetic flux den~ity can be determined which will therapeutically reduce the rate of growth of malignant neoplasm 24 in accordance with the present invention. By using the charge-to-mass ratio of a preselected ion, a ~peci2ic cyclotron resonance frequency for the ion can be determined.
By then tuning cancer treatment apparatus 20 to maintain a combined magnetic flux density having the proper cyclotron resonance frequency, - 2~2~3~
2,716-OOS
the neoplastic tissue containing the preselected ion can be treated to bring about the desired decrease in the proliferation rate of the cancer cells. More specifically, in a prefered embodiment of the invention, by tuning to Cal+ or K+ it is believed that progression of a tumor in the presence of serum lacking fetal growth factors can be slowed in accordance with the present invention.
Hence, it will be appreciated by those skilled in the art that in the present invention, by synergi6tically enhancing the effects of chemotherapeutic agents in the treatment of cancer, it may be pos6ible to reduce the quantity of or the time course of the chemotherapeutic age3ts administered to the patient, resulting in a decrease in dose-related side effects.
It will also now be appreciated by the prior explanation of preferred embodiment6 of the present invention and from the equation for establishing a cyclotron resonance relationship, that either the frequency of the fluctuating magnetic field or the magnitude or intensity of the magnetic flux density along the predetermined axis, or both the frequency and the intensity of the flux density, can be ad~usted to provide a magnetic field which has the desired characteristlcs. However, it is preferred to maintain a constant frequency which thus requires that the intensity of the applied magnetic flux den~ity be adju~ted to compensate for changes in the local magnetic field in order to maintain a constant ratio of frequency to magnetic flux density. For example, if it is necessary to maintain a frequency of 16 Hz and an average flux density of 4.07 x 10-5 Tesla for K~, changes in the local field which would otherwise cause unwanted -- 2~29~ 2,716-005 deviations in the combined magnetic flux density must be corrected by increasing or decreasing the applied magnetic flux density accordingly.
This is most preferably performed by the microprocessor in connection with both the field generating means and the field-sensing device.
Alternatively, if changes in the combined magnetic flux density occur due to changes in the local magnetic field, the frequency of the oscillations can then be changed so that the preferred ratio is maintained. Once again, it is important to realize that the value of B
is the average composite magnetic flux density parallel to the predetermined axis since the magnitude of the flux density changes as the field is oscillated. It will be understood that detection of change6 in the magnetic field due to change~ in the ambient component should be at intervals frequent enough to provide a frequency-to-magnetic field ratio which i8 substantially constant, notwithstanding the changes in the local field component.
Referring again to Figures 1 and 2 of the drawings, each field coil 36, 38 preferably has up to about 3000 turns or loops of conducting wire, the diameter d of each loop being preferably up to about 300 centimeters. The number of turns of wire N, the diameter of th~ coils, the separation of the coils, and the wire gauge are critical only insofar a~ conventional practice requires con6traints on these and other te~ign pArameters to allow optimal performance characteristics in achieving predeterminet flux densities as required in the preferred practice of the present invention. As stated, other magnetic field generating means may be suitable for use in the present invention and are contemplated as falling within the scope of this invention.
2~2~
62,716-005 It is also to be understood that the applied magnetic field which results in a combined magnetic flux density along predetermined axis 54 may be produced by a sinusoidal signal or from a full-wave rectified signal applied to field coils 36, 3~. It may also be appropriate in some instances to reduce components of the local magnetic field which are not parallel to predetermined axis 54 to zero through the use of additional coils positioned at right angles to coils 28 and 30 to create an opposite but equal field. It may also be suitable to reduce the local magnetic field component to zero throughout treatment using additional coils or the like.
Referring now to Figure 4 of the drawings, a block diagram is shown which depicts one preferred arrangement of the circuits of cancer treatment apparatus 20 in functional segments. Numerous other circuit arrangements may be possible if the principles of the present invention are faithfully observed. Microcontroller or microprocessor 100 is seen by which the composite magnetic field is maintained at a constant pretetermined level despite changes in the ambient component as previously de6cribed. In this re6pect, input 102 is provided by which a set point value of the predetermined composite magnetic flux density along a predetermined axis through the target tissue is input into miCroproce880r 100. A8 will be shown, the composite field strength is compared to thi8 8et point value to generate an error equal to the difference in the set point value and the measured value of the compo8ite magnetic flux density along the axis.
Magnetic field sensor 104 is provided by which the magnitude of the composite field which passe~ through the target tissue along the , ~92~8 2,716-005 axis is measured. It is preferred that magnetic field sensor 104 comprise a Hall-effect or a flux gate device each of which, as will be known by those skilled in the art,can sense both time-varying and static magnetic fields and each produces an analog signal. The magnetic field sensor 104 constantly monitors the composite magnetic field, sending a signal to microprocessor 100. It will be understood that the output of a Hall-effect or flux gate magnetic sensor is relatively small; thus, magnetic field sensor amplifier 106 is provided by which the signal from magnetic field sensor 104 is amplified, for example, up to three thousand times its original value. Since these devices produce an analog signal, analog-to-digital converter 107 is provided by which the amplified signal from magnetic field sensor 104 is converted to a digital signal which can be used by microprocesgor 100. It is preferred that the analog-to-digital converter be provided on-board the microprocessor chip.
As will be appreciated, the amplification of the magnetic field sen~or signal may produce an unwanted noise level. Also, sudden changes in the magnetic field intensity may occur which make it difficult to determine the true average value of the composite magnetic flux don~ity. Henco, the signal from analog-to-digital converter 107 which i~ input into microprocessor 100 is filtered by software filter 108 to removo shot nolse and sudden fluctuations in the composite field tetected by magnetic field sensor 104. Although it is preferred that filter 108 comprise softwAre in microprocessor 100, a discrete filter could be used. In this embodiment, software filter 108 is a digital filter, prcferably an integrator with a time conAtant of approximately 0.5 seconds. In other words, the changes in the magnitude of the 2~2~
2,716-005 composite magnetic field which are compensated for by increasing or decreasing the applied field are long-tenm changes of 0.5 seconds or more. Hence, the time constant of filter 108 should be such that momentary fluctuations are filtered out.
Microprocessor 100 includes logic which calculates the non-~ero net average value of the composite magnetic flux density. This non-zero average value is then compared at a comparator 110 in microprocessor 100 to the predetermined dc reference or offset value which is input into microprocessor 100 via input 102. It should be noted that this reference value is preferably established by dedicated circuitry in microprocessor 100, although variable input means could be included by which the set point value could be changed. An error statement is then generated defining the difference in the measured value of the compo6ite magnetic flux density and the set point or reference value. Microprocessor 100 then determines the magnitude of the output necessary to drive magnetic field generating coils 112 to bring the composite magnetic flux density back to the set point.
Software field modulator or oscillator 114 is provided by which an ac or fluctuatin~ component is ~uperimposed on the digital output ~ignal which i8 input into digital-to-analog converter 116. From the previouc di~cus~ion of the present invention, it will be understood that software field modulator 114 of microproces60r 100 in the preferred embodiment of the present invention is preset to a fixed~ predetermined frequency to produce the desired predetermined ratio of frequency-to-magnctic flux density value. In another embodiment, the feedback system of the present invention i8 such that changes in the - 2~2~3~
2,716-005 composite magnetic flux density are measured, whereupon microprocessor 100 determines the necessary change in frequency to maintain the predetermined relationship. In that embodiment, software field analog converter 116 be provided on-board the microprocessor chip. Hence, software field modulator 114 provides the ac component at node 118.
The signal from digital-to-analog oonverter 116 is fed to voltage-to-current amplifier 120, the output of which drives magnetic field generating coils 112 in the desired manner. Hence, the composite field is held substantially constant despite changes in the ambient component.
While several arrangements of power sources are suitable, it is preferred that power supply 122 be provided to power magnetic field QenAor amplifier 106, microprocessor 100 and magnetic field sensor 104, the latter via bias circuitry 124. A separate power source 126 is preferred for voltage to current amplifier 120.
, Having fully described one preferred embodiment of the apparatus of the present invention, including its manner of con~truction, operation and use, the method of the present invention will now be described. It iB to be understood that this description of the method incorporates the foregoing discussion of the novel apparatus. In one embodlment, the present in~ention provides a method of reducing the rate of growth of a neoplasm in man or animals. This is achieved in one aspect by generating a fluctuating, directionally-oriented magnetic field which projects through the cancer cells, for example a malignant neoplasm such as a sarcoma, in the ~2~3~
2,716-005 pre$ence of a chemotherapeutic agent as previous described. It is to be understood that the present invention may also be useful in reducing the rate of growth of benign tumors. The magnetic field generating means preferred for use is previously described. The magnetic field so generated has a magnetic flux density of precisely controlled parameters which passes through the target neoplasm parallel to a predetermined axis projecting through the neoplasm. As will be known by those skilied in the art and as has been clearly explained, the local magnetic field to which the neoplasm is subjected will have a component which is parallel to the predetermined axis and which thus aids or opposes the applied or generated magnetic field along the axis. At times, the local component may be zero. In the method of the present invention, the density of this combined magnetic flux, and more specifically the net average non-zero value of the combined magnetic flux density, is controlled to provide a precise relationship between the flux density along the axis and the frequency of the applied magnetic field which is 08cillating at a predetermined value. Most preferably this is accomplishet by adjusting the intensity of the applied field to compensate for changes in the local field. Thus, in one embodiment, the present invention provides a method of treating cancer by creating a magnetic field which penetrates a malignant neoplasm and which has a predetermined relation~hip between frequency of oscillation and average flux density. In the most preferred embodiment, the predetermined relationship or ratio of frequency-to-field intensity is determined with reference to the equation:
fc/B = q/(2~m) ., - 2~2~3~
62,716-005 where fc is the frequency of the combined magnetic field along the predetermined axis in ~ertz, B is the non-zero net average value of the magnetic flux density of the combined magnetic field parallel to the - axis in Tesla and qtm is in Coulombs per kilogram and has a value of from about 5 x 105 to about 100 x 106. B preferably has a value not in excess of about 1 x 10-2 Tesla.
In order to maintain a fluctuating magnetic field having the desired parameters, it may be necessary to monitor changes in the composite magnetic field parallel to the predetermined axls. As stated, this is preferably carried out with a Hall-effect device or the like which is capable of sensing both static and time-varying magnetic flux and which produces an analog signal. This analog signal is periodically sampled by microprocessing means which then calculates the necessary frequency and/or magnitude of the applied magnetic field to maintain the preprogrammed, predetermined ratio previously de6cribed. Of course, it will now be understood that it is the combined magnetic flux which is sensed by the magnetic field sensor. The magnetic field generating means is uset to adjust the magnitude of this composite field where appropriate.
In one embodiment, the method includes controlling the a~-rsge value of the applied magnetic flux density along a predetermined axis to maintain a predetermined ratio of frequency-to-composite ~agnetic flux den8ity. In another embodiment, the frequency of the fluctuations is ad~usted to maintain this relation~hip in which changes in the combined magnetic flux den~ity due to changes in the local magnetic field are detected. Moreover, a combination of these two ~` 2~2~
2,716-005 methods may be u6ed wherein both the frequency and the magnitude of the magnetic field flux density are adjusted to maintain ~he predetermined relationship of the present invention.
~ ence, in one aspect the method of the present invention includes the steps of creating and maintaining a predetermined relationship between the frequency of a fluctuating magnetic field and the flux density of the field. In particularly preferred embodiments, a frequency of 16 Hertz and an average flux density of 2.09 x 10 5 Tesla are utilized which corresponds to cyclotron resonance for Ca++. This combination of frequency and flux den~ity i8 particularly useful in decreasing the proliferation rate of cancer cells in the presence of a chemotherapeutic agent. Another preferred frequency which is useful ;s 16 Hertz and 4.07 x 10-5 Tesla whlch corresponds to cyclotron resonance for K+.
In a preferred embodiment of the method of the present ~nvention, the ratio of frequency-to-flux den~ity is determined by selecting a preselected ion present in the neoplasm and tuning the fluctuating compo3ite magnetic flux density to the specific cyclotron re~onance frequency for the ion. The preferred ions for lncrea6ing the inhibition of cancer cells in the presence of a chemotherapeutic agent are Li+, K+, Mg++, and Ca++. Tuning to other ions such as Mn++, Zn++ or Cu+ may al~o provide beneficial results.
Finally, the subject neoplastic tissue is exposed to the therapeutic magnetic flux in accordance with the pre~ent invention for a period of time sufficient to bring about the desired result. It i6 -- 2~2939~
2,716-005 believed that exposure in accordance with the present invention o~
approximately .5 hr. to 24 hr./day will typically provide beneficial re~ults.
In another preferred embodiment of the present invention, the treatment heads of cancer treatment apparatus 20 contain two discrete but otherwise equal windings. Each head contains a dc winding and an ac winding. These windings are closely wound, either as alternate wires, as alternate layers, or in ad~acent planes. Those skilled in the art will recognize that the closeness of the winding arrangement will ensure that the two separate magnetic fields generated at a point distant from the two windings (when each carries substantially the same current) will be substantially the same. The dc winding in one coil is connected in series aidin8 to the dc winding in the other coil. The ac winding in one coil is similsrly connected in series aiding to the ac winding in the other coil.
The pair of dc windings are energized by a dc power supply thst provides a current which reduces the component of the local or smbicnt fielt along the sxis of the coil pair at the desired treatment region to a value that i8 substantially zero. Again, the ambient field 1- mea~urcd by magnetic field sensing means such as a Hall devi~e or a fluxgate magnetometer or the like. The ac windings, in this embodiment, arc preferably energized by a full-wave rectifier circuit providing a current which produceo a resulting ac magnetic field component along the coll sxis at the de~ired treatment region that varies in time at the therapeutic frequency. The rms current of the rectified signal in the ac coil pair i~ adjusted until a pre~elected rms magnetic field --- 2~2~
2,716-005 component at the treatment region is achieved. It will be understood that once the ambient field is measured, knowledge of the coil geometry and number of turns will allow a predetermined calibration, enabling the operator to automatically achieve the required ambient field nulling current as well as the rms current necessary to create the preselected rms magnetic field.
In this embodiment utilizing a rectified si~nal in the ac windings, the frequency of the fluctuating magnetic field is set at a predetermined value, and the effective or root-mean-square value of the applied magnetic flux density is then regulated to produce a ratio of frequency to flux density that acts to reduce the rate of growth of cancer cells. Preferred ratios of frequency-to-field intensity are determined with reference to the equation:
fO = q/2~m where fO i8 the frequency of the fluctuating magnetic field in Hertz, Bo is the non-zero rms v~lue of the magnetic field component winding along the coil axis in Teala, (q/m) is in Coulombs per kilogram and has a value of from about 5 x 105 to about 100 x 106. Bo preferably has a value not in exce8s of 1 x 10-2 Tesla. In one embodiment, the values of q and m are 8elected with reference to the charge and mass of a preselected ion. Other relationships between frequency and magnitude may be u~eful or even desirable in a particular application.
In another embodiment, a sinusoidal current is employed in the ac windings with a direct current offset resulting in a non-zero :' --` 2~2~3~
2,716-005 average magnetic field to achieve the required magnetic field along the predetermined axis that is therapeutically effective.
In still another embodiment, and referring now to Figure 5 of the drawings, three pairs of Helmholtz-like coils generate applied magnetic fields along the x, y and z axes of a Cartesian coordinate system. Coil pair A comprises treatment heads 200 and 202. Coil pair B
comprises treatment heads 204 and 206, and coil pair C similarly comprises a pair of opposed coils, only one of which is shown in phantom a6 treatment head 208. It will be appreciated that these coils may comprise single windings or may be provided in the combination ac and dc windings as previou~ly described. Also, it i8 preferred that each pair be provided with a magnetic field sensing device in order to measure the magnetic field component along each respective axis. In other words, the axes of the three coil pairs will be mutually perpendicular, intersecting at the de~ired treatment region, i.e., the target malignant neoplasm. The therapeutic frequency is generated by each coil pair in the aforementioned described manner. Where the coil pair~ include ac and dc winding~, the ambient field component along each axis is reduced to substantially zero.
In still another embodiment of the present invention~ the growth rate of a neoplasm in the presence of a chemotherapeutic agent is reduced by creating and maintaining a predetermined relationship between thc frequency of the fluctuations and the non-zero average value of the magnctic flux den~ity along the predetermined axis based on the charge to-mass ratio of the preselected ion, wherein thic predetermined relation~hip i6 determined using the equation fch = XBq/2~m.
---` 2~2~3~
, 62,716-005 Accordingly, fch is the frequeney of the fluctuating magnetic flux density in Hertz, B is the non-zero average value of the flux density parallel to the predetermined axis in Tesla, q is the charge of the preselected ion in Coulombs, m is the mass of the preselected ion in kilograms, and X is a preselected odd integer greater than one. In this manner, a number of higher harmonic frequencies are provided by which therapeutic results may be achieved.
It will be recognized that the fundamental therapeutic frequency fc is effectively multiplied by a selected odd integer to produce a frequency which also causes the desired therapeutic result.
Unless otherwise specified, as used herein, the term "odd integers" or "odd integer" shall mean positive, non-zero integers. The preferred odd integers for use in the present invention which provide harmonic frequencies that should be effective in reducing the growth rate of cancer are selected from the group consisting of the following integers: three, five, seven, nine, eleven, thirteen, fifteen, aeventeen and nineteen. Additional harmonic frequencies based on multiplying the fundamental frequency by an odd integer may also be suitable in some applications. As indicated, the frequencies for a given preselected ion and known magnetic flux density B can be determined with reference to the equation fch = XBql2~m where fch is the frequency in Hertz of the fluctuating magnetic field along a predctermined axis extending through the target tissue, B is the magnetic flux density along the axis in Tesla, q is the charge of the pre~elected ion in Coulombs, m is the mass of the preselected ion in kilogram~, and X i8 a selected odd integer greater than one. It is believed that many of the preferred odd multiple harmonic frequencies . ' ' , . , '. , ' :' ' ' . ' ' '. -. ' ' ~ :
~29~
2,716-005 will be substantially as effective in treating cancer as are the fundamental frequencies. A more thorough description of harmonic tuning is set forth in the aforementioned U.S. Patent Application Serial No.
343,017 which is incorporated herein by reference.
In still another aspect, the present invention provides a method for decreasing the proliieration rate of cancer cells which comprises generating an applied magnetic field parallel to a predetermined axis which projects through the designated space. In the presence of at least two different predetermined ionic species in the target cancer cells or tissue and a chemotherapeutic agent, the neoplasm is exposed to the applied magnetic field. In one embodiment, the neoplasm is also exposed to a local magnetic field having a component parallel to the predetermined axis. The magnetic flux density along the predetermined axia i8 f luctuated to create a non-zero average value.
Where a local f ield is also present, this non-zero average value is the net non-zero average value of the applied and local field components parallel to the predetermined axis as previously described in connection with the other embodiments of the present invention.
A predetermined relationship between the frequency of the fluctuation~ ant the non-zero average value of the magnetic flux density along the axi~ i8 then created and maintained which simultaneously controls the movement of two or more preselected ions. Ion movement is brought about to decrease the growth rate of the neoplasm. In one embodiment, the predetermined relationship is determined by first sol~lng the equation fc - Bq/2~m at a generally randomly selected value of B for each di~tinct preselected ion, where fc is the frequency of the 2~2~
2,716-005 field fluctuations in Hertz, B is the non-zero average value of the flux density parallel to the predetermined axis in Tesla, q is the charge of each preselected ion in Coulombs, and m is the mass of each preselected ion in kilograms. The value of B is preferably less than about 10 2 T.
This establishes the fundamental cyclotron frequency for each ion. A
value fcs is preferably selected such that none of the individual ion fc alues deviate more than 5 percent from the fcs value. In most instances, there will be no fcs value available based on the fundamental fc values of the preselected ions. Accordingly, a higher odd harmonic frequency of at least one of the preselected ions is determined with the equation fch = XBq/2~m as previously explained. The values of fc and fch are examined to determine whether an fch value can be selected based on a 10 percent and most preferably a 5 percent deviation factor. If not, the process is continued for each value of fCh~ beginning with the lowest odd harmonic fch values until a value of fc8 can be established within the 5 percent deviation. Hence, at the value selected for B
during the calculation of the fc or fch values, the magnetic flux density to which the target tissue is exposed is fluctuated along the axis at the fc8 frequency. This specific relationship between frequency and field stren8th brings about simultaneous transmembrane movement of the preselected ion8 for decreasing the proliferstion rate of the target cancer cells.
In more detail, the fundamental frequency at which the fluctuating mflgnetic field would be oscillated for cyclotron resonance regulation of transmembrane ion movement is calculated $ndividually for each different ionic species to be regulated using the equation fc =
Bq/2~m for a selected value of B, which is again the non-zero average . ' ' ' : -.
- 2~2~
2,716-005 value of the flux density along the predetermined axis. As previously explained, fc is in Hertz, q is in Coulombs9 m is in kilograms, and q/m is the charge-to-mass ratio of the preselected ion. Once the fundamental cyclotron resonance frequency (fc) of each ion to be regulated is calculated, a regu]ating frequency (fcs) is determined which is preferably within 5 percent of the fundamental frequency f~ or an odd harmonic frequellcy fch of each preselected ion. The odd harmonic frequencies are determined again using the equation fch = XBq/2~m, where X is an odd integer greater than one. It will be understood that the equation fch = XBq/2~m can be used to determine the fundamental frequency fc by using a value of L for X. While the value of fcs will not typically be available which is common to the fundamental frequencies and/or odd harmonic frequencies for each preselected ion, it has been found that an fcs value which is within about 10 percent and preferably about 5 percent of each fc value or fch value of the ions to be re~ulated satisfactorily provides simultaneous transmembrane movement of each preselected ion in the fie]d.
It will al60 be understood that the values of fch are a functlon of B. Thus, it may be possible to obtain an fcs value for a particular set of ions which is within the preferred 5 percent deviation at a de~ignated B value, but not a higher B value. For use in the pre~ent invent~on, the value of B is preferably less than about 1 x 10-2 T, with a peak-to-peak amplitude of about 2.0 to about 20,000 m Tesla.
The preferred ions are those previously set forth. A more thorough description of multiple tuning is set forth in the aforementioned U.S.
Patent Application Serial No. 343,017 which is incorporated herein by reference.
~2~g 62,716-005 It will therefore be appreciated that in the broadest sense, the present invention provides a method and apparatus for regulating ~he growth characteristics of cancer cells, i.e. treating cancer, by subjecting the cells to a magnetic environment in which the ratio of the magnetic flux density to the fre~uency of oscillation of a fluctuating field component is maintained at a predetermined relationship based on the cyclotron resonance frequency of at least one ion in the field.
This relationship may be selected to decrease the proliferation rate of cancer cells exposed to a particular chemotherapeutic agent or selected to increase the differentiation of of cancer cell neurites to inhibit malignancy. It may be possible to select a relationship which decreases the rate at which cancer cell proliferation occurs even without the use of a chemotherapeutic agent. In its most preferred embodiments, the present invention provides a method and apparatus which includes tuning to the cyclotron resonant frequency of Ca++ or K+ or a selected multiple of these frequencies in the presence of a chemotherapeutic agent to decrease proliferation rate. In another mo~t preferred aspect, the predetermined relationship is baEed on multiple harmonic tuning for both Ca++ and Mg++ in the presence of a chemotherapeutic agent where the relationship represents three times the fundamental frequency of the c~lcium ion and five times the fundamental frequency of the magnesium ion. In the latter ca~e, it is the formation of neurites which is 8timulated.
In still another a~pect the present invention provides an apparatus for the systemic therapeutic treatment of cancer. By "systemic treatment" it is meant that substantially all of the subject's body is simultaneously expo~ed to the therapeutic magnetic fields in -3~-- 202~3~g 2,716-005 accordance with the present invention. Accordingly, and referring now to Figure 6 of the drawings, systemic treatment apparatus 280 is shown which comprises a tube or cylinder 282 of a non-magnetic material such as plastic. Tube 282 houses a large solenoid 284 which contains multiple turns of wire 286 and which extends substantially the entire length of systemic treatment apparatus 280. Gurney or platform 288 is provided on a track system (not shown) which allows platform 288 to move between a first position outside of tube 282 to a second position inside of tube 282. A controller 270 is provided along with the necessary circuitry for energizing solenoid 284 to create a magnetic field in the direction of axis 250, which in this embodiment projects through the central bore of solenoid 2B4. In other words, and as will be appreciated by those skilled in the art, the magnetic flux generated by solenoid 284 will run through the center of the coil. Patient 272 is placed on a platform 288 and platform 288 is then moved into position inside tube 282. Thus patient 272 is posit~oned inside solenoid 284 with the applied magnetic flux penetrating the patient's entire body in the direction of predetermined axis 250. In one embodiment a magneeic field sensor 274 is also provided to measure the magnetic flux density along axis 250 and may be mounted on a track system within tube 282. It may be suitable in some applications to mount tube 282 on a rotatable stand such that tube 282 can be rotated to change the position of patient 272 and sxis 250 with respect to the local magnetic field.
Other configurations of systemic treatment apparatus 280 may be suitable or even desirable ln a particular application such as large flat coils ~for example having diameters of six feet or greater) in Nelmholtz arrangement with one coil being placed on esch side of patient 272. In this alternative arrangement, sxis 250 would extend transverse to the -- 2~2~3~
.
2,716-005 patient's body rather than from toe-to-head as shown in Figure ~. Of course, the direction of the magnetic field may also be directly opposite to the direction of axis 250 depending upon the direction of current through solenoid 284. Systemic treatment apparatus 280 is thus used to create a magnetic field of predetermined parameters inside tube 282. While this predetermined re]ationship is preferably maintained by adjusting the applied flux to compensate for changes in the local field component; alternatively, the frequency can be adjusted to preserve the desired ratio.
For ~ystemic treatment, a patient 272 afflicted with cancer is placed on platform 288 which is then moved into position within tube 282 and thus within solenoid 284. Patient 272 is then subjected to a fluctuating magnetic field of the nature previously described for a period of time sufficient to bring about the desired systemic treatment. It i8 believed that exposure in accordance with the systemic treatment embodiment of the present invention of about .5hr. to 24hr./day until the desired result is achieved.
Referring now to Figure 7, a block diagram is shown which is preferred for U60 in connection with the systemic treatment apparatus 280. Operating console 320 forms the control center for operating sy~t-miC treatment apparatus 280. The console is comprised of a plurallty of control elements 322 and a visual display device 324 for monitoring the wave form display of the solenoid current signal 325.
The plurallty of control elements 322 include a gurney positioning dial 326 for controlling the lateral movement of the gurney platform.
Magnetic ficld sensor ad~usting dial 328 allows the operator to 2~2~3~
2,716-005 selectively position the magnetic field sensor 327 within the center of treatment solenoid 2~4. The treatment structure rotating dial 330 allows the operator to rotate the concentric solenoid and platform 288 in the horizontal plane in that embodiment where a supporting stand or turntable (not shown) is provided. This horizontal movement allows the solenoid coil to be positioned so that it may compensate for undesired local magnPtic fields. Switch elements 332 allow the operator to effect various other control tasks, such as turning the concentric solenoid current on or off, or setting the cyclotron resonance frequency for the ion of choice. Each of the above-mentioned dials and switch elements produce signals which go to various elements of system treatment apparatus 280 to accomplish the various functions described herein. The signal produced by the gurney positioning dial 326 leaves operating console 320 along cable 334 as does the signal produced by the treatment structure rotating dial 330. The signal6 334 interface with various motors and other drive hardware to effect the positioning of platform 288 within solenoid 284 and the positioning of tube 282 with respect to the local magnetic field. Control line 336 transmits the signal developed by the magnetic field sensor adjusting dial 328 to a magnetic sensor positioning device 338 which allows the magnetic sen~or 327 to be positioned at various locations within the center of the solenoid 2~4.
After dials 326 through 330 and switches 332 have been set, systemic treat~ent spparatus 280 is ready for operation. The frequency which ha6 been selected by the operator is output along line 340 to the sine wave generator 342. The sine wave generator 342 responds to the frequency ~elected in accordance with the principles of the present invention by generating a sinusoidal waveform which posses~es one-half of the desired frequency with no DC offset. The signal is then sent from the sine wave 2~2~3~
62,716-005 generator 34Z to a full-wave rectifier circuit 346. Rectifier 346 not only transforms the sinusoidal waveform produced by generator 342 to a rectified DC signal, it also has the effect of doubling the frequency of the output of the sine wave generator. The rectified signal is then sent from the full-wave rectifier 346 to the programmable power supply 3~8 where it is amplified to a suf~icient power level which is necessary to develop a sufficiently strong magnetic field within the solenoid 284. The amplified signal is then sent from the programmable power supply 348 along cable 350 to solenoid 284. Solenoid 284 then converts the amplified current to a uniform magnetic field density within the concentric solenoid winding 284 along axis 250 shown in Figure 6.
Because of localized magnetic fields, the magnetic field, as it exists within the concentric solenoid winding, is not always absolutely predictable. Thus, magnetic sensor 327 is mounted in close proximity to the patient so that the magnetic flux density within solenoid 284 can be constantly monitored. A signal, which is proportional to the magnetic flux density within treatment solenoid 284, is output by the magnetic sensor 327 and then filtered by filter 331 to eliminate any undesired high-frequency ele~ents. The output of low-frequency filter 331 is then delivered to operating console 320 along cable 333 so that it can be displayet on the visual display device 324. The output of low-frequency filtor 331 i8 also sent to analog amplifier 335 so that it can be properly conditioned to be used within the programmable power supply 348. The programmable power supply 348 uses the output from analog amplifier 335 as a means for maintaining a uniform density magnetic field within the center of solenoid 284. This ta6k may be performed within the programmable power supply by mean6 of standard analog feedback techniques or may be accomplished by means of a digital processor.
, - 2 0 2 ~62,716-005 The following examples are provided to more fully illustrate the present invention and are not intended to limit the scope of the invention as defined in the appended claims.
~rL~
N-18 neuroblastoma tumor cells from the American Type Culture Collection (ATCC) were cultured in Linbro 12-well culture plates in either I-10 or I-H media, at 37 C, with 52 COg in air at 100%
humidity. The formulae for the media is as follows:
Dulbecco's Minimum Es~ential Medium (double strength) 50 ml Fetal Calf Serum 10 ml 20% Glucose solution 3 ml L-Glutamine (200 mM solution) 1 ml Penicillin/Streptomycin (Gibco Prepared) 1 ml H20 q.s. 100 ml I-N
DMEM (2X) 50 ml Norse Serum 25 ml 20Z Glucose 3 ml L-Glutamine 1 ml Peniclllin/Streptomycin (Gibco Prepared) 1 ml N20 q.8. 100 ml 50X of the cultures received ARA-C (Cytosine Arabinoside) at a final concentration of 0.25 micrograms/ml, an inhibitor of neuroblastoma growth. Experimental cultures also received 24 hour combined magnetic field stimulation adjusted to ion cyclotron resonance values for Ca+~ or K+ according to the method and formula of the present invention. Treatment was accomplished by placing the culture dishes in - 2~2~8 2,716-005 the space between the energized Helmholtz-aiding coils in the incubator so that the combined magnetic fields passed through the culture medium and cells parallel to the surface of the medium and the bottom of the dish. The following protocol was used:
Culture A~A-C ÇB_IQn No. of Cultures Control I-10 Yes none 9 Control I-H Yes none 9 Control I-10 No none 9 Control I-H No none 9 I-10 Yes Ca 9 I-10 No Ca 9 I-H Yes Ca 9 I-H No Ca 9 I-10 Yes K 9 I-10 No K 9 I-H Yes K 9 I-H No K 9 The medium in each culture dish was renewed every other day.
After 3 days of culture, the dishes were removed from the incubator, and the cell proliferation rate was established by making cell counts in each dish. The cells having recognizable neurites (outgrowths at least twice as long as the cell diameter) were also counted. The data are expre~sed as number of cells per dish and percent of cells having neurite~.
~S~
Ça~LQ~Y No- Cell~/Diah ~ v~ C~ Neurite6 p VB C
C + ARA-C (I-10) 37.50 - 16.87 C + ARA-C (I-H) 15.78 - 9.29 C N0 ARA-C(I-10) 66.78 - 12.71 C N0 ARA-C (I-H) 46.67 - 20.64 -- 2~2~
62,716-005 ~ategory No. Cells/D~ Ç Z Nçurites p vs C
Ca + ARA-C (I-10) 46.34 .10 9.92 .05 Ca + ARA-C (I-~) 30.78 .01 14.45 .10 Ca N0 ARA-C (I-10) 64.72 N.S. 11.59 N.S.
Ca N0 ARA-C (I-H) 33.33 .10 22.08 N.S.
K + ARA-C (I-10) 46.56 .10 12.44 N.S.
K + ARA-C (I-H) 20.44 N.S. 12.75 N.S.
K No ARA-C (I-10) 68.00 N.S. 12.57 N.S.
K No ARA-C (I-H) 24.00 .01 20.93 N.S.
These results indicate that CR fields can influence the growth of tumors in vitro and can alter the effects of an antitumor drug on the cells. The tuning for Ca+~ and K+ had little effect on the outgrowth of neurites. The tuning for Ca had some effect, depressing outgrowth strongly in I-10, which contains strong fetal growth factors and enhancing growth slightly in l-H, which lacks the growth factors of I-10.
Neither Ca++ nor K+ tuning overcame the strong effect of cell proliferation factors contained in I-10 medium as a result of the incorporation of the fetal calf serum. The effect was essentially null, even in the presence of ARA-C. However, when I-H was used, which is more nearly similar to normal adult serum by virtue of the absence of the fetal cell proliferation factors, the CR tuning for Ca produced an increase in cell proliferation, partly overcoming the inhibitory effect of the ARA-C.
When K+ tuning was used in I-H medium, in the presence of ARA-C, there was essentially no effect, the ARA-C being a strong inhibitor notwithstanding.
:'~
' --- 2~2~13~8 62,716-005 In the absence of the ARA-C, using the I-H medium, Calcium tuning produced a slight depression of cell proliferation.
When K tuning was used in the absence of ARA-C in I-H medium, there was a very strong suppression of cell proliferation. In fact, the suppression produced by the K+ signal was statistically equivalen~ to the effect of the potent pharmacological agent, suggesting that under some circumstances, the use of cyclotron resonance may be as effective a treatment modality as a standard pharmacological agent, but perhaps without the negative side effects of the pharmacological agent.
~IPLE~ I I
In this example the medium was identical to I-10 above, except the serum concentration was reduced to 2.0 ml. In the following table, the reduction in proliferation achieved by the present invention i8 again demonstrated with respect to the synergistic effect of cyclotron resonance treatment in the presence of chemotherapeutic cancer agent~. The experiments were conducted for 72-hour periods. The c811s were N-18 neuroblastoma cells.
K ~ potassium ion (K~
Ca - calcium ion (Ca++) H Mg/Ca 3/5 harmonic tuning C- control plates without ARA-C and without cyclotron resonance expo8ure C+ - control plates with ARA-C and without cyclotron resonance exposure ~- ~ experimental plates without ARA-C and with cyclotron resonance exposure E+ - experimental plates with ARA-C and with cyclotron resonance exposure .5 - 1/2 hour field exposure per 24 hours 24 continuous field exposure .- ' ~ ".
.
.
62,716-005 2Q2~3~
(ARA-C = cyto~ine arabinoside [conc. 0.25 microgram61ml~) (cell processes re~ers to neurites) TOTAL CELI.S/MM2 +- S.D.
ION/TIME C- C~ E- E~
K/.5 H47.8-27.4 28.5-14.9 215.1-124.2 43.6-22.9 K/24 H81.9-59.0 34.1-19.3 213.7-95.8 50.3-28.0 Ca/.5 H33.3-15.0 18.6-9.0 129;3-44.2 26.2-1~.~
H/.5 H 142.9-55.1 33.3-22.0 167.0-60.4 26.3-11.1 Mg/.5 H 36.5-40.5 11.7-9.3 51.7-34.8 lo.7-~.a ~H ~ Mg/Ca, 3~5 Harmonlc Tunlng) ~ CE~S WITH PROCESSES +- S.D.
C- C~ E- E+
K/.5 H10.8-6.3 13.9-8.9 11.1-6.a 10.0-7.5 K/24 H9.0-~.6 7.2-7.6 7.3-3.2 4.2-3.2 Ca/.5 H12.9-6.8 19.4-11.9 17.2-6.3 14.6-10.9 H/.5 H21.2-6.6 12.9-8.7 20.1-5.9 15.2-7.6 Mg/-.5 H9.9-6.9 6.3-11.2 8.6-5.2 3.8-~.7 STATISTICA~ COMPARISONS, TOTA~ CELLS
~t, (p)) C- vs C~ E- v~ E~ C- v3 E- C~ vs E~
K/.5 H3.57 (~.001)a.O3 ~<,001)7.89 (<.001)3.35 (~.005) K/24 H 4.50 (~.001)9.9~ (~.001)7.29 (<.001)2.~g (~.01) Ca/.O H 5.03 (~.001)13.06 (~.001)12.35 ~<.001)2.36 ~.05) H~.O N11.0~ (~.001)13.75 (~.001)1.78 (N.S.)1.72 (N.S.) M5~/.5 H 3.56 (~.000) 6.99 (<.001) 1.~2 (N.S-) 0-54 (N.S.) X CEL~S WITH PROCESSES
~t, (p)) C- v- C~ E- vs E~ C- v~ E- C~ v~ E~
K/.O N 1.63 (N.S.)0.65 (N.S.~ 0.19 (N.S.) 1.96 (-.05) K/2~. H 1.20 (N.8.)3,75 (~.001)1.88 (N.S.) 2.11 (<.05) C~/.O N 2.a~ (~.01)1.26 (N.S.) 2.e1 (<.01) 1.80 (N.S.) H/.O H ~.. 06 (~.001) 3.05 ~.01) 0,77 (N.S-) 1.18 (N.S.) M~/.O N 1.0~ ~N-S.) 3.09 ~.005) 0.43 (N.~.~ 1.04 (N.S.) n ~or a11 xp-r~m-nts ~ 36 ~3-- : .
2~2~3~
62,716-005 Thus, it is apparent that there has been provided in accordance with the invention a method and apparatus that fully satisfies the objects, aims and advantages set forth above. While the invention has been described in connection with specific embodiments thereof, it is evident that many alternatives, modifications, and variations will be apparent to those skilled in the art in light of the foregoing description. For example, it is to be understood that higher harmonic tuning and multiple ion tuning as described herein may be useful in connection with the contemporaneous use of chemotherapeutic cancer agents. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims.
r,2, 1 16-005 MET~OD AND APPARAll.~S FQR D~C~
ll~CIINICAL FIELD
The present invention relates generally to the treatment of cancer. More specifically, it provides in one aspect a method and apparatus by which a reduction in the proliferation rate of cancer cells is achieved through the use of fluctuating magnetic fields which are tuned to preselected frequencies. In the presence of a chemotherapeutic agent, target cancer cells are exposed to the therapeutic fields, producing a reduction in the proliferation of cancer cells greater than that of the chemotherapeutic agent alone. In another aspect, the present invention reduces malignancy by potentiating differentiation of the cells.
BAC~G~OUND OF T~ rNVENTION
Appro~imately one-fifth of all deaths in the United States are caused by cancer. An estimated $20 billion is spent annually in the United State~ in connection with the care and treatment of cancer patients. Although vast sums are spent on cancer research worldwide, little is known about the initiation and progression of this disease.
A~ will be appreciated by tho~e skilled in the art, cancer cells are relatively autonomou~ in that they fail to respond to normal biolo~ical signals that control cellular growth and metabolism in the living organism. Malignant tumors are characterized by their ability to metastasize. In metastasis, cancer cells spread through the organism ~2~ 2,716-005 producing tumors at sites remote from the point of origin. It is generally accepted that the number of cell membrane processes is inversely proportional to the probabilit~ of cell metastasis. Malignant neoplasms are generally classified as those arising from supportive tissues such as connective tissue, bone, cartilage or striated muscle (sarcomas) and those arising from epithelial tissue (carcinomas). In another type of cancer known as "leukemia," cancer cells circulate predominantly in the bloodstream. In general, leukemias originate in the lymphatic tissues and bone marrow where blood components are formed. After a neoplasm develops in an organism, it may progress from a benign form to a malignant form or from a low-level malignancy to a rapidly proliferating malignancy. Although millions of cells may metastasize from a primary tumor, it is known that only a few of these cells actually result in metastatic lesions at other sites.
While the behavior of cancer cells is unpredictable, it is generally acknowledged that early recognition of cancer is paramount to successful trestment. The most common modern-day method of treating cancer is surgical intervention. Both primary tumors and metastatic tumors may be surgically removed. It is also known that malignant tumor~, particularly lymphomas, leukemias and carcinomas can be treated by radiation therapy, for example by exposure to gamma rays and the like. More recently, advances have been made in the use of chemotherapeutic agents, often in conjunction with surgical and/or radiation treatment. It wlll be appreciated by those skilled in the art that rapidly progressing cancers have a high percentage of cells undergolng mitosis, i.e. a large growth fraction, and it is these cancers that are particularly susceptible to chemotherapy. More 62 716-0o5 ~ ~ 2 9 3 ~ ~
recently, immunotherapeutic techniques which utilize antibodies to which cytocidal agents are linked have met with limited success. However, the need for a more effective treatment for cancer is clearly evidenced by the large nu~ber of cancer deaths worldwide.
In United States Patent No. 4,622,952, entitled "Cancer Treatment Method," a method cf cancer treatment is described by whi~h the application of external electromagnetic energy allegedly achieves biophysical alterations including thermal changes, the stimulation of intracellular interferon production and the stimulation of intracellular prostaglandin production. The process includes the step of empirically tuning external electromagnetic energy to a "resonant" frequency which achieves a precise increment of heat rise within the cancer cell and which stimulate~ the intracellular production of interferon and/or prostaglandins. The present invention utilizes a group of resonant frequencies, not derived from heating consideration, but derived instead from a basic formula that acts to selectively control the transport of variou~ electrolyte ions into and out of cancer cells, in a manner refiulting in sub~tantially no measurable temperature increa~e within the cells.
In recent years, multi-disclplinary investigations of phy~iologicsl processes have provided evidence suggesting that electric and msgnetic fielts play an important role in cell and tissue behavior.
In United States Patent Number 4,818,697, entitled "Techniques for Enhancing the Permeability of Ions Through Membranes," which has been assigned to the assignee of the present invention and the disclosure of which is incorporated herein by reference, a method and apparatus are 20293~8 62,716-005 disclosed by which transmembrane movement of a preselected ion is magnetically regulated using a time-varying magnetic field The fluctuating magnetic field is preferably tuned to the cyclotron resonance energy absorption frequency of the preselected ion This important discovery brought to light the interplay of local magnetic fields and frequency dependence in ion transport mechanisms In United States Patent Application Serial Number 172,268, filed March 23, 1988, the disclosure of which is incorporated herein by reference, the inventors of the present invention disclose that cyclotron resonance can be used to control~ tissue development In United States Patent Application Serial Number 254,43R, entitled '~ethod and Apparatus for Controlling the Growtb of Non-Osseous, Non-Cartilaginous, Solid Connective Tissue," filed October 6, 1988, the di~closure of which is incorporatet herein by reference, the present inventor~ disclo~c a method of controlling the growth of non-osseous, non-cartilaglnou~ connective tissue which Dtilize~ cyclotron resonance frequencie~ In United~State~ P-tent Application Serial Number 295,164, entitled "TechQique- for Controlling O~teoporosi~ UsiDg Non-Invasive Magnetic Field~," filed January 9, 1989, the disclosure of which is incorpor-tet herein by reference, the prosent inventors disclo~e a thod of controlling osteoporosis using cyclotron resonance magnetic fi~lt~ In United State~ Patent Application Serial Number 343,017, fllet April 25, 1989, eneitled "Methods and Apparatus for Regulating Tran~membrane Ion Movement UtiIizing Selective Harmonic Frequencies and Simultaneou~ Multipl- Ion Regulation," the disclosure of which is incorporatot heroin by reference, the present inventor~ disclose a m-thot of utilizing therapeutic higher-harmonic frequencie~ and a method - -, , -2~2~
2,716-005 of simultaneously controlling the transport of multiple ions. In United States Patent Application Serial Number 3951247~ filed August 17~ 1989, entitled "Treatment for Stroke Victims," the present inventors describe a method and apparatus for magnetically treating stroke victims.
The present invention discloses a new and unique apparatus for non~invasive treatment of cancer which is directed at reducing the rate of growth of neoplasms through the action of a fluctuating magnetic field.
~ Q~Y OF T~E INV~NTION
In one aspect, the present invention provides an apparatus for decrea~ing the proliferation rate of cancer cells in the presence of 8 chemotherapeutic agent. That is, the conventional reduction in the number of cancer cells produced by exposing the cells to a chemotherapeutic agent is enhanced by the magnetic fields of the present invention. The inventive apparatus includes mean~ for generating an applied magnetic flux parallel to a predetermined axis and projecting through a predetermined space. The predetermined space i8 occupied by cancer cells or a tumor present in a living subject, preferably either man or animal, in the presence of a chemotherapeutic agent. It ~hould al80 be noted that the present invention may also be useful in the treatment of plant tumors. Means for measuring total magnetic flux ten6ity parallel to the predeterminet axis extending through the pretetermined fipace is provided 80 that the msgnetic flux density along the axis can be monitored. Means in association with the flux generating means is provided 60 that the applied magnetic flux can be : ' ,, 2~293~
2,716-005 oscillated. Finally, means for creating and maintaining a relationship between the rate of fluctuation of the magnetic flux and the intensity of the magnetic flux density is provided, where the predetermined relationship decreases the proliferation rate of the target cancer cells. In another aspect, this predetermined relationship is such that the number of cell membrane processes is increased to decrease metastatic potential.
In one embodiment, the means for applying a magnetic flux includes two opposed field coils arranged in Helmholtz configuration such that an applied magnetic field having known parameters along the predetermined axis can be generated between the coils. In another embodiment, a second pair of field coils are placed such that they generate an applied magnetic flux along an axis perpendicular to the predetermined axis defined by the first coil pair. In this same manner, a third pair of opposed coil~ can be utilized such that magnetic fields are applied by the three coil pairs along the x, y, z axes of a Carte~ian coordinate system. The second and third coil pairs are ~imilarly actuatet to provide a predetermined relationship between the frequency of the magnetic flux and the intensity of the magnetic flux ten~ity.
In another a6pect, a method for decreasing the proliferation of cancer cell~ is provided utilizing the apparatus of the present invention. Therein, a tumor comprising cancer cells in the presence of a chemotherapeutic agent in a living subject, either man or animal, is po~itioned ad~acent to the magnetic field generating means. A specific magnetic flux extending through the space in which the target cancer . ..: ::
62,716-OOS 2~29~
cells are positioned is generated parallel to a predetermined axis projecting through the cells. A relationship is then created between the frequency of the oscillating magnetic flux and the intensity of the magnetic flux density where the relationship decreases the proliferation rate of the target cancer cellæ, i.e. the number of cancer cells existing after a predetermined period is less than that with chemotherapy alone. In a preferred embodiment of the present invention, the magnetic flux generating means compriæes a pair of field coils as previously described. Also, in a preferred embodiment of the invention, the predetermined therapeutic relationship between the frequency of the magnetic flux permeating the cancer cells and the in~ensity of the magnetic flux is detenmined by the cyclotron resonance equation fc/B =
q/(2~m), where fc i8 the frequency in Hertz, B is the average value of the magnetic flux density in Tesla parallel to the predetermined axis, q/m has a value of from about 5 x 105 to about lOO x 106 Coulombs per kilogram and where B has a value of less than about l x 10-2 Tesla. In a particularly preferred embodiment, q/m i6 the charge-to-mass ratio of a preselected ion present in the cancer cells.
In still another aspect, a system for decreasing the proliferation of cancer cells iB provided which includes means for generatlng an spplied magnetic flux parallel to a predetermined axis and pro~ectlng through a predetermined space where the space is occupied by cancer cells of a living subject in the presence of a chemotherapeutic agent. In this particular configuration, the magnetic flux generating means lncludes at least two opposed field coils having an axis extending through ant parallel to the predetermined axis projecting through the predetermined space. Each of the field coils ha~ at least two - 2~2~39~
2,716-005 windings. One winding is designated an ac winding and the other is designated a dc winding. Means in association with the coils is provided for supplying a direct current to the dc winding and an alternating current to the ac winding. Means for measuring the ambient or local field existing in the predetermined space in the region of the cancer cells is also provided. Means in association with the flux generating means for controlling the direct current to the dc windings is supplied such that the dc windings may be activated to create a magnetic flux which reduces the ambient magnetic flux to substantially zero. A full-wave rectifier circuit and an oscillator are provided in as60ciation with the ac windings and the current supply means in order to produce an ac magnetic field component along the predetermined axis in the predetermined 6pace which has a preselected rms value, where the rms value deçreases the proliferation of cancer cells. In addition, the system may use a sinusoidal signal to the ac windings, offset by a constant bias current equal to the rms-value utilized when full-wave rectification is used.
The system may further include a second pair of oppo~ed field coils which define an axis extending through the region of the cancer cell~ which i~ perpendicular to the predetermined axi6 defined by the flr~t coil pair. Further, a third coil pair can be provided such that tho ~mbient flelt along the x, y, z axes of a Cartesian coordinate ~ystem is reduced to zero, with an applied field having the therapeutic non-zoro average value a6 provided by the pre~ent invention being generated along each of the axes.
With respect to the aforementioned system which includes ac windings and dc windings, there is provided by the present inven~ion a 2~2~39~
2,716-005 method for decreasing the proliferation of cancer cells which comprises the steps of generating an applied magnetic flux parallel to a predetermined axis which projects through a predetermined space, with the space being occupied by cancer cells in a living subject in the presence of a chemotherapeutic agent. The ambient field along the predetermined axis in the predetermined space is measured using a magnetic field sensor which is capable of measuring both static and time-varying magnetic fields. Utilizing the dc windings and a power supply, a magnetic flux is generated which reduces the ambient field to substantially zero along the axis. The ac windings are then used to generate an ac magnetic field having a component along the predetermined axis which has a non-zero average value that i~ effective in decreasing the proliferation rate of cancer cells.
In stlll another aspect, the present invention provides a method for the therapeutic treatment of cancer in which the proliferation rate of cancer cells i8 reduced by the fluctuating magnetic fielts provided by the present invention without the concurrent application of a chemotherapeutic a8ent.
Still further, treatment in accordance with the present invention i~ in one embodiment effective in stimulating the differentiation of cell processes, i.e., neurites to decrease the metastatic potent~al of the cells.
The aforementioned control of cancer cell growth is also achieved to varying extents in one embodiment of the present invention through the use of higher-harmonic tuning and multiple ion tuning is also provided.
, 2~2~8 62,716-005 ~ ^
BRIEF DES~IPTION OF T~E DRAWLNGS
Figure 1 diagrammatically illustrates one preferred placement of the apparatus of the present invention.
Figure 2 is a front elevational view of the treatment heads of the present invention in one embodiment.
Figure 3 is a graph which illustrates the magnetic flux density value (B) in the present invention.
Figure 4 is a block diagram of the functional elements of a preferred circuit for use in the present invention.
Figure 5 is a side elevational view in which the present invention i8 shown utilizing three pairs of coils.
Figure 6 is a perspective view of the present invention for use in systemic treatment of cancer.
~ igure 7 i~ a block diagram of the circuitry of one embodiment of the pre~ent invention for use in sy6temic treatment.
~SCRIPTIOW OF TRF PR~F~R~eD ~M~ODIMRNTS OF Tae INV~NTIQN
Referring now to Figure 1 of the drawings, cancer treatment apparatus 20 is shown in position on a subject' 8 leg 22. It is to be -- 2~293~
2,716-005 understood that both the apparatus and the method of the present invention are suitable for use in decreasing the proliferation rate of cancer cells in both animal and human subjects. As used herein, the term "cancer" shall have its customary meaning, although it is to be noted that the present invention may be useful in the treatment of non-cancerous neoplasms as well as cancerous neoplasms. The term "decreasing the proliferation" and "decreasing the proliferation rate"
shall mean that the number of cancer cells existing after a predetermined period of treatment in accordance with the present invention is less per unit volume than the number of cancer cells in a control without treatment in accordance with the present invention. The term "chemotherapeutic agent" shall mean one or more of the various anti-cancer treatment drugs, the identity and nature of which will be known by those of skill in the art. It i8 known that many of these agent~ produce a decrease in cancer cell proliferation rates. Thus, the target tissue which is to be affected is a region of cancer cells such a8 a malignant tumor. Although the present invention has been shown to be useful in decreasing the proliferation rate of neurobla~toma tumor cells in the presence of a chemotherapeutic agent, it i6 believed that thé present invention will be effective in the treatment of other cancer cell~, including carcinoma, leukemia, ~arcoma, lymphoma, melanoma, myeloma and the like.
A malignant neoplasm 24, shown here as a sarcoma in the ~ub~ect's thigh, is positioned in a pretetermined volume 26 between treatment heats 28 and 30 of cancer treatment apparatus 20. It is within this pretetermined space or volume that the therapeutic o~cillating magnetic field i8 generated. Hence, as will be appreciated, ,. . :
. . .
--` 2~9~8 2,716-005 there exist within space 26 cancer cells which are multiplying by mitotic division in the uncontrolled manner characteristic of cancers.
As with all cancer treatments, it is preferred that treatment be commenced immediately following detection of the condition. In this embodiment of the invention, a chemotherapeutic agent, for example cytosine arabinoside, is administered to the subject in the customary manner. The dosage will be consistent with the known effective dosage for the particular chemotherapeutic agent, although it is anticipated that a reduction in the standard dosage may be facilitated by the pre~ent invention. Accordingly, a cancer chemotherapeutic agent is administered to the patient either systemically or locally, for example through the use of cancer cell-specific antibodies to which chemotherapeutic agents are conjugated. The most preferred chemotherapeutic agents which are suitable in the practice of the present invention are those which demonstrate substantially enhanced therapeutic action in the treatment of cancer when administered in connection with selected frequencies of cyclotron resonance tuning as provided by the present invention over control applications of the chemotherapeutic a8ent without exposure to the magnetic fields of the present invention. This can be readily determined by in vitro or n vivo animal experiment~. Preferred chemotherapeutic agents believed to be u~eful in this respect include alkylating agents and nucleic acid analo8~-In order to better appreciate the configuration of treatmentheads 28 and 30 as provided by the present invention, reference is now made to Figure 2 of the drawings in which trestment heads 28 and 30 are shown a~ including housings 32 and 34 of a non-magnetic material such as 2~3~
2,716-005 plastic. ~ach housing 32, 34 encloses a field coil 36 and 38. At least one of the treatment heads encloses a magnetic field sensing device 40, such as a Hall-effect device, shown in Figure 2 enclosed within housing 32 of treatment head 28. The power source for driving the field coils is preferably external, but may be a battery or the like shown as power source 42 in treatment head 30. Straps 44 and 46 are provided by which cance~ treatment apparatus can be conveniently attached to the patient.
While field coils 36 and 38 are the preferred means by which an applied magnetic field i8 generated in the present invention, those skilled in the art will appreciate that other electromagnets or possibly permanent magnets may be adapted for u~e in the present invention, and any such use is intended to come within the scope of the present invention. Also, the radius of each field coil 36 and 38, as well as the turns of the windings, may vary in accordance with the principles of the present invention. In the most preferred arrangement, the geometry and relative position of treatment heads 28 and 30 during treatment are such that field coils 36 and 38 operate as Helmholtz coils. Hence, thofie skilled in the art will recognize that in the mo6t preferred arrangement, field coils 36 and 38 are su~stantially identical, f$eld-aiding, parallel coaxial coils separated by a distance equal to tha rsdius of each coil.
It will be appreciated that the malignant neoplasm to be affected will generally be subject to local magnetic influences. As u~ed hercin, the term "local magnetic field," "ambient magnetic field"
or the like shall be dcfined as the magnetic influences, including the earth's magnetic field or geomagnetic field, which create a local 2,716-005 magnetic flux that flows through the target tissue. "Magnetic flux density" shall be defined in the customary manner as the number of magnetic field lines per unit area through a section perpendicular to the direction of flux. Factors contributing to the local magnetic field in addition to the geomagnetic fi.eld may include localized regions of ferromagnetic materials or the like. In one embodiment of the present invention, field coils 36 and 38 are used to create an applied, fluctuating magnetic field which, when combined with the local magnetic field parallel to a predetermined axis extending longitudinally between treatment heads 28 and 30, produces a combined magnetic field or composite field having a componen~ along the axis which has a precisely controlled, predetermined ratio of frequency to average magnetic flux den6ity.
In one embodiment, and referring again to Figure 2 of the drawings, this relationship is created using microprocessor 48 which is in communication with electronics neces6ary to control the oscillation and intensity of the magnetic flux which permeates the target cells.
Also, leads 50 and 52 are shown by which the various components of cancer treatment apparatus 20 are interconnected, along with other such leadH which are not 6hown. Magnetic sensor or magnetometer 40 measures the total or composite magnetic flux which passes through the predetermined space between treatment heads 28 and 30 thus providing an accurate measurement of the magnetic field which permeates the malignant neopla8m 24. Predetermined axis 54 is shown in Figure 1 as extending between treatmcnt heads 28 and 30. It will be appreciated that the applied field generated using treatment head6 28 and 30 may be in either direction of predetermined axis 54 and that the local or ambient 3 ~ ~
2,716-005 magnetic field will also have a component along axis 54 which either augments or decreases the applied magnetic flux. The relatively low applied flux density in the precise, predetermined relationships of combined flux density and frequency provided by the present invention are to be maintained during treatment, notwithstanding the influence of the local magnetic field. This may be achieved in es~entially two preferred manners which will be explained more fully herein. Thus, magnetic field sensor 40 is provided to determine the level of the magnetic flux density of the local magnetic field.
The unexpected and superior result~ of the present invention are achieved by creating a fluctuating magnetic field having a magnetic flux density parallel to predetermined axi6 54, with the magnetic flux density alon~ axis 54 bein8 maintained at a predetermined ratio of the frequency of the fluctuations to the non-zero value of the magnetic flux density. In this embodiment, the magnetic flux density parallel to predetermined axis 54 has a non-zero time-average value. More specifically, as illustrated in Figure 3 of the drawings, the therapeutic magnetic field of the present invention can be thought of as a static field having refer~nce level A on which a fluctuating magnetic field is ~uperlmposed. It comprise~ a time-varying component which vario~ in amplitute but not direction and a steady reference value around which the time-varying component varies. Reference level A is the non-zero average value of the flux density (B). Therefore, it will be understood that the non-zero time-average, or net average value where the magnetic field is the combination of the local field and the applied field, along predetermined axis 54 is utilized since the magnitude B of the composite flux density changes at a predetermined rate due to 2 ~
2,716-005 oscillation or fluctuation of the applied magnetic flux. Thus, an average value is utilized which is a non-zero average value illustrated at point (c). This reflects that although the magnetic flux density along the axis is oscillating at a controlled rate, the field is regulated to ensure that the field is always unipolar; that is, the field is always in the same direction along predetermined axis 54.
As stated, it has been found that rather precise relationships of the flux density of the magnetic field to the frequency of the fluctuations are used in the present invention to provide therapeutic results. These ratios of frequency to composite flux density are found in accordance with the following equation:
fc/B = q/(2~m) where fc is the frequency of the combined magnetic field in Hertz, B is the net average value of the magnetic flux density of the magnetic field (the combined field where a local field component is present) parallel to predetenmined axis 54 in Tesla and q/m has a value of from about 5 x 105 to about 100 x 106 Coulombs per kilogram. B preferably has a value not in exceaa of about 1 x 10-2 Tesla. In order to increase the inhibition of cancer cells in the presence of a chemotherapeutic agent, the following frequency and associated combined magnetic flux density (B) are preferred:
fc (Hertz~ 8 (~esla) 16 20.9 X 10-6 at an ac amplitude, peak-to-peak of 40 microTesla.
-- 2~3!~
62,716-005 In use, malignant neoplasm 24 in the presence of a chemotherapeutic agent is then subjected to a fluctuating magnetic field as described herein for a period of time effective to inhibit the rate of growth of the neoplasm by decreasing the proliferation rate of cancer cells. While the length of time necessary for successful treatment may vary, it is anticipated that up to about 100 days of treatment will provide beneficial results. Longer treatment may be desirable in certain applications.
` In another embodiment of the present invention, values for q and m are determined with reference to a preselected ionic species. It will be known by those skilled in the art that the biochemical milieu of a malignant neoplasm comprises a mixture of various ions in the intracellular and intercellular fluids. These ions include potassium ions, magnesium ions, sodium ions, chloride ions, phosphate ions, sulfate ions, carbonate ions, bicarbonate ions and the like and various lons formed by the dissociation of amino acids, proteins, sugars, nucleotides and enzymes. By utilizing the values of charge and mass for a preselected ion in the equation set forth above, which will be recognized by those skilled in the art as the cyclotron resonance relationship solved for fc/B, ratios of frequency to magnetic flux den~ity can be determined which will therapeutically reduce the rate of growth of malignant neoplasm 24 in accordance with the present invention. By using the charge-to-mass ratio of a preselected ion, a ~peci2ic cyclotron resonance frequency for the ion can be determined.
By then tuning cancer treatment apparatus 20 to maintain a combined magnetic flux density having the proper cyclotron resonance frequency, - 2~2~3~
2,716-OOS
the neoplastic tissue containing the preselected ion can be treated to bring about the desired decrease in the proliferation rate of the cancer cells. More specifically, in a prefered embodiment of the invention, by tuning to Cal+ or K+ it is believed that progression of a tumor in the presence of serum lacking fetal growth factors can be slowed in accordance with the present invention.
Hence, it will be appreciated by those skilled in the art that in the present invention, by synergi6tically enhancing the effects of chemotherapeutic agents in the treatment of cancer, it may be pos6ible to reduce the quantity of or the time course of the chemotherapeutic age3ts administered to the patient, resulting in a decrease in dose-related side effects.
It will also now be appreciated by the prior explanation of preferred embodiment6 of the present invention and from the equation for establishing a cyclotron resonance relationship, that either the frequency of the fluctuating magnetic field or the magnitude or intensity of the magnetic flux density along the predetermined axis, or both the frequency and the intensity of the flux density, can be ad~usted to provide a magnetic field which has the desired characteristlcs. However, it is preferred to maintain a constant frequency which thus requires that the intensity of the applied magnetic flux den~ity be adju~ted to compensate for changes in the local magnetic field in order to maintain a constant ratio of frequency to magnetic flux density. For example, if it is necessary to maintain a frequency of 16 Hz and an average flux density of 4.07 x 10-5 Tesla for K~, changes in the local field which would otherwise cause unwanted -- 2~29~ 2,716-005 deviations in the combined magnetic flux density must be corrected by increasing or decreasing the applied magnetic flux density accordingly.
This is most preferably performed by the microprocessor in connection with both the field generating means and the field-sensing device.
Alternatively, if changes in the combined magnetic flux density occur due to changes in the local magnetic field, the frequency of the oscillations can then be changed so that the preferred ratio is maintained. Once again, it is important to realize that the value of B
is the average composite magnetic flux density parallel to the predetermined axis since the magnitude of the flux density changes as the field is oscillated. It will be understood that detection of change6 in the magnetic field due to change~ in the ambient component should be at intervals frequent enough to provide a frequency-to-magnetic field ratio which i8 substantially constant, notwithstanding the changes in the local field component.
Referring again to Figures 1 and 2 of the drawings, each field coil 36, 38 preferably has up to about 3000 turns or loops of conducting wire, the diameter d of each loop being preferably up to about 300 centimeters. The number of turns of wire N, the diameter of th~ coils, the separation of the coils, and the wire gauge are critical only insofar a~ conventional practice requires con6traints on these and other te~ign pArameters to allow optimal performance characteristics in achieving predeterminet flux densities as required in the preferred practice of the present invention. As stated, other magnetic field generating means may be suitable for use in the present invention and are contemplated as falling within the scope of this invention.
2~2~
62,716-005 It is also to be understood that the applied magnetic field which results in a combined magnetic flux density along predetermined axis 54 may be produced by a sinusoidal signal or from a full-wave rectified signal applied to field coils 36, 3~. It may also be appropriate in some instances to reduce components of the local magnetic field which are not parallel to predetermined axis 54 to zero through the use of additional coils positioned at right angles to coils 28 and 30 to create an opposite but equal field. It may also be suitable to reduce the local magnetic field component to zero throughout treatment using additional coils or the like.
Referring now to Figure 4 of the drawings, a block diagram is shown which depicts one preferred arrangement of the circuits of cancer treatment apparatus 20 in functional segments. Numerous other circuit arrangements may be possible if the principles of the present invention are faithfully observed. Microcontroller or microprocessor 100 is seen by which the composite magnetic field is maintained at a constant pretetermined level despite changes in the ambient component as previously de6cribed. In this re6pect, input 102 is provided by which a set point value of the predetermined composite magnetic flux density along a predetermined axis through the target tissue is input into miCroproce880r 100. A8 will be shown, the composite field strength is compared to thi8 8et point value to generate an error equal to the difference in the set point value and the measured value of the compo8ite magnetic flux density along the axis.
Magnetic field sensor 104 is provided by which the magnitude of the composite field which passe~ through the target tissue along the , ~92~8 2,716-005 axis is measured. It is preferred that magnetic field sensor 104 comprise a Hall-effect or a flux gate device each of which, as will be known by those skilled in the art,can sense both time-varying and static magnetic fields and each produces an analog signal. The magnetic field sensor 104 constantly monitors the composite magnetic field, sending a signal to microprocessor 100. It will be understood that the output of a Hall-effect or flux gate magnetic sensor is relatively small; thus, magnetic field sensor amplifier 106 is provided by which the signal from magnetic field sensor 104 is amplified, for example, up to three thousand times its original value. Since these devices produce an analog signal, analog-to-digital converter 107 is provided by which the amplified signal from magnetic field sensor 104 is converted to a digital signal which can be used by microprocesgor 100. It is preferred that the analog-to-digital converter be provided on-board the microprocessor chip.
As will be appreciated, the amplification of the magnetic field sen~or signal may produce an unwanted noise level. Also, sudden changes in the magnetic field intensity may occur which make it difficult to determine the true average value of the composite magnetic flux don~ity. Henco, the signal from analog-to-digital converter 107 which i~ input into microprocessor 100 is filtered by software filter 108 to removo shot nolse and sudden fluctuations in the composite field tetected by magnetic field sensor 104. Although it is preferred that filter 108 comprise softwAre in microprocessor 100, a discrete filter could be used. In this embodiment, software filter 108 is a digital filter, prcferably an integrator with a time conAtant of approximately 0.5 seconds. In other words, the changes in the magnitude of the 2~2~
2,716-005 composite magnetic field which are compensated for by increasing or decreasing the applied field are long-tenm changes of 0.5 seconds or more. Hence, the time constant of filter 108 should be such that momentary fluctuations are filtered out.
Microprocessor 100 includes logic which calculates the non-~ero net average value of the composite magnetic flux density. This non-zero average value is then compared at a comparator 110 in microprocessor 100 to the predetermined dc reference or offset value which is input into microprocessor 100 via input 102. It should be noted that this reference value is preferably established by dedicated circuitry in microprocessor 100, although variable input means could be included by which the set point value could be changed. An error statement is then generated defining the difference in the measured value of the compo6ite magnetic flux density and the set point or reference value. Microprocessor 100 then determines the magnitude of the output necessary to drive magnetic field generating coils 112 to bring the composite magnetic flux density back to the set point.
Software field modulator or oscillator 114 is provided by which an ac or fluctuatin~ component is ~uperimposed on the digital output ~ignal which i8 input into digital-to-analog converter 116. From the previouc di~cus~ion of the present invention, it will be understood that software field modulator 114 of microproces60r 100 in the preferred embodiment of the present invention is preset to a fixed~ predetermined frequency to produce the desired predetermined ratio of frequency-to-magnctic flux density value. In another embodiment, the feedback system of the present invention i8 such that changes in the - 2~2~3~
2,716-005 composite magnetic flux density are measured, whereupon microprocessor 100 determines the necessary change in frequency to maintain the predetermined relationship. In that embodiment, software field analog converter 116 be provided on-board the microprocessor chip. Hence, software field modulator 114 provides the ac component at node 118.
The signal from digital-to-analog oonverter 116 is fed to voltage-to-current amplifier 120, the output of which drives magnetic field generating coils 112 in the desired manner. Hence, the composite field is held substantially constant despite changes in the ambient component.
While several arrangements of power sources are suitable, it is preferred that power supply 122 be provided to power magnetic field QenAor amplifier 106, microprocessor 100 and magnetic field sensor 104, the latter via bias circuitry 124. A separate power source 126 is preferred for voltage to current amplifier 120.
, Having fully described one preferred embodiment of the apparatus of the present invention, including its manner of con~truction, operation and use, the method of the present invention will now be described. It iB to be understood that this description of the method incorporates the foregoing discussion of the novel apparatus. In one embodlment, the present in~ention provides a method of reducing the rate of growth of a neoplasm in man or animals. This is achieved in one aspect by generating a fluctuating, directionally-oriented magnetic field which projects through the cancer cells, for example a malignant neoplasm such as a sarcoma, in the ~2~3~
2,716-005 pre$ence of a chemotherapeutic agent as previous described. It is to be understood that the present invention may also be useful in reducing the rate of growth of benign tumors. The magnetic field generating means preferred for use is previously described. The magnetic field so generated has a magnetic flux density of precisely controlled parameters which passes through the target neoplasm parallel to a predetermined axis projecting through the neoplasm. As will be known by those skilied in the art and as has been clearly explained, the local magnetic field to which the neoplasm is subjected will have a component which is parallel to the predetermined axis and which thus aids or opposes the applied or generated magnetic field along the axis. At times, the local component may be zero. In the method of the present invention, the density of this combined magnetic flux, and more specifically the net average non-zero value of the combined magnetic flux density, is controlled to provide a precise relationship between the flux density along the axis and the frequency of the applied magnetic field which is 08cillating at a predetermined value. Most preferably this is accomplishet by adjusting the intensity of the applied field to compensate for changes in the local field. Thus, in one embodiment, the present invention provides a method of treating cancer by creating a magnetic field which penetrates a malignant neoplasm and which has a predetermined relation~hip between frequency of oscillation and average flux density. In the most preferred embodiment, the predetermined relationship or ratio of frequency-to-field intensity is determined with reference to the equation:
fc/B = q/(2~m) ., - 2~2~3~
62,716-005 where fc is the frequency of the combined magnetic field along the predetermined axis in ~ertz, B is the non-zero net average value of the magnetic flux density of the combined magnetic field parallel to the - axis in Tesla and qtm is in Coulombs per kilogram and has a value of from about 5 x 105 to about 100 x 106. B preferably has a value not in excess of about 1 x 10-2 Tesla.
In order to maintain a fluctuating magnetic field having the desired parameters, it may be necessary to monitor changes in the composite magnetic field parallel to the predetermined axls. As stated, this is preferably carried out with a Hall-effect device or the like which is capable of sensing both static and time-varying magnetic flux and which produces an analog signal. This analog signal is periodically sampled by microprocessing means which then calculates the necessary frequency and/or magnitude of the applied magnetic field to maintain the preprogrammed, predetermined ratio previously de6cribed. Of course, it will now be understood that it is the combined magnetic flux which is sensed by the magnetic field sensor. The magnetic field generating means is uset to adjust the magnitude of this composite field where appropriate.
In one embodiment, the method includes controlling the a~-rsge value of the applied magnetic flux density along a predetermined axis to maintain a predetermined ratio of frequency-to-composite ~agnetic flux den8ity. In another embodiment, the frequency of the fluctuations is ad~usted to maintain this relation~hip in which changes in the combined magnetic flux den~ity due to changes in the local magnetic field are detected. Moreover, a combination of these two ~` 2~2~
2,716-005 methods may be u6ed wherein both the frequency and the magnitude of the magnetic field flux density are adjusted to maintain ~he predetermined relationship of the present invention.
~ ence, in one aspect the method of the present invention includes the steps of creating and maintaining a predetermined relationship between the frequency of a fluctuating magnetic field and the flux density of the field. In particularly preferred embodiments, a frequency of 16 Hertz and an average flux density of 2.09 x 10 5 Tesla are utilized which corresponds to cyclotron resonance for Ca++. This combination of frequency and flux den~ity i8 particularly useful in decreasing the proliferation rate of cancer cells in the presence of a chemotherapeutic agent. Another preferred frequency which is useful ;s 16 Hertz and 4.07 x 10-5 Tesla whlch corresponds to cyclotron resonance for K+.
In a preferred embodiment of the method of the present ~nvention, the ratio of frequency-to-flux den~ity is determined by selecting a preselected ion present in the neoplasm and tuning the fluctuating compo3ite magnetic flux density to the specific cyclotron re~onance frequency for the ion. The preferred ions for lncrea6ing the inhibition of cancer cells in the presence of a chemotherapeutic agent are Li+, K+, Mg++, and Ca++. Tuning to other ions such as Mn++, Zn++ or Cu+ may al~o provide beneficial results.
Finally, the subject neoplastic tissue is exposed to the therapeutic magnetic flux in accordance with the pre~ent invention for a period of time sufficient to bring about the desired result. It i6 -- 2~2939~
2,716-005 believed that exposure in accordance with the present invention o~
approximately .5 hr. to 24 hr./day will typically provide beneficial re~ults.
In another preferred embodiment of the present invention, the treatment heads of cancer treatment apparatus 20 contain two discrete but otherwise equal windings. Each head contains a dc winding and an ac winding. These windings are closely wound, either as alternate wires, as alternate layers, or in ad~acent planes. Those skilled in the art will recognize that the closeness of the winding arrangement will ensure that the two separate magnetic fields generated at a point distant from the two windings (when each carries substantially the same current) will be substantially the same. The dc winding in one coil is connected in series aidin8 to the dc winding in the other coil. The ac winding in one coil is similsrly connected in series aiding to the ac winding in the other coil.
The pair of dc windings are energized by a dc power supply thst provides a current which reduces the component of the local or smbicnt fielt along the sxis of the coil pair at the desired treatment region to a value that i8 substantially zero. Again, the ambient field 1- mea~urcd by magnetic field sensing means such as a Hall devi~e or a fluxgate magnetometer or the like. The ac windings, in this embodiment, arc preferably energized by a full-wave rectifier circuit providing a current which produceo a resulting ac magnetic field component along the coll sxis at the de~ired treatment region that varies in time at the therapeutic frequency. The rms current of the rectified signal in the ac coil pair i~ adjusted until a pre~elected rms magnetic field --- 2~2~
2,716-005 component at the treatment region is achieved. It will be understood that once the ambient field is measured, knowledge of the coil geometry and number of turns will allow a predetermined calibration, enabling the operator to automatically achieve the required ambient field nulling current as well as the rms current necessary to create the preselected rms magnetic field.
In this embodiment utilizing a rectified si~nal in the ac windings, the frequency of the fluctuating magnetic field is set at a predetermined value, and the effective or root-mean-square value of the applied magnetic flux density is then regulated to produce a ratio of frequency to flux density that acts to reduce the rate of growth of cancer cells. Preferred ratios of frequency-to-field intensity are determined with reference to the equation:
fO = q/2~m where fO i8 the frequency of the fluctuating magnetic field in Hertz, Bo is the non-zero rms v~lue of the magnetic field component winding along the coil axis in Teala, (q/m) is in Coulombs per kilogram and has a value of from about 5 x 105 to about 100 x 106. Bo preferably has a value not in exce8s of 1 x 10-2 Tesla. In one embodiment, the values of q and m are 8elected with reference to the charge and mass of a preselected ion. Other relationships between frequency and magnitude may be u~eful or even desirable in a particular application.
In another embodiment, a sinusoidal current is employed in the ac windings with a direct current offset resulting in a non-zero :' --` 2~2~3~
2,716-005 average magnetic field to achieve the required magnetic field along the predetermined axis that is therapeutically effective.
In still another embodiment, and referring now to Figure 5 of the drawings, three pairs of Helmholtz-like coils generate applied magnetic fields along the x, y and z axes of a Cartesian coordinate system. Coil pair A comprises treatment heads 200 and 202. Coil pair B
comprises treatment heads 204 and 206, and coil pair C similarly comprises a pair of opposed coils, only one of which is shown in phantom a6 treatment head 208. It will be appreciated that these coils may comprise single windings or may be provided in the combination ac and dc windings as previou~ly described. Also, it i8 preferred that each pair be provided with a magnetic field sensing device in order to measure the magnetic field component along each respective axis. In other words, the axes of the three coil pairs will be mutually perpendicular, intersecting at the de~ired treatment region, i.e., the target malignant neoplasm. The therapeutic frequency is generated by each coil pair in the aforementioned described manner. Where the coil pair~ include ac and dc winding~, the ambient field component along each axis is reduced to substantially zero.
In still another embodiment of the present invention~ the growth rate of a neoplasm in the presence of a chemotherapeutic agent is reduced by creating and maintaining a predetermined relationship between thc frequency of the fluctuations and the non-zero average value of the magnctic flux den~ity along the predetermined axis based on the charge to-mass ratio of the preselected ion, wherein thic predetermined relation~hip i6 determined using the equation fch = XBq/2~m.
---` 2~2~3~
, 62,716-005 Accordingly, fch is the frequeney of the fluctuating magnetic flux density in Hertz, B is the non-zero average value of the flux density parallel to the predetermined axis in Tesla, q is the charge of the preselected ion in Coulombs, m is the mass of the preselected ion in kilograms, and X is a preselected odd integer greater than one. In this manner, a number of higher harmonic frequencies are provided by which therapeutic results may be achieved.
It will be recognized that the fundamental therapeutic frequency fc is effectively multiplied by a selected odd integer to produce a frequency which also causes the desired therapeutic result.
Unless otherwise specified, as used herein, the term "odd integers" or "odd integer" shall mean positive, non-zero integers. The preferred odd integers for use in the present invention which provide harmonic frequencies that should be effective in reducing the growth rate of cancer are selected from the group consisting of the following integers: three, five, seven, nine, eleven, thirteen, fifteen, aeventeen and nineteen. Additional harmonic frequencies based on multiplying the fundamental frequency by an odd integer may also be suitable in some applications. As indicated, the frequencies for a given preselected ion and known magnetic flux density B can be determined with reference to the equation fch = XBql2~m where fch is the frequency in Hertz of the fluctuating magnetic field along a predctermined axis extending through the target tissue, B is the magnetic flux density along the axis in Tesla, q is the charge of the pre~elected ion in Coulombs, m is the mass of the preselected ion in kilogram~, and X i8 a selected odd integer greater than one. It is believed that many of the preferred odd multiple harmonic frequencies . ' ' , . , '. , ' :' ' ' . ' ' '. -. ' ' ~ :
~29~
2,716-005 will be substantially as effective in treating cancer as are the fundamental frequencies. A more thorough description of harmonic tuning is set forth in the aforementioned U.S. Patent Application Serial No.
343,017 which is incorporated herein by reference.
In still another aspect, the present invention provides a method for decreasing the proliieration rate of cancer cells which comprises generating an applied magnetic field parallel to a predetermined axis which projects through the designated space. In the presence of at least two different predetermined ionic species in the target cancer cells or tissue and a chemotherapeutic agent, the neoplasm is exposed to the applied magnetic field. In one embodiment, the neoplasm is also exposed to a local magnetic field having a component parallel to the predetermined axis. The magnetic flux density along the predetermined axia i8 f luctuated to create a non-zero average value.
Where a local f ield is also present, this non-zero average value is the net non-zero average value of the applied and local field components parallel to the predetermined axis as previously described in connection with the other embodiments of the present invention.
A predetermined relationship between the frequency of the fluctuation~ ant the non-zero average value of the magnetic flux density along the axi~ i8 then created and maintained which simultaneously controls the movement of two or more preselected ions. Ion movement is brought about to decrease the growth rate of the neoplasm. In one embodiment, the predetermined relationship is determined by first sol~lng the equation fc - Bq/2~m at a generally randomly selected value of B for each di~tinct preselected ion, where fc is the frequency of the 2~2~
2,716-005 field fluctuations in Hertz, B is the non-zero average value of the flux density parallel to the predetermined axis in Tesla, q is the charge of each preselected ion in Coulombs, and m is the mass of each preselected ion in kilograms. The value of B is preferably less than about 10 2 T.
This establishes the fundamental cyclotron frequency for each ion. A
value fcs is preferably selected such that none of the individual ion fc alues deviate more than 5 percent from the fcs value. In most instances, there will be no fcs value available based on the fundamental fc values of the preselected ions. Accordingly, a higher odd harmonic frequency of at least one of the preselected ions is determined with the equation fch = XBq/2~m as previously explained. The values of fc and fch are examined to determine whether an fch value can be selected based on a 10 percent and most preferably a 5 percent deviation factor. If not, the process is continued for each value of fCh~ beginning with the lowest odd harmonic fch values until a value of fc8 can be established within the 5 percent deviation. Hence, at the value selected for B
during the calculation of the fc or fch values, the magnetic flux density to which the target tissue is exposed is fluctuated along the axis at the fc8 frequency. This specific relationship between frequency and field stren8th brings about simultaneous transmembrane movement of the preselected ion8 for decreasing the proliferstion rate of the target cancer cells.
In more detail, the fundamental frequency at which the fluctuating mflgnetic field would be oscillated for cyclotron resonance regulation of transmembrane ion movement is calculated $ndividually for each different ionic species to be regulated using the equation fc =
Bq/2~m for a selected value of B, which is again the non-zero average . ' ' ' : -.
- 2~2~
2,716-005 value of the flux density along the predetermined axis. As previously explained, fc is in Hertz, q is in Coulombs9 m is in kilograms, and q/m is the charge-to-mass ratio of the preselected ion. Once the fundamental cyclotron resonance frequency (fc) of each ion to be regulated is calculated, a regu]ating frequency (fcs) is determined which is preferably within 5 percent of the fundamental frequency f~ or an odd harmonic frequellcy fch of each preselected ion. The odd harmonic frequencies are determined again using the equation fch = XBq/2~m, where X is an odd integer greater than one. It will be understood that the equation fch = XBq/2~m can be used to determine the fundamental frequency fc by using a value of L for X. While the value of fcs will not typically be available which is common to the fundamental frequencies and/or odd harmonic frequencies for each preselected ion, it has been found that an fcs value which is within about 10 percent and preferably about 5 percent of each fc value or fch value of the ions to be re~ulated satisfactorily provides simultaneous transmembrane movement of each preselected ion in the fie]d.
It will al60 be understood that the values of fch are a functlon of B. Thus, it may be possible to obtain an fcs value for a particular set of ions which is within the preferred 5 percent deviation at a de~ignated B value, but not a higher B value. For use in the pre~ent invent~on, the value of B is preferably less than about 1 x 10-2 T, with a peak-to-peak amplitude of about 2.0 to about 20,000 m Tesla.
The preferred ions are those previously set forth. A more thorough description of multiple tuning is set forth in the aforementioned U.S.
Patent Application Serial No. 343,017 which is incorporated herein by reference.
~2~g 62,716-005 It will therefore be appreciated that in the broadest sense, the present invention provides a method and apparatus for regulating ~he growth characteristics of cancer cells, i.e. treating cancer, by subjecting the cells to a magnetic environment in which the ratio of the magnetic flux density to the fre~uency of oscillation of a fluctuating field component is maintained at a predetermined relationship based on the cyclotron resonance frequency of at least one ion in the field.
This relationship may be selected to decrease the proliferation rate of cancer cells exposed to a particular chemotherapeutic agent or selected to increase the differentiation of of cancer cell neurites to inhibit malignancy. It may be possible to select a relationship which decreases the rate at which cancer cell proliferation occurs even without the use of a chemotherapeutic agent. In its most preferred embodiments, the present invention provides a method and apparatus which includes tuning to the cyclotron resonant frequency of Ca++ or K+ or a selected multiple of these frequencies in the presence of a chemotherapeutic agent to decrease proliferation rate. In another mo~t preferred aspect, the predetermined relationship is baEed on multiple harmonic tuning for both Ca++ and Mg++ in the presence of a chemotherapeutic agent where the relationship represents three times the fundamental frequency of the c~lcium ion and five times the fundamental frequency of the magnesium ion. In the latter ca~e, it is the formation of neurites which is 8timulated.
In still another a~pect the present invention provides an apparatus for the systemic therapeutic treatment of cancer. By "systemic treatment" it is meant that substantially all of the subject's body is simultaneously expo~ed to the therapeutic magnetic fields in -3~-- 202~3~g 2,716-005 accordance with the present invention. Accordingly, and referring now to Figure 6 of the drawings, systemic treatment apparatus 280 is shown which comprises a tube or cylinder 282 of a non-magnetic material such as plastic. Tube 282 houses a large solenoid 284 which contains multiple turns of wire 286 and which extends substantially the entire length of systemic treatment apparatus 280. Gurney or platform 288 is provided on a track system (not shown) which allows platform 288 to move between a first position outside of tube 282 to a second position inside of tube 282. A controller 270 is provided along with the necessary circuitry for energizing solenoid 284 to create a magnetic field in the direction of axis 250, which in this embodiment projects through the central bore of solenoid 2B4. In other words, and as will be appreciated by those skilled in the art, the magnetic flux generated by solenoid 284 will run through the center of the coil. Patient 272 is placed on a platform 288 and platform 288 is then moved into position inside tube 282. Thus patient 272 is posit~oned inside solenoid 284 with the applied magnetic flux penetrating the patient's entire body in the direction of predetermined axis 250. In one embodiment a magneeic field sensor 274 is also provided to measure the magnetic flux density along axis 250 and may be mounted on a track system within tube 282. It may be suitable in some applications to mount tube 282 on a rotatable stand such that tube 282 can be rotated to change the position of patient 272 and sxis 250 with respect to the local magnetic field.
Other configurations of systemic treatment apparatus 280 may be suitable or even desirable ln a particular application such as large flat coils ~for example having diameters of six feet or greater) in Nelmholtz arrangement with one coil being placed on esch side of patient 272. In this alternative arrangement, sxis 250 would extend transverse to the -- 2~2~3~
.
2,716-005 patient's body rather than from toe-to-head as shown in Figure ~. Of course, the direction of the magnetic field may also be directly opposite to the direction of axis 250 depending upon the direction of current through solenoid 284. Systemic treatment apparatus 280 is thus used to create a magnetic field of predetermined parameters inside tube 282. While this predetermined re]ationship is preferably maintained by adjusting the applied flux to compensate for changes in the local field component; alternatively, the frequency can be adjusted to preserve the desired ratio.
For ~ystemic treatment, a patient 272 afflicted with cancer is placed on platform 288 which is then moved into position within tube 282 and thus within solenoid 284. Patient 272 is then subjected to a fluctuating magnetic field of the nature previously described for a period of time sufficient to bring about the desired systemic treatment. It i8 believed that exposure in accordance with the systemic treatment embodiment of the present invention of about .5hr. to 24hr./day until the desired result is achieved.
Referring now to Figure 7, a block diagram is shown which is preferred for U60 in connection with the systemic treatment apparatus 280. Operating console 320 forms the control center for operating sy~t-miC treatment apparatus 280. The console is comprised of a plurallty of control elements 322 and a visual display device 324 for monitoring the wave form display of the solenoid current signal 325.
The plurallty of control elements 322 include a gurney positioning dial 326 for controlling the lateral movement of the gurney platform.
Magnetic ficld sensor ad~usting dial 328 allows the operator to 2~2~3~
2,716-005 selectively position the magnetic field sensor 327 within the center of treatment solenoid 2~4. The treatment structure rotating dial 330 allows the operator to rotate the concentric solenoid and platform 288 in the horizontal plane in that embodiment where a supporting stand or turntable (not shown) is provided. This horizontal movement allows the solenoid coil to be positioned so that it may compensate for undesired local magnPtic fields. Switch elements 332 allow the operator to effect various other control tasks, such as turning the concentric solenoid current on or off, or setting the cyclotron resonance frequency for the ion of choice. Each of the above-mentioned dials and switch elements produce signals which go to various elements of system treatment apparatus 280 to accomplish the various functions described herein. The signal produced by the gurney positioning dial 326 leaves operating console 320 along cable 334 as does the signal produced by the treatment structure rotating dial 330. The signal6 334 interface with various motors and other drive hardware to effect the positioning of platform 288 within solenoid 284 and the positioning of tube 282 with respect to the local magnetic field. Control line 336 transmits the signal developed by the magnetic field sensor adjusting dial 328 to a magnetic sensor positioning device 338 which allows the magnetic sen~or 327 to be positioned at various locations within the center of the solenoid 2~4.
After dials 326 through 330 and switches 332 have been set, systemic treat~ent spparatus 280 is ready for operation. The frequency which ha6 been selected by the operator is output along line 340 to the sine wave generator 342. The sine wave generator 342 responds to the frequency ~elected in accordance with the principles of the present invention by generating a sinusoidal waveform which posses~es one-half of the desired frequency with no DC offset. The signal is then sent from the sine wave 2~2~3~
62,716-005 generator 34Z to a full-wave rectifier circuit 346. Rectifier 346 not only transforms the sinusoidal waveform produced by generator 342 to a rectified DC signal, it also has the effect of doubling the frequency of the output of the sine wave generator. The rectified signal is then sent from the full-wave rectifier 346 to the programmable power supply 3~8 where it is amplified to a suf~icient power level which is necessary to develop a sufficiently strong magnetic field within the solenoid 284. The amplified signal is then sent from the programmable power supply 348 along cable 350 to solenoid 284. Solenoid 284 then converts the amplified current to a uniform magnetic field density within the concentric solenoid winding 284 along axis 250 shown in Figure 6.
Because of localized magnetic fields, the magnetic field, as it exists within the concentric solenoid winding, is not always absolutely predictable. Thus, magnetic sensor 327 is mounted in close proximity to the patient so that the magnetic flux density within solenoid 284 can be constantly monitored. A signal, which is proportional to the magnetic flux density within treatment solenoid 284, is output by the magnetic sensor 327 and then filtered by filter 331 to eliminate any undesired high-frequency ele~ents. The output of low-frequency filter 331 is then delivered to operating console 320 along cable 333 so that it can be displayet on the visual display device 324. The output of low-frequency filtor 331 i8 also sent to analog amplifier 335 so that it can be properly conditioned to be used within the programmable power supply 348. The programmable power supply 348 uses the output from analog amplifier 335 as a means for maintaining a uniform density magnetic field within the center of solenoid 284. This ta6k may be performed within the programmable power supply by mean6 of standard analog feedback techniques or may be accomplished by means of a digital processor.
, - 2 0 2 ~62,716-005 The following examples are provided to more fully illustrate the present invention and are not intended to limit the scope of the invention as defined in the appended claims.
~rL~
N-18 neuroblastoma tumor cells from the American Type Culture Collection (ATCC) were cultured in Linbro 12-well culture plates in either I-10 or I-H media, at 37 C, with 52 COg in air at 100%
humidity. The formulae for the media is as follows:
Dulbecco's Minimum Es~ential Medium (double strength) 50 ml Fetal Calf Serum 10 ml 20% Glucose solution 3 ml L-Glutamine (200 mM solution) 1 ml Penicillin/Streptomycin (Gibco Prepared) 1 ml H20 q.s. 100 ml I-N
DMEM (2X) 50 ml Norse Serum 25 ml 20Z Glucose 3 ml L-Glutamine 1 ml Peniclllin/Streptomycin (Gibco Prepared) 1 ml N20 q.8. 100 ml 50X of the cultures received ARA-C (Cytosine Arabinoside) at a final concentration of 0.25 micrograms/ml, an inhibitor of neuroblastoma growth. Experimental cultures also received 24 hour combined magnetic field stimulation adjusted to ion cyclotron resonance values for Ca+~ or K+ according to the method and formula of the present invention. Treatment was accomplished by placing the culture dishes in - 2~2~8 2,716-005 the space between the energized Helmholtz-aiding coils in the incubator so that the combined magnetic fields passed through the culture medium and cells parallel to the surface of the medium and the bottom of the dish. The following protocol was used:
Culture A~A-C ÇB_IQn No. of Cultures Control I-10 Yes none 9 Control I-H Yes none 9 Control I-10 No none 9 Control I-H No none 9 I-10 Yes Ca 9 I-10 No Ca 9 I-H Yes Ca 9 I-H No Ca 9 I-10 Yes K 9 I-10 No K 9 I-H Yes K 9 I-H No K 9 The medium in each culture dish was renewed every other day.
After 3 days of culture, the dishes were removed from the incubator, and the cell proliferation rate was established by making cell counts in each dish. The cells having recognizable neurites (outgrowths at least twice as long as the cell diameter) were also counted. The data are expre~sed as number of cells per dish and percent of cells having neurite~.
~S~
Ça~LQ~Y No- Cell~/Diah ~ v~ C~ Neurite6 p VB C
C + ARA-C (I-10) 37.50 - 16.87 C + ARA-C (I-H) 15.78 - 9.29 C N0 ARA-C(I-10) 66.78 - 12.71 C N0 ARA-C (I-H) 46.67 - 20.64 -- 2~2~
62,716-005 ~ategory No. Cells/D~ Ç Z Nçurites p vs C
Ca + ARA-C (I-10) 46.34 .10 9.92 .05 Ca + ARA-C (I-~) 30.78 .01 14.45 .10 Ca N0 ARA-C (I-10) 64.72 N.S. 11.59 N.S.
Ca N0 ARA-C (I-H) 33.33 .10 22.08 N.S.
K + ARA-C (I-10) 46.56 .10 12.44 N.S.
K + ARA-C (I-H) 20.44 N.S. 12.75 N.S.
K No ARA-C (I-10) 68.00 N.S. 12.57 N.S.
K No ARA-C (I-H) 24.00 .01 20.93 N.S.
These results indicate that CR fields can influence the growth of tumors in vitro and can alter the effects of an antitumor drug on the cells. The tuning for Ca+~ and K+ had little effect on the outgrowth of neurites. The tuning for Ca had some effect, depressing outgrowth strongly in I-10, which contains strong fetal growth factors and enhancing growth slightly in l-H, which lacks the growth factors of I-10.
Neither Ca++ nor K+ tuning overcame the strong effect of cell proliferation factors contained in I-10 medium as a result of the incorporation of the fetal calf serum. The effect was essentially null, even in the presence of ARA-C. However, when I-H was used, which is more nearly similar to normal adult serum by virtue of the absence of the fetal cell proliferation factors, the CR tuning for Ca produced an increase in cell proliferation, partly overcoming the inhibitory effect of the ARA-C.
When K+ tuning was used in I-H medium, in the presence of ARA-C, there was essentially no effect, the ARA-C being a strong inhibitor notwithstanding.
:'~
' --- 2~2~13~8 62,716-005 In the absence of the ARA-C, using the I-H medium, Calcium tuning produced a slight depression of cell proliferation.
When K tuning was used in the absence of ARA-C in I-H medium, there was a very strong suppression of cell proliferation. In fact, the suppression produced by the K+ signal was statistically equivalen~ to the effect of the potent pharmacological agent, suggesting that under some circumstances, the use of cyclotron resonance may be as effective a treatment modality as a standard pharmacological agent, but perhaps without the negative side effects of the pharmacological agent.
~IPLE~ I I
In this example the medium was identical to I-10 above, except the serum concentration was reduced to 2.0 ml. In the following table, the reduction in proliferation achieved by the present invention i8 again demonstrated with respect to the synergistic effect of cyclotron resonance treatment in the presence of chemotherapeutic cancer agent~. The experiments were conducted for 72-hour periods. The c811s were N-18 neuroblastoma cells.
K ~ potassium ion (K~
Ca - calcium ion (Ca++) H Mg/Ca 3/5 harmonic tuning C- control plates without ARA-C and without cyclotron resonance expo8ure C+ - control plates with ARA-C and without cyclotron resonance exposure ~- ~ experimental plates without ARA-C and with cyclotron resonance exposure E+ - experimental plates with ARA-C and with cyclotron resonance exposure .5 - 1/2 hour field exposure per 24 hours 24 continuous field exposure .- ' ~ ".
.
.
62,716-005 2Q2~3~
(ARA-C = cyto~ine arabinoside [conc. 0.25 microgram61ml~) (cell processes re~ers to neurites) TOTAL CELI.S/MM2 +- S.D.
ION/TIME C- C~ E- E~
K/.5 H47.8-27.4 28.5-14.9 215.1-124.2 43.6-22.9 K/24 H81.9-59.0 34.1-19.3 213.7-95.8 50.3-28.0 Ca/.5 H33.3-15.0 18.6-9.0 129;3-44.2 26.2-1~.~
H/.5 H 142.9-55.1 33.3-22.0 167.0-60.4 26.3-11.1 Mg/.5 H 36.5-40.5 11.7-9.3 51.7-34.8 lo.7-~.a ~H ~ Mg/Ca, 3~5 Harmonlc Tunlng) ~ CE~S WITH PROCESSES +- S.D.
C- C~ E- E+
K/.5 H10.8-6.3 13.9-8.9 11.1-6.a 10.0-7.5 K/24 H9.0-~.6 7.2-7.6 7.3-3.2 4.2-3.2 Ca/.5 H12.9-6.8 19.4-11.9 17.2-6.3 14.6-10.9 H/.5 H21.2-6.6 12.9-8.7 20.1-5.9 15.2-7.6 Mg/-.5 H9.9-6.9 6.3-11.2 8.6-5.2 3.8-~.7 STATISTICA~ COMPARISONS, TOTA~ CELLS
~t, (p)) C- vs C~ E- v~ E~ C- v3 E- C~ vs E~
K/.5 H3.57 (~.001)a.O3 ~<,001)7.89 (<.001)3.35 (~.005) K/24 H 4.50 (~.001)9.9~ (~.001)7.29 (<.001)2.~g (~.01) Ca/.O H 5.03 (~.001)13.06 (~.001)12.35 ~<.001)2.36 ~.05) H~.O N11.0~ (~.001)13.75 (~.001)1.78 (N.S.)1.72 (N.S.) M5~/.5 H 3.56 (~.000) 6.99 (<.001) 1.~2 (N.S-) 0-54 (N.S.) X CEL~S WITH PROCESSES
~t, (p)) C- v- C~ E- vs E~ C- v~ E- C~ v~ E~
K/.O N 1.63 (N.S.)0.65 (N.S.~ 0.19 (N.S.) 1.96 (-.05) K/2~. H 1.20 (N.8.)3,75 (~.001)1.88 (N.S.) 2.11 (<.05) C~/.O N 2.a~ (~.01)1.26 (N.S.) 2.e1 (<.01) 1.80 (N.S.) H/.O H ~.. 06 (~.001) 3.05 ~.01) 0,77 (N.S-) 1.18 (N.S.) M~/.O N 1.0~ ~N-S.) 3.09 ~.005) 0.43 (N.~.~ 1.04 (N.S.) n ~or a11 xp-r~m-nts ~ 36 ~3-- : .
2~2~3~
62,716-005 Thus, it is apparent that there has been provided in accordance with the invention a method and apparatus that fully satisfies the objects, aims and advantages set forth above. While the invention has been described in connection with specific embodiments thereof, it is evident that many alternatives, modifications, and variations will be apparent to those skilled in the art in light of the foregoing description. For example, it is to be understood that higher harmonic tuning and multiple ion tuning as described herein may be useful in connection with the contemporaneous use of chemotherapeutic cancer agents. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims.
Claims (34)
1. A method for treating cancer comprising the steps of:
positioning a magnetic field generating means adjacent a biological subject afflicted with cancer;
generating a magnetic flux with said magnetic field generating means, said magnetic flux extending through said subject parallel to a predetermined axis projecting through said subject; and fluctuating said magnetic flux and controlling the density of said magnetic flux to create and maintain a predetermined relationship between the frequency of said fluctuations and the magnitude of said magnetic flux density which regulates the growth characteristics of cancer cells in said subject.
positioning a magnetic field generating means adjacent a biological subject afflicted with cancer;
generating a magnetic flux with said magnetic field generating means, said magnetic flux extending through said subject parallel to a predetermined axis projecting through said subject; and fluctuating said magnetic flux and controlling the density of said magnetic flux to create and maintain a predetermined relationship between the frequency of said fluctuations and the magnitude of said magnetic flux density which regulates the growth characteristics of cancer cells in said subject.
2. The method recited in Claim 1, wherein said magnetic flux is combined with an ambient magnetic flux.
3. The method recited in Claim 1, wherein said predetermined relationship of said frequency to said magnitude of said magnetic flux density is determined by using the equation fc/B = q/(2mm) where fc is said frequency in Hertz, B is the average value of said magnetic flux density in Tesla parallel to said predetermined axis, q/m has a value of from about 5 x 105 to about 100 x 106 in Coulombs per kilogram and where B preferably has a value not in excess of about 1 x 10-2 Tesla.
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4. The method recited in Claim 3, wherein q and m are, respectively, equal to the charge and mass of a preselected ionic species.
5. The method recited in Claim 4, wherein said preselected ionic species is selected from the group consisting of Zn++, Mn++, Cu+, Li+, K+, Mg++ and Ca++.
6. The method recited in Claim 1 wherein a chemotherapeutic cancer agent is substantially contemporaneously present in said subject during said treatment.
7. A method for treating cancer comprising the steps of:
positioning a patient afflicted with cancer inside an enclosure, said enclosure having an associated magnetic field generating means, such that said patient occupies a predetermined space;
generating a magnetic flux with said magnetic field generating means, said magnetic flux extending through said predetermined space and said patient parallel to a predetermined axis projecting through said predetermined space; and fluctuating said magnetic flux and controlling the density of said magnetic flux to create and maintain a predetermined relationship between the frequency of said fluctuations and the magnitude of said magnetic flux density which reduces the rate of proliferation of cancer cells in said patient.
positioning a patient afflicted with cancer inside an enclosure, said enclosure having an associated magnetic field generating means, such that said patient occupies a predetermined space;
generating a magnetic flux with said magnetic field generating means, said magnetic flux extending through said predetermined space and said patient parallel to a predetermined axis projecting through said predetermined space; and fluctuating said magnetic flux and controlling the density of said magnetic flux to create and maintain a predetermined relationship between the frequency of said fluctuations and the magnitude of said magnetic flux density which reduces the rate of proliferation of cancer cells in said patient.
8. The method recited in Claim 7, wherein said magnetic flux is combined with an ambient magnetic flux.
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9. The method recited in Claim 7, wherein said predetermined relationship of said frequency to said magnitude of said magnetic flux density is determined using the equation:
fc/B = q/(2mm) where fc is said frequency in Hertz, B is the average value of said magnetic flux density in Tesla parallel to said predetermined axis, q/m has a value of from about 5 x 105 to about 100 x 106 in Coulombs per kilogram and where B preferably has a value not in excess of about 1 x
fc/B = q/(2mm) where fc is said frequency in Hertz, B is the average value of said magnetic flux density in Tesla parallel to said predetermined axis, q/m has a value of from about 5 x 105 to about 100 x 106 in Coulombs per kilogram and where B preferably has a value not in excess of about 1 x
10-2 Tesla.
10. The method recited in Claim 7, wherein q and m are, respectively, equal to the charge and mass of a preselected ionic species.
10. The method recited in Claim 7, wherein q and m are, respectively, equal to the charge and mass of a preselected ionic species.
11. The method recited in Claim 7, wherein a chemotherapeutic cancer agent is substantially contemporaneously present in said patient during said treatment.
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12. An apparatus for reducing the growth rate of a neoplasm comprising:
means for generating an applied magnetic flux parallel to a predetermined axis and projecting through a predetermined space containing a neoplasm;
means for measuring magnetic flux density parallel to said predetermined axis in said predetermined space;
means associated with said flux generating means for fluctuating said applied magnetic flux; and means for creating and maintaining a relationship between the rate of fluctuation of said magnetic flux and the intensity of said magnetic flux density, where said predetermined relationship reduces the rate of growth of said neoplasm.
means for generating an applied magnetic flux parallel to a predetermined axis and projecting through a predetermined space containing a neoplasm;
means for measuring magnetic flux density parallel to said predetermined axis in said predetermined space;
means associated with said flux generating means for fluctuating said applied magnetic flux; and means for creating and maintaining a relationship between the rate of fluctuation of said magnetic flux and the intensity of said magnetic flux density, where said predetermined relationship reduces the rate of growth of said neoplasm.
13. The apparatus recited in Claim 12, wherein said means for generating an applied magnetic flux includes at least one field coil.
14. The apparatus recited in Claim 129 wherein said means for generating an applied magnetic flux includes two field coils arranged in a Helmholtz configuration.
15. The apparatus recited in Claim 12, wherein said means for measuring the magnetic flux density parallel to said predetermined axis in said predetermined volume includes a magnetometer.
16. The apparatus recited in Claim 12, wherein said means for creating and maintaining said relationship includes microprocessing means.
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17. The apparatus recited in Claim 12, further including a first housing of a non-magnetic material enclosing one of said field coils and a second housing of non-magnetic material enclosing the other of said field coils.
18. A method for reducing the rate of growth of cancer cells in a biological subject, comprising:
generating an applied magnetic flux parallel to a predetermined axis and projecting through a predetermined space, said space being occupied by cancer cells, said flux generating means having at least two field coils, said field coils having an axis extending there through parallel to said predetermined axis, each of said field coils further having at least two windings, one of said windings of each coil being an ac winding and the other of said windings being a dc winding, said ac winding having as associated full-wave rectifier and an oscillator;
measuring an ambient field existing in said predetermined space along said predetermined axis in the region of said cancer cells;
said applied magnetic flux generating step including the steps of generating with said dc winding a magnetic flux which reduces said ambient field to substantially zero ant generating with said ac windings an ac magnetic field having a component along said predetermined axis in said predetermined space, said ac magnetic field component having a preselected rms value which reduces the rate of proliferation of said cancer cells.
62,716-005
generating an applied magnetic flux parallel to a predetermined axis and projecting through a predetermined space, said space being occupied by cancer cells, said flux generating means having at least two field coils, said field coils having an axis extending there through parallel to said predetermined axis, each of said field coils further having at least two windings, one of said windings of each coil being an ac winding and the other of said windings being a dc winding, said ac winding having as associated full-wave rectifier and an oscillator;
measuring an ambient field existing in said predetermined space along said predetermined axis in the region of said cancer cells;
said applied magnetic flux generating step including the steps of generating with said dc winding a magnetic flux which reduces said ambient field to substantially zero ant generating with said ac windings an ac magnetic field having a component along said predetermined axis in said predetermined space, said ac magnetic field component having a preselected rms value which reduces the rate of proliferation of said cancer cells.
62,716-005
19. A system for the treatment of cancer, comprising:
means for generating an applied magnetic flux parallel to a predetermined axis and projecting through a predetermined space, said space being occupied by a malignant neoplasm, said flux generating means including at least two coaxial field coils having an axis extending there through parallel to said predetermined axis, each of said field coils having at least two windings, one of said windings of each coil being an ac winding and the other of said windings being a dc winding;
means in association with said coils for supplying a direct current to said dc windings and an alternating current to said ac winding;
means for measuring an ambient field existing in said predetermined space in the region of said neoplasm, means in association with said flux generating means for controlling said direct current to said dc windings such that said dc windings create a magnetic flux which reduces said ambient field to substantially zero; and a full-wave rectifier circuit and an oscillator in association with said ac windings and said current supply means for producing an ac magnetic field component along said predetermined axis in said predetermined space having a preselected rms value which reduces the rate of growth of said malignant neoplasm.
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means for generating an applied magnetic flux parallel to a predetermined axis and projecting through a predetermined space, said space being occupied by a malignant neoplasm, said flux generating means including at least two coaxial field coils having an axis extending there through parallel to said predetermined axis, each of said field coils having at least two windings, one of said windings of each coil being an ac winding and the other of said windings being a dc winding;
means in association with said coils for supplying a direct current to said dc windings and an alternating current to said ac winding;
means for measuring an ambient field existing in said predetermined space in the region of said neoplasm, means in association with said flux generating means for controlling said direct current to said dc windings such that said dc windings create a magnetic flux which reduces said ambient field to substantially zero; and a full-wave rectifier circuit and an oscillator in association with said ac windings and said current supply means for producing an ac magnetic field component along said predetermined axis in said predetermined space having a preselected rms value which reduces the rate of growth of said malignant neoplasm.
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20. The system recited in Claim 19, further including a second pair of coaxial field coils, said second pair of field coils defining a longitudinal axis extending through said second pair of field coils, said second pair of field coils being positioned relative to said predetermined space such that said longitudinal axis of said second pair of field coils is perpendicular to said predetermined axis.
21. The system recited in Claim 20, further including a third pair of coaxial field coils, said third pair of field coils defining another longitudinal axis extending through said third pair of field coils, said third pair of field coils being positioned relative to said predetermined space such that said longitudinal axis of said third pair of field coils is perpendicular to said predetermined axis and said longitudinal axis defined by said second pair of field coils.
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22. A method for reducing the rate of growth of a neoplasm, comprising:
generating an applied magnetic field parallel to a predetermined axis projecting through a space in which a neoplasm of a living subject is positioned, said applied magnetic field resulting in a magnetic flux density in said space of a known average value parallel to said predetermined axis;
fluctuating said magnetic flux density such that said known average value is a non-zero average value;
creating a predetermined relationship between the frequency of said fluctuations and said non-zero average value of said magnetic flux density, wherein said predetermined relationship is determined using the equation fch = XBq/2mm, where fch is the frequency of the fluctuating magnetic flux density in Hertz, B is the non-zero average value of the flux density parallel to said predetermined axis in Tesla, q is the charge of a preselected ion present in said neoplasm in Coulombs, m is the mass of said preselected ion in kilograms, and X is a selected odd integer greater than 1, such that said predetermined relationship is effective in reducing the rate of growth of said neoplasm.
generating an applied magnetic field parallel to a predetermined axis projecting through a space in which a neoplasm of a living subject is positioned, said applied magnetic field resulting in a magnetic flux density in said space of a known average value parallel to said predetermined axis;
fluctuating said magnetic flux density such that said known average value is a non-zero average value;
creating a predetermined relationship between the frequency of said fluctuations and said non-zero average value of said magnetic flux density, wherein said predetermined relationship is determined using the equation fch = XBq/2mm, where fch is the frequency of the fluctuating magnetic flux density in Hertz, B is the non-zero average value of the flux density parallel to said predetermined axis in Tesla, q is the charge of a preselected ion present in said neoplasm in Coulombs, m is the mass of said preselected ion in kilograms, and X is a selected odd integer greater than 1, such that said predetermined relationship is effective in reducing the rate of growth of said neoplasm.
23. The method recited in Claim 22, wherein said space is subject to a local magnetic field having a component parallel to said predetermined axis and wherein said non-zero average value of said magnetic flux density is a net average value which includes the magnetic flux density of said component of said local magnetic field.
62,716-005
62,716-005
24. The method recited in Claim 22, wherein said selected odd integer is selected from the group consisting of odd integers from 1 to 19 .
25. The method recited in Claim 22, wherein said means for creating said predetermined relationship includes a magnetic field sensor and a microprocessor.
26. The method recited in Claim 22, wherein said preselected ion is selected from the group consisting of Mn++, Zn++, Cu+, Li+, K+, Mg++
and Ca++.
62,716-005
and Ca++.
62,716-005
27. A method for reducing the rate of growth of a neoplasm, comprising the steps of:
generating a fluctuating applied magnetic field parallel to a predetermined axis projecting through a space in which a neoplasm of a living subject is positioned, said applied magnetic field resulting in a magnetic flux density in said space of a known non-zero average value parallel to said predetermined axis;
fluctuating said magnetic flux density such that said known average value is a non-zero average value;
selecting at least two ions present in said neoplasm;
determining a value fch for each of said selected ions where fch = XBq/2mm, where B is said non-zero average value of said magnetic flux density along said axis, q is the charge of each of said ions in Coulombs, m is the mass of each of said ions in kilograms and X is a selected positive non-zero odd integer, said fch value being a therapeutic value which reduces the rate of growth of said neoplasm;
selecting a value fcs in Hertz from which each value fch deviates less than a predetermined percentage;
fluctuating said magnetic field parallel to said axis at a rate which is equal to said fcs value; and maintaining the ratio of said fcs rate of fluctuation to said non-zero average value of said magnetic flux density parallel to said axis, whereby said ratio is effective in reducing the growth rate of said neoplasm.
generating a fluctuating applied magnetic field parallel to a predetermined axis projecting through a space in which a neoplasm of a living subject is positioned, said applied magnetic field resulting in a magnetic flux density in said space of a known non-zero average value parallel to said predetermined axis;
fluctuating said magnetic flux density such that said known average value is a non-zero average value;
selecting at least two ions present in said neoplasm;
determining a value fch for each of said selected ions where fch = XBq/2mm, where B is said non-zero average value of said magnetic flux density along said axis, q is the charge of each of said ions in Coulombs, m is the mass of each of said ions in kilograms and X is a selected positive non-zero odd integer, said fch value being a therapeutic value which reduces the rate of growth of said neoplasm;
selecting a value fcs in Hertz from which each value fch deviates less than a predetermined percentage;
fluctuating said magnetic field parallel to said axis at a rate which is equal to said fcs value; and maintaining the ratio of said fcs rate of fluctuation to said non-zero average value of said magnetic flux density parallel to said axis, whereby said ratio is effective in reducing the growth rate of said neoplasm.
28. The method recited in Claim 27, wherein said predetermined percentage is less than 5 percent.
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62,716-005
29. The invention recited in Claim 27, wherein said at least two different selected ions comprises three ions .
30. The method recited in Claim 27, wherein said selected odd integer is selected from the group consisting of 1, 3, 5, 7, 9, 11, 13, 15, 17 and 19.
31. The method recited in Claim 27, wherein said apparatus includes a magnetic field sensor and a microprocessor.
32. The method recited in Claim 27, wherein said selected ions are selected from the group consisting of Zn++, Mn++, Cu+, Li+, K+, Mg++
and Ca++.
and Ca++.
33. The method recited in claim 1, wherein said biological subject is a plant.
34. The method recited in claim 1, wherein malignancy of said cells is inhibited by stimulating differentiation of said cells.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US07/437,485 US5045050A (en) | 1989-11-15 | 1989-11-15 | Method and apparatus for the treatment of cancer |
| US437,485 | 1989-11-15 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2029398A1 true CA2029398A1 (en) | 1991-05-16 |
Family
ID=23736650
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002029398A Abandoned CA2029398A1 (en) | 1989-11-15 | 1990-11-06 | Method and apparatus for the treatment of cancer |
Country Status (4)
| Country | Link |
|---|---|
| US (1) | US5045050A (en) |
| AU (1) | AU6592390A (en) |
| CA (1) | CA2029398A1 (en) |
| DE (1) | DE4036770A1 (en) |
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| US5183456A (en) * | 1989-11-15 | 1993-02-02 | Life Resonances, Inc. | Method and apparatus for the treatment of cancer |
| US5131904A (en) * | 1990-05-04 | 1992-07-21 | Richard Markoll | Treatment of arthritis with magnetic field therapy and apparatus therefor |
| US5269747A (en) * | 1990-09-21 | 1993-12-14 | American Medical Electronics, Inc. | Double-transducer system for PEMF therapy |
| US5181902A (en) * | 1990-09-21 | 1993-01-26 | American Medical Electronics, Inc. | Double-transducer system for PEMF Therapy |
| US5195941A (en) * | 1991-01-07 | 1993-03-23 | American Medical Electronics, Inc. | Contoured triangular transducer system for PEMF therapy |
| US6322491B1 (en) | 1992-01-21 | 2001-11-27 | Nu-Magnetics, Inc. | Flexible magnetic insole |
| US5316634A (en) * | 1992-06-16 | 1994-05-31 | Life Resonances, Inc. | Portable magnetic field analyzer for sensing ion specific resonant magnetic fields |
| US5450858A (en) * | 1993-02-02 | 1995-09-19 | Zablotsky; Theodore J. | Lumbosacral belt |
| DE4329884C2 (en) * | 1993-09-06 | 1997-08-21 | Ruhenstroth Bauer Gerhard Prof | Device for influencing those properties of biological material that correlate with the occurrence of certain atmospheric radiation (Atmospherics) |
| US5919679A (en) * | 1994-10-27 | 1999-07-06 | The United States Of America As Represented By The Environmental Protection Agency | Method and apparatus for altering ionic interactions with magnetic fields |
| WO1996039493A1 (en) * | 1995-06-06 | 1996-12-12 | U.S. Environmental Protection Agency | Method and apparatus for altering ionic interactions with chemicals and chemical processes using magnetic fields |
| US5718246A (en) * | 1996-01-03 | 1998-02-17 | Preferential, Inc. | Preferential induction of electrically mediated cell death from applied pulses |
| US5880661A (en) * | 1996-04-01 | 1999-03-09 | Emf Therapeutics, Inc. | Complex magnetic field generating device |
| US6007476A (en) * | 1997-10-22 | 1999-12-28 | Emf Therapeutics, Inc. | Non-particle, non-photonic device and method for affecting angiogenesis |
| US6083149A (en) * | 1997-10-22 | 2000-07-04 | Emf Therapeutics, Inc. | Magnetic field device and method for inhibiting angiogenesis and retarding growth rates of tumors in mammals |
| CA2295134A1 (en) * | 1998-01-15 | 1999-07-22 | Amethyst Technologies, Inc. | Improved pulsed electromagnetic energy treatment apparatus and method |
| EP0966988A1 (en) * | 1998-06-24 | 1999-12-29 | Santi Tofani | Apparatus and method for interfering with pathological cells survival |
| ITPD980191A1 (en) * | 1998-08-04 | 2000-02-04 | Getullio Talpo | EQUIPMENT FOR TREATMENTS ON THE HUMAN BODY WITH VARIABLE MAGNETIC FIELDS. |
| US6149577A (en) * | 1999-03-18 | 2000-11-21 | Emf Therapeutics, Inc. | Apparatus and method for creating a substantially contained, finite magnetic field useful for relieving the symptoms pain and discomfort associated with degenerative diseases and disorders in mammals |
| US7326170B1 (en) | 1999-06-18 | 2008-02-05 | Miller Wendell E | Method and apparatus for restoring or enhancing an ambient magnetic field |
| AT409932B (en) * | 2000-03-27 | 2002-12-27 | Mediscan Gmbh | MAGNETIC FIELD GENERATOR FOR A COIL FOR TREATING HUMAN, ANIMAL OR VEGETABLE TISSUE |
| US6623419B1 (en) | 2002-04-25 | 2003-09-23 | Access Business Group International Llc | Therapeutic back belt and related method of manufacture |
| US20050059153A1 (en) * | 2003-01-22 | 2005-03-17 | George Frank R. | Electromagnetic activation of gene expression and cell growth |
| WO2005117696A2 (en) * | 2004-05-27 | 2005-12-15 | Parker Richard F | Method and apparatus for generating a therapeutic magnetic field |
| DE102005007851A1 (en) * | 2005-02-21 | 2006-08-24 | Siemens Ag | Irradiation apparatus for irradiating a living organism with electromagnetic radiation to affect the biologic structure of the organism |
| US10625089B1 (en) * | 2019-08-15 | 2020-04-21 | Abraham Liboff | System for treatment of Alzheimer's disease using magnetic fields |
| US20220249856A1 (en) * | 2021-02-11 | 2022-08-11 | Dan Dietz | Method of treating tumors and causing full regrowth and regeneration of tissue |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4105017A (en) * | 1976-11-17 | 1978-08-08 | Electro-Biology, Inc. | Modification of the growth repair and maintenance behavior of living tissue and cells by a specific and selective change in electrical environment |
| US4134395A (en) * | 1976-12-29 | 1979-01-16 | Biomagnetics International, Inc. | Method of using magnetic fields to conduct a screening diagnostic examination |
| CA1113156A (en) * | 1979-09-24 | 1981-11-24 | Roland A. Drolet | Electro-magnetic therapeutic system |
| US4428366A (en) * | 1981-05-06 | 1984-01-31 | Alfred B. Kurtz | Electromagnetic apparatus and method for the reduction of serum glucose levels |
| US4528265A (en) * | 1982-05-11 | 1985-07-09 | Becker Robert O | Processes and products involving cell modification |
| US4622952A (en) * | 1983-01-13 | 1986-11-18 | Gordon Robert T | Cancer treatment method |
| IT1159024B (en) * | 1983-06-02 | 1987-02-25 | Ruggero Cadossi | METHOD AND DEVICE FOR THE TREATMENT OF FABRICS AND LIVING CELLS THROUGH ELECTROMAGNETIC FIELDS BUTTONS |
| US4654574A (en) * | 1983-06-29 | 1987-03-31 | Sheldon Thaler | Apparatus for reactively applying electrical energy pulses to a living body |
| AU3825585A (en) * | 1984-01-31 | 1985-08-08 | Trojan Systems Pty. Ltd. | Magnetic coil programme control device |
| CA1192261A (en) * | 1984-02-29 | 1985-08-20 | David J. Stewart | Magnetic biological device |
| US4665898A (en) * | 1984-05-23 | 1987-05-19 | Maxwell Laboratories, Inc. | Malignancy treatment |
| US4548208A (en) * | 1984-06-27 | 1985-10-22 | Medtronic, Inc. | Automatic adjusting induction coil treatment device |
| US4587597A (en) * | 1984-11-19 | 1986-05-06 | Meyers Charles J | Emergency exit light or the like |
| US4932951A (en) * | 1988-03-23 | 1990-06-12 | Life Resonances, Inc. | Method and apparatus for controlling tissue growth and an applied fluctuating magnetic field |
| US4818697A (en) * | 1986-10-27 | 1989-04-04 | Life Resonances, Inc. | Techniques for enhancing the permeability of ions through membranes |
-
1989
- 1989-11-15 US US07/437,485 patent/US5045050A/en not_active Expired - Fee Related
-
1990
- 1990-11-06 CA CA002029398A patent/CA2029398A1/en not_active Abandoned
- 1990-11-08 AU AU65923/90A patent/AU6592390A/en not_active Abandoned
- 1990-11-14 DE DE4036770A patent/DE4036770A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| AU6592390A (en) | 1991-05-23 |
| DE4036770A1 (en) | 1991-05-16 |
| US5045050A (en) | 1991-09-03 |
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| Date | Code | Title | Description |
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| EEER | Examination request | ||
| FZDE | Discontinued |