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Field of the Invention
This invention relates to the field of cancer treatment. More specifically
the invention relates to an improvement in the timing of and the
application of a cancer treatment mode.
BACKGROUND OF THE INVENTION
A safe and effective cancer treatment has been the goal of investigators
for a substantial period of time. Such a technique, to be successful in
the destruction of the cancer cells in situ, must be selective in effect
upon the cancer cells and produce no irreversible damage to the normal
cells. In sum, cancer treatment must selectively differentiate cancer
cells from normal cells and must selectively weaken or kill the cancer
cells without affecting the normal cells.
It has been known that there are certain physical differences that exist
between cancer cells and normal cells. One primary physical difference
that exists is in the temperature differential characteristics between the
cancer cells and the normal cells. Cancer cells, because of their higher
rates of metabolism, have higher resting temperatures compared to normal
cells. The normal resting temperature of the cancer cell is known to be
37.5.degree. Centigrade, while that of the normal cell is 37.degree.
Centigrade. Another physical characteristic that differentiates the cancer
cells from the normal cells is that cancer cells die at lower temperatures
than do normal cells. The temperature at which a normal cell will be
killed and thereby irreversibly will be unable to perform normal cell
functions is a temperature of 46.5.degree. Centigrade, on the average. The
cancer cell, in contrast, will be killed at the lower temperature of
45.5.degree. Centigrade. The temperature elevation increment necessary to
cause death in the cancer cell is determined to be at least approximately
8.0.degree. Centigrade, while the normal cell can withstand a temperature
increase of at least 9.5.degree. Centigrade.
Based upon the foregoing, a cancer treatment method has been disclosed by
the applicant in his U.S. Pat. No. 4,106,488 (the contents of which are
incorporated herein by reference) which involves inducing the selective
`death` of cancer cells in a host organism by introducing minute
paramagnetic, diamagnetic or ferromagnetic particles to the organism
intravenously, and inductively heating the phagocytized particles,
utilizing a helical coil surrounding the host and a high frequency
alternating electromagnetic field provided by an electronic oscillator,
the heating being effected to raise the intracellular temperature of
affected cells sufficiently to cause cell death. The treatment relies
inter alia upon certain known differences in normal and abnormal cells, in
particular the enhanced ability of cancer cells to phagocytize particulate
material, and their lower temperature threshold for necrosis as detailed
above.
This treatment has been found effective in the selective removal, without
surgery, of primary tumors in host organisms, including spontaneously
generated tumors recognized to be more difficult objects of therapy. The
method offers particular promise in the case of metastatic cancer where
the metastatic sites, are inoperable and/or poorly dealt with through
chemotherapy, since the Gordon treatment is effected from without the host
and may be applied to any region without significant deleterious effect on
surrounding normal tissue
Now it has nevertheless been necessary, in further studies, to refine
several aspects of the treatment protocol as disclosed in U.S. Pat. No.
4,106,488 to accomplish the particularized goal for an individual
treatment with greater certitude, accuracy and flexibility. The
implementation of this improved treatment method in part utilizes
inventive aspects which are the subject of other applications for U.S.
Letters Patent by the same inventor as recited hereinafter. For example, a
fuller understanding of the technology underlying the Gordon treatment
reveals the operation of subtle mechanisms which can themselves become a
contributing factor in the course of treatment. Thus, the generation of
intracellular substances such as interferon may be stimulated or enhanced
during, or as a result of treatment, as disclosed in copending and
commonly assigned application Ser. No. 418,298 of the same inventor,
incorporated herein by reference.
SUMMARY OF THE INVENTION
The present invention resides principally in a process for treating a host
organism including a cell population constituting an invasive abnormality
comprising introducing within the host phagocytizable particles capable of
being inductively heated in response to an imposed high frequency
alternating electromagnetic field where the time of treatment (to effect
said inductive heating) is correlated with the maximum responsiveness of
particles in the tissue, the object of immediate treatment, as measured by
the magnetic susceptibility of the intracellularly localized particles
within such tissue. The invention is grounded in the recognition that as
various substances are metabolized within a cell, their magnetic
characteristics, such as magnetic susceptibility vary.
In particular, the present invention relates to a process for the treatment
of cancer in at least one region of host organism containing cancer cells
and normal cells without substantially damaging living normal cells
comprising:
providing to a host organism minute particles capable of being inductively
heated and of a size capable of being absorbed into cancer cells,
determining, after a period of metabolic time, the magnetic susceptibility
of the particles with said region,
subjecting the organism to an alternating electromagnetic field to
inductively heat said particles at that point in metabolic time when the
maximum difference in magnetic susceptibility between the cancer cell and
normal cells within said region occurs, and
continuing the inductive heating of said particles to attain an increase in
intracellular temperature to selectively kill the cancer cells.
In a further embodiment the subject invention provides a process for the
treatment of cancer in at least one region of a host organism containing
cancer cells and normal cells without substantially damaging living normal
cells comprising: providing to the host organism minute encapsultated
tumoricidal material, said encapsulating material capable of being removed
upon entering the cancer cell, determining after a period of metabolic
time, the magnetic susceptibility of the particles with said region,
subjecting the organism to an alternating, oscillating or pulsed
electromagnetic field at that point in metabolic time when the maximum
difference is magnetic susceptibility between the cancer cells and normal
cells occurs thereby removing said encapsulating material and releasing
said tumoricidal material within the cancer cells.
According to this embodiment, the release of the tumoricidal material is
effected by melting or vibrating the encapsulating material thereby
releasing said tumoricidal material. Particularly useful tumoricidal
material includes antibodies, radioactive isotopes, and chemotherapeutic
agents such as 5-flurouracil, nitrogen mustard, actinomycin D,
methotrexate, cytoxan and vincristine.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1A illustrates the relationship of magnetic susceptibility to particle
uptake with time.
FIG. 1B illustrates the difference in magnetic susceptibility between two
hypothetical cell populations.
DETAILED DESCRIPTION OF THE INVENTION
The use of magnetic susceptibility as a particle probe affords the
advantage of basing the treatment level and timing upon a functional
magnetic parameter directly related to inductive heating rather than upon
only a potentially functional parameter, i.e., the mere physical presence
of the particles. The use of magnetic susceptibility as a particle probe
at lower energy levels also affords a more sensitive tool because the
magnetic susceptibility is responsive to the interface between the
particles and their environment.
As a result, the point at which normal and abnormal cells exhibit the
greatest disparity in effective particle population in the region probed
can be pinpointed accurately, establishing the optimum period for
treatment relative to maximum preservation of the normal cell population
with selective necrosis of the greatest number of abnormal cells.
Although the magnetic characteristic of magnetic susceptibility has been
selected for detailed discussion herein. The invention also contemplates
the use of the magnetic characteristics such as magnetic permeability, or
magnetic moments when sensed with the appropriate sensing devices.
In the sensing phase, magnetic susceptibility is used diagnostically, over
a period of metabolic time, as described and claimed in copending and
commonly assigned application Ser. No. 468,644 of the same inventive
entity, incorporated herein by reference. Thus in the instant application
of magnetic susceptibility the particles are periodically monitored to
provide for the determination of that point, in sensed metabolic time, at
which selective localization and optimal susceptibility of the particles
within certain tissues, organs, or even within individual cells has been
achieved. Taken with other indicia, it is possible then to establish an
optimum treatment period, again by referencing the maximum particle
responsiveness in the treatment region.
Magnetic susceptibility has also been used heretofore in connection with
the Gordon treatment, as disclosed in U.S. Pat. No. 4,163,683, where
magnetic susceptibility measurements are correlated with temperature (an
interdependent variable) in accomplishing the related induction heating
step controllably. There is no recognition, however, that the values for
magnetic susceptibility, independent of the induction heating step or the
imposition of an electromagnetic field can be usefully correlated (to
maximization of particle concentration) with time to optimize treatment
effectiveness, as demonstrated herein.
Thus, in accordance with the present invention, a developing plot of
magnetic susceptibility of the region of the host organism sensed (by
sensitive magnetic sensing equipment such as a vibrating magnetometer, a
squid magnetometer or a fluxgate magnetometer) with elapsed time is
examined (and if computer assisted, the plot is projected employing an
appropriate algorithm), and the one or more maxima (representing maximum
relative susceptibility of particles in abnormal vs. normal tissue) are
selected for application of the induction heating step. Such sensing may
be accomplished without application of the electromagnetic field, or if
the treatment capability is concurrently applied, temperature effects if
any are factored out of the readings, and resultant plots.
Diagnostic mapping as originally contemplated involved a constant low power
trace, and a determination of particle location and concentration by
differential comparison of mappings taken over a time interval.
Unfortunately, such an approach tends to reflect events, specifically the
concentration of particles, which have already occurred. By definition,
the optimum treatment time cannot be ascertained in this manner.
To further illustrate the attendant advantage of the subject invention
reference is made to FIG. 1. FIG. 1A depicts the relationship between
magnetic susceptibility and particle uptake in cells. The magnetic
susceptibility data was extracted from copending application U.S. Ser. No.
468,644 wherein the magnetic susceptibility represents a measurement of
the induced magnetic moment in relation to the magnetic field strength.
The uptake curve is inferred from the analysis of histological examination
of tissue slices, the photomicrographs of which indicate the presence of
particles for periods of weeks after injection.
It is clear that subjecting an organism to treatment at point A is much
preferable than at point B since treatment during a period of high
magnetic susceptibility allows for a more efficient response to
alternating magnetic field. If, however, particle uptake were to be used
as the treatment criterion point X.sub.1 and X.sub.2 would be given equal
consideration as representing a period of maximum particle uptake. The
application of equal amounts of energy at point X.sub.1 and X.sub.2 would
result in a far less effective treatment due to the less than optimal
state of the particles at point X.sub.2
FIG. 1B illustrates another aspect of the instant invention. FIG. 1B
depicts the relative magnetic susceptibility between cell populations. The
difference in timing could result from a difference in particle uptake, a
difference in the rate of metabolism of the particles or a combination
thereof. It is clear that treatment at point C would likely affect the
first population to a greater extent then the second, compare points
Y.sub.1 and Y.sub.2. Conversely treatment at point D would likely have an
opposite effect (compare point Z.sub.2 with Z.sub.1).
As with any treatment, the first consideration is the condition of the host
organism, or patient, in all of the medically recognized respects, thus
providing sufficient information to permit the requisite targeting of a
selective treatment mode. In the case of invasive abnormalities and
especially cancer, it is naturally desirable to locate the primary sites,
or the metastatic site for further treatment, and this may be accomplished
as aforesaid, by using the Gordon methodology itself, as described in
fuller detail hereinbelow, employed in a low energy detection mode.
In order to provide a suitable frame of reference in which to fully
understand the refinements disclosed herein, the treatment regimen may be
construed to be comprised of pre-treatment, and post-treatment phases
and/or considerations. It is recognized, of course, that inherently an
operation in one phase will necessarily affect other phases since the
regimen is highly integrated.
The choice of particle type can be highly significant to effective
treatment, particularly where subcellular localization or other subtle
differentiations in metabolic activity, for example, are conveniently
utilized to maximize particle uptake in the region selected for the Gordon
treatment. Suitable particles and exemplifications of selection parameters
are disclosed and examined in copending and commonly assigned application
Ser. No. 464,870 of the same inventor, incorporated herein by reference.
Although metabolizable particles are especially useful, metabolically
inert particles which are still able to be magnetically mapped, may also
be usefully employed.
Furthermore, the pre-treatment stage can be managed in such manner as to
maximize particle uptake. In particular, a metal deficient diet will aid
in assimilation, transport and localization of a particle based upon the
needed metal. In the same sense, the choice of particle suspension can be
important, e.g., selection of ionic character or level, or pH in the
preferred colloidal vehicle.
Once the particles have been introduced into the host organism, they are in
a dynamic state due to the action of the extracellular, and intracellular
environment to which they are exposed. In this latter respect, it will be
understood that from assimilation through execretory function, body
mechanisms related to the character of the particles' chemical and
physical characteristics (including elemental form, ionic character, size,
shape, reactivity, biofunction, etc.) as well as the particles'
participation in cellular-function or migration through related metabolic
pathways, operate to provide a certain traceable sequence of particle
locations with the passage of time. Such a determination of the location
and metabolic state of the particles may be made at energy levels
sufficient to sense the presence of the particles but insufficient to
effect any meaningful induction heating.
In a particularly advantageous aspect of the methodology, the chemical
constitution of the particle embodies a radioisotope, antibodies or
chemotherapeutic agents or metabolic precursors thereof in free or
encapsulated forms intended for delivery and application in the region
also to be treated by induction heating, in order to achieve a certain
synergy of action.
In accordance with a preferred embodiment of the invention the
characteristics of the imposed field are selectively varied, in contrast
to the essentially invariant alternating electromagnetic field previously
disclosed. Thus, the wave shape may be modified for a given treatment or
varied within a given treatment in such a manner to change frequency or
amplitude. The field may even be maintained in a static form and then
alternated, in one sequence or an iterated series thereof.
It has been appreciated that the imposition of a localized, static field
may be used to enhance particle uptake as well as increase the efficiency
of energy absorption form the alternating field applied during the
treatment phase.
Conveniently, where a static field is imposed, the magnetometer
measurements are made periodically, during scheduled interruptions in the
generation of the field until the projected plot of magnetic
susceptibility vs. time approaches a maximum for the targeted treatment
region, whereafter the field characteristics are modified for the selected
treatment, e.g., to a higher energy high frequency alternating
electromagnetic field. It will of course be understood that magnetic
susceptibility measurements may also be made during interruptions in the
high frequency field in the treatment phase.
In another embodiment the application of the localized static field may
occur concurrently with the application of an alternating, oscillating or
pulsed electromagnetic field. That is to say, the localized static field
may be susperimposed on the host organism while the alternating,
oscillating or pulsed field is also being applied.
Such measurements may be used to provide correlations with induced
treatment temperatures, as described in Gordon U.S. Pat. No. 4,136,683
although this does not constitute part of the present invention, per se.
Reference to magnetic susceptibility plotting mediate the treatment phase
may of course be augmented or for that matter supplanted by plots over an
extended time, particularly where assimilation and localization of the
particles requires such a time frame, in a metabolic sense, or for change
of ionic condition with diet or fluid intake, or development of modified
hormonal levels, etc.
When the inventive treatment is in conjuction with chemotherapeutic agents,
there are attendant advantages in correlating the introduction of the
chemotherapeutic agent to the treatment region (whether introduced by
ingestion, etc.) to the induction heating such that the actions of the
agent is coordinated with the effect of such treatment.
Thus, in particular cases, the chemotherapeutic effect may precede or
follow the induction heating to augment the treatment. It will be
appreciated that the chemotherapeutic agent may form part of the
constitution of the particles used for the induction heating such that the
active element is released at a tumor site. Such particles are disclosed
in the application Ser. No. 464,870 referred to above.
Post-treatment may involve the reverse phenomenon, as described in the
pre-treatment phase where the provision or body fluids, or diet is
employed to deliver substitute materials aiding in the excretion of the
particles supplied for treatment.
The application of chelating therapy to facilitate the sequestering and
ultimate excretion of the particles is not ruled out by the above
procedure, although such therapy is not considered to be a part of the
subject invention per se.
Reference herein to tissue, organ or cell population is intended in its
most embracive and comprehensive sense, referring in general to the region
of the host organism affected by the invasive abnormality, or the
treatment region, as the context requires.
To further illustrate the operation of the subject procedure, the following
treatment scenario is provided.
The subject receives an intravenous injection of colloidally suspended
inductible heatable particles, such as iron porphyrin (FeTPPS.sub.4) at a
dosage of 10 mg/kg. Magnetic susceptibility mapping measurements are made
periodically to follow the distribution of the particles within the body.
The subject is then exposed to a static magnetic field in the range of 500
gauss to 80 kilogauss, the exact exposure being determined by the
practitioner. This exposure acts to enhance uptake of the particles in the
desired treatment area as well as to increase the efficiency of subsequent
energy absorption. Measurements of the magnetic susceptibility may be made
and recorded utilizing magnetometry equipment such as a "Squid" or
flux-gate type. When the magnetic susceptibility of the particles in the
treatment area relative to surrounding tissue is at a peak, the subject is
exposed to an alternating electromagnetic field as described in applicants
U.S. Patent No. 4,106,488. The static magnetic field of 500 gauss to 80
kilogauss is preferably applied immediately prior to the application of
the alternating electromagnetic field to optimize energy delivery to the
particles since the acquisition of magnetic moment and alignment help to
enhance the effect of the alternating electromagnetic field. Although not
wishing to be bound by the following, the applicant suggests that the
enhancement may be the result of:
(a) the creation of an environment more favorable for the intracellular
absorption of particles, and/or
(b) the orientation of the particles with configurarions for better
subsequent absorption of electromagnetic energy, and/or
(c) the creation of an environment fostering intracellular migration of
particles towards the nucleus thereby increasing the efficacy of
treatment, and/or
(d) the fostering of the clustering of particles which result in greater
subsequent energy absorption.
Regardless of the explanation proffered, the subject is treated when the
magnetic susceptibility is greatest in the treatment area relative to
other surrounding tissues and when the particles are in the optimum
relative electromagnetic energy absorption state to be inductively heated.
Hence the target area will be selectively treated while the surrounding
tissue will be subjected to the least amount of damage.
Chelating agents such as desferroxamine may be utilized to enhance
secretion of the particles after treatment. Chloroquine or other similar
agents may also aid in iron secretion as well.
Although the effective electromagnetic fields referred to herein have been
characterized as alternating electromagnetic fields, there is no evidence
which would preclude the use of electromagnetic fields of the oscillating
or pulsed type and such fields are contemplated by the subject invention.
Thus, the subject invention not only provides an effective method for
monitoring the treatment phase so as to allow for treatment techniques
based upon limited increases in temperature (i.e., rises in temperature of
9.5.degree. C), but also provides for an additional treatment technique.
In this further embodiment, since the subject invention provides a means
for specific particle distribution and a sensing of the responsiveness to
the various treatment fields, high temperature treatment modalities are
also possible. The 9.5.degree. C. limitation as discussed supra is, of
course, predicated on the case situation in which particle distribution,
magnetic state, and orientation were equal in all cancer cells and normal
cells under the treatment conditions. However, employing the improved
methods of the subject invention thereby affecting specific particle
distribution, orientation, differential magnetic susceptibility, timing
and other parameters described herein, between the cancer cells and the
normal cells within the target area, increases in the intracellular
temperature up to 100.degree. C. are possible without substantially
damaging the surrounding normal cells.
Irreversible cell death and biological alterations are induced by the
energy input to the particle and thereupon to the interior of the cancer
cell. Thus the same energy input may be accomplished by application over a
long period of time with a consistant small temperature rise (8.degree. to
9.degree. C. for 10-20 minutes) or when the same total amount of energy is
applied over a short period of time a higher temperature results
(100.degree. C. for a few seconds).
Obviously, timing and energy parameters may be adjusted to provide a
spectrum of intracellular temperature which may be utilized depending upon
the treatment appropriate in specific cases.
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