The Revised Metabolic Oncolytic Regimen
for Effecting
Lysis in Solid Tumors
Anthony G. Payne, N.M.D.,
Ph.D., M.D. (hon.)
_________________________________________________________________________________________
Keywords: antiangiogenic;
anti-anxiety; ATP; cancer; cobalt phthalocyanines; Cone metabolic therapy; COX
pathway; cyclooxygenase pathway; Essential Fatty Acids; experimental cancer
treatment; ferritin-mediated intracellular hyperthermia; gamma radiation; high
protein diet; hyperthermia; hypoxic cell clusters; insulin; iron
phthalocyanines; pulsed magnetic fields; lactate; lipoxygenase; LOX pathway;
melatonin; NDGA; oncolysis; oncolytic; p53 gene; paleodiet; quercitin; solid
tumors; thyroid hormone
_________________________________________________________________________________________
The Metabolic
Oncolytic Regimen is based on the seminal work of former NASA scientist
Clarence Cone, Jr., Ph.D. My permutation of the oncolytic approach to treating
solid tumors was first published during December 1996. Since that time this
species of metabolic therapy has been further refined and modified so as to
make achieving oncolysis more probable. This paper outlines my hypothesis and
the revised (2001) and updated
regimen in its entirety.
Special thanks to Li-Chuan Chen, Ph.D., a former
post-doctoral fellow at the NIH's Center
for Alternative & Complementary Medicine, who provided information and
insights which helped me take the Metabolic Oncolytic Regimen the next
step forward in its evolution. And to Stephen G. Ayre, M.D., and the late
Donato Perez Garcia Y'Bellon, M.D. , both of whom I had the distinct pleasure
of meeting at a NIH sponsored
conference (POMES) in Bethesda, Maryland, for the insights afforded by their
innovative use of insulin and chemotherapeutic agents in the treatment of
cancer (Insulin Potentiation Therapy).
The Metabolic
Oncolytic Regimen is based on an approach to achieving lysis in solid
tumors pioneered by Clarence Cone, Jr., Ph.D. (NASA, retired). Dr. Cone's novel
therapy, which is reflected in patents granted various versions of same [U.S.
patent #s 4,724,230 (1988), 4,724,234 (1988), and 4,935,450 (1990)] essentially
involves manipulating various metabolic and biochemical pathways such that
tumors produce prodigous quantities of lactic acid. This is achieved using a
specific dietary regimen plus various synthetic and natural drugs , e.g,., the
bioflavinoid quercitin is employed to block export of lactate from the tumor
which results in a lethal drop in intratumor pH. [The Cone therapy involves two
treatment phases with a resting or nontreatment interval between them].
The principle shortcoming of the Cone therapy lies in the fact that it is hypoxic clusters within certain solid tumors - and not the entire tumor - which synthesizes and exports lactic acid (Something which came to light after Dr. Cone's original patent application was filed). The Cone therapy is thus very appropriate and quite effective in helping eradicate hypoxic intratumor cell communities. It does not, however, address the lysis of the non-hypoxic regions of solid tumors per se.
The Metabolic
Oncolytic Regimen is a marriage of Cone's basic hypoxic tumor cell lysing
technique with others geared to deal a lethal blow to both hypoxic and
non-hypoxic tumor cells. It also incorporates compounds and therapeutic
techniques which complement the Cone approach (Most of which were not available
and/or widely used when Dr. Cone filed for his patents).
Fifty percent (50%) or more of solid tumors are characterized by specific genetic and extragenetic (intracellular) features that create a therapeutic "window of opportunity" for effecting oncolysis via the manipulation of various metabolic pathways. A brief review of certain aspects of tumor cell biology is needed to demonstrate this. One of the key players in the genesis of solid tumors is the p53 gene [We all inherit a maternal and paternal copy of this particular regulatory gene]. In normal cells the p53 gene complex is not active.However, when cells incur damage viz exposure to ionizing radiation, toxic agents, etc., the p53 genes switch on and begin synthesizing a protein which typically arrests cell growth (thus allowing time for DNA repair) or activates a cellular self-destruct mechanism called apoptosis. When mutations occur in either the maternal or paternal copy of the p53 gene in a tumor cell - but not both - the cell will produce the p53 protein and, in the increasingly hypoxic environment that accompanies tumor growth, undergoes apoptosis. In essence, the oxygen efficit encourages tumor cell lysis. Unfortunately, tumors circumvent this effect by creating new blood vessels (neovascularization) which provide needed oxygen and nutrients. These vessels are usually very leaky such that blood plasma readily infiltrates intracellular spaces. This process generates intratumor pressures that impede blood flow and thereby reestablishes an oxygen deficit.
This picture is complicated by the tendency of tumors to give rise to cells which possess mutations to both maternal and paternal copies of the p53 gene. These cells do not produce the p53 protein and thus multiply unchecked. They are typically the most aggressive and drug resistant cells in a tumor - and tend to thrive in the most hypoxic regions of same [Those cells able to produce p53 protein die off in the hypoxic intratumor microenvironment. Those lacking functional p53 genes proliferate and thus give rise to clusters of like cells within the tumor].
Given this profile, it follows that the most effective therapeutic approach would be to encourage tumor microenvironment hypoxia via interference with angiogenesis (neovascularization). This will facilitate the lysis of tumor cells that synthesis viable p53 protein.
But what about those tumor cells that do not produce p53 protein? Would not encouraging intratumor hypoxia select for especially aggressive tumor cells? It will indeed. Actually, it adds nothing new to the clinical picture as this selection process is well under way early on in tumorigenesis. As we cannot presently circumvent this process, the principle objective becomes one of introducing therapeutic agents and metabolic challenges that have a selective and lethal effect on hypoxic cells.
As the suppression of the neovascularization or angiogenesis mechanism can be effected in a rather straightforward manner via the introduction of antiangiogenic drugs or natural compounds, e.g. thalidomide, possibly certain shark cartilage extracts, etc., we will focus primarily on the metabolic processes unique to tumor cells in the grip of profound hypoxia (and how we can effectively exploit same).
Tumor cells that lack sufficient oxygen to engage aerobic metabolic pathways typically begin to rely on anaerobic ones to supply needed substrate. These cells convert most of their pyruvate to lactate (and not acetyl Coenzyme A [AcCoA]), which is then excreted from same (1-3). This cellular aberration has several consequences: Only a small percentage (5-6%) of the chemical energy in glucose molecules can be liberated and utilized [Glucose is totally oxidized in normal cells]. As a result, the rate at which tumor cells can generate ATP (from glucose via the Respiratory Chain and Acid Cycle) is limited. To prevent cell lysis due to energy deprivation, malignant cells begin to rely on the mitochondrial B(eta)-oxidation of fatty acids to AcCoA (which can then enter the Citric Acid Cycle) and on the enzymatic transformation of amino acids into metabolically useful compounds (4,5).
The
reliance of hypoxic tumor cells on this "alternative" metabolic
pathway can be exploited along these lines:
(a) The oxidative catabolism of free fatty acids and amino acids (via the Respiratory Chain and Citric Acid Cycle) might be inhibited in hypoxic cancer cells via the judicious use of agents which inhibit their availability, i.e., partially inhibit hepatic fatty acid synthesis and keep plasma amino acid levels within the normal range, thus decreasing ATP production;
and
(b) The
ATP that is produced could be rapidly depleted by (the) use of compounds that
stimulate ATPase activity.
The net
effect of a and b (above) should be rather straightforward:
Hypoxic tumor cells will compensate for this compromised metabolic state of affairs by increasing the rate of intracellular glycolysis. This, too, can be exploited by the introduction of substances that interfere with the shuttling of lactate out of the tumor cell. This will cause a drop in the intracellular pH level that will undermine vital cancer cell metabolic processes (6). Tumor cell lysis is anticipated. What is needed then are therapeutic agents and dietary measures that will:
·
Limit the hepatic
synthesis of free fatty acids plus inhibit lipolysis elsewhere in the cancer
patient's
body.
·
Keep plasma amino acid
levels within the range required to sustain general health [Normal cells will
rapidly utilize the amino acids liberated by the catabolism of foods. Excess
aminos - typically the end result of metabolic processes stimulated by the
stress-induced release of adrenal hormones - will be available for use by
cancer cells].
·
Interfere with the transport
of lactate out of the hypoxic tumor cells.
·
Provide sufficient
nourishment and caloric intake to meet the metabolic requirements of normal
cells without supplying excess fats or protein that will be used to meet the
metabolic needs of tumor cells.
The
following are compounds that will help achieve the therapeutic objectives
delineated above for the p53 protein-producing tumor cells, as well as those
which do not synthesis the protein.
The 10-carbon compound limonene has been shown to inhibit
the synthesis of ubiquinone (Coenzyme Q10) in tumor cell mitochondria, thereby
reducing the amount of chemical energy produced to meet metabolic needs (7). It
also blocks protein prenylation, a process crucial to the synthesis of proteins
involved in regulating cell growth and cycling (Coleman et al, in press). Lavender (Lavendula)
oil is rich in limonene.
This compound inhibits ATP citrate lyase, i.e., the
cytoplasmic enzyme that cleaves citrate to produce AcCoA and oxalo-acetate (8).
Numerous animal studies have shown that L-hydroxycitrate significantly
depresses in vivo lipogenesis in a
dose dependent manner in the liver, adipose tissues, and small intestine (9).
This therapeutic activity is of immense clinical value, as tumors release or
bring about the release of lipolytic agents which free up fatty acids for the
synthesis of new tumor cells (McDevitt et al, 1995).
It should be noted that L-hydroxycitrate, in both animal
and human trials, has demonstrated a mild anorexiant effect which might limit
its use in patients with tumor-induced anorexia and cachexia (NOTE: Recent studies indicate that
L-hydroxycitrate may not exert any appreciable weight-reducing effects). However,
L-hydroxycitrate's appetite suppressant effects should be offset by the
administration of exogenous thyroid hormone [Thyroid is an integral part of the
oncolytic regimen]. Update: In recently published clinical trials,
L-hydroxycitrate failed to induce significant weight loss. The anorexiant
effect would appear a nonissue.
Interestingly, the cachexia commonly associated with
malignancy should in many ways be addressed by the Metabolic Oncolytic Regimen. In animal studies, insulin has been
found to drop during certain stages of tumor formation. The MOR includes use of exogenous insulin -
see below (This insures glucose availability to normal cells, as well as
increasing cell membrane permeability - which may potentiate the cytotoxicity
of various agents used in the Regimen);
glucose is often converted to fat before being utilized. The MOR introduces L-hydroxycitrate which
partially inhibits the conversion of glucose and other sugars derived from
dietary carbohydrates to lipids. This glucose is available to provide energy
for normal cells, as well as substate the hypoxic tumor cells will turn into
lactate (Which will be at least partially blocked from being shuttled out of
the tumor cells by quercitin - see below); while most hepatic glucose
processing "plugs into" the Cori Cycle, i.e., glucose from the liver
is transported to the muscles where it is converted into pyruvate and back to
glucose (Then to lactate - which circulates back to the liver and is converted
into pyruvate, then glucose - which leaves the liver and travels back to active
muscles, etc.) The Metabolic Oncolytic
Regimen should appreciably interfere with lactate transport out of not only
hypoxic tumor cells, but active muscle tissue as well, thus "throwing a
monkey wrench" into the Cori Cycle.
The
pineal-synthesized hormone melatonin is a fatty acid transport inhibitor (10).
Depriving tumor cells of metabolically useful fatty acids is an important
component of the MOR.
Concentrated Garlic or Insulin i.m.
Concentrated garlic extract or preferably exogenously supplied insulin [Isophane - slow release]
will elevate the level of circulating (free) insulin in cancer patients (11).
Ths is desirable, as insulin has a pronounced anti-lipolytic effect (12). It
also is increases cell permeability thus making it easier for chemotherapeutic
drugs to have a lethal effect on tumor cells. The physicians who pioneered Insulin Potentiation Therapy (Donato
Perez Garcia , M.D. , his son Donato Perez Garcia y Bellon, M.D., and grandson
Donato Perez Garcia, M.D.) report that the doses of conventional cytotoxic and
other antitumor drugs employed to lyse cancer cells is reduced manyfold (Go to http://www.iptq.com/)
Exogenous
thyroid hormone should contribute to the achieve of desired (oncolytic)
objectives by:
(1) increasing hepatic removal and degradation of
cortisol, which brings about plasma reductions of same; and
(2) stimulating ATPase activity (so as to
"waste" ATP).
The
lipolytic activity of thyroid hormone should be offset by the anti-lipolytic
effects of insulin and prostaglandin E1.
It should be noted that the diet advocated herein (See
Dietary Guidelines section below) which
closely mirrors the paleodiet (Stone Age Diet), has been found to boost thyroid
levels in one published study (University Of Illinois At Urbana-Champaign is
the original source):
http://www.sciencedaily.com/releases/2001/04/010404080611.htm
This bioflavinoid interferes with intracellular mechanisms that transport lactate out of cancer cells dependent on anaerobic metabolic processes [Its interaction with the calcium regulatory protein calmodulin appears to have an added antitumor effect (13)]. When lactate shuttling is compromised intracellular pH falls resulting in cell lysis (apoptosis).
The apoptosis-inducing effect of an acidic pH has support from a study showing that alkalinization of lovastatin-treated tumor cells abolished the cytotoxicity of the drug (14). Lovastatin's cyctotoxicity is linked primarily to its ability to create an acidic intracellular pH. The acidic pH induces the activation of a pH-dependent endonuclease which causes DNA fragmentation. It has been demonstrated that this particular enzyme can be rapidly inactivated by the stimulation of the Na/H antiporter, an acid exporter, with phorbol ester. This strongly implicates an acidic pH and pH-dependent endonuclease in effecting cell lysis (Chen, LC, 1996).
Accordingly,
it seems likely that quercitin-induced lactic acidosis in (glycolytic) tumor
cells may bring about pH-endonuclease activity that leads to tumor cell die
off.
NOTE: Quercitin has been shown to have cytotoxic
effects via such mechanisms as: (a) Arrest of cell progression at the G1/S
interphase (Two studies indicate blockage at the G2/M interphase); (b)
suppression of glycolysis and ATP production; (c) interference with ion pump
systems; (d) interference with various signal transduction pathways (Protein
kinase C, casein kinase II, etc.); and (e) inhibits DNA polymerase B and I
(15). [Quercitin is also an effective 5-lipoxygenase inhibitor. Recently
published studies indicate that arachidonic acid stimulates the growth of
several types of cancer viz-a-viz being metabolized through the 5-lipoxygenase
pathway into 5-HETE series of eicosataenoids (16)].
(If dietary omega 3 intake is low - more below under Fats): Supplementation with a source of
essential fatty acids which, in the context of this cancer treatment approach,
should: (a) Help provide modest levels of those fatty acids required to
maintain general health and; (b) serve as a substrate for the synthesis of
various prostaglandins - PGE1 being of immense value because it inhibits
lipolysis (17). Emphasis to be on a high omega 3 to omega 6 fatty acids intake.
The rationale? Archidonate lipoxygenase (LOX) and their metabolites appear to
play an integral role in mediating growth factors which support tumor cell
proliferation and growth. The LOX pathway may also be a vital component in the
regulation of tumor cell survival and apoptosis (18).
(Liquid) Shark Cartilage
Shark cartilage contains proteins that inhibit tumor-produced collagenases crucial to angiogenesis, as well as a single protein dubbed "cartilage derived inhibitor" (CDI) which blocks endothelial cell migration and proliferation [A crucial pathway in angiogenesis] (19). When tumors are deprived of the ability to form new blood vessels, they fail to thrive and in at least some instances become encapsulated and experience partial or complete lysis (20).
Animal experiments and human clinical trials involving
cartilage extracts in the treatment of various neoplasia carried out by I.
William Lane, Ph.D., et al produced
evidence of efficacy sufficiently compelling to convince FDA officials to grant
an IND [Investigational New Drug] application. NCI sponsored clinical trials
involving Lane's (patented) pharmaceutical grade shark were in the works during
1997, but support was subsequently withdrawn when NCI officials determined the
evidence on hand was not compelling enough to justify pursuing same. The NCI
has, however, expressed a willingness to reverse itself should proponents
produce compelling new evidence of shark cartilage's efficacy (in the treatment
of cancer).
While the evidence to-date concerning shark cartilage's ability to retard or arrest tumor neovascularization may not be copious or indisputably substantive, there is (in the author's opinion) sufficient data to indicate that there is probably "smoke in the woodpile.” According to many experts, shark cartilage is poorly absorbed when taken in the form of a encapsulated powder or as a powder mixed with water or fruit juice. There is a liquid extract version which is reputed to be bioassimilable. NIH sponsored clinical trials involving same are in the works (2001).
It should be noted that bovine cartilage and the soybean isoflavone genistein have both shown antiangiogenic activity. They are not herein recommended due to the fact (that) neither contains antiantiogenic proteins in quantities close to rivaling shark cartilage [Drs. I. William Lane and A. Lee estimate that shark cartilage contains 1,000 more potential antiangiogenic activity per shark than
is true of individual bovines]. (21)
NOTE: There are a number of other antiangiogenic
inhibitors presently undergoing testing in clinical trials. Among those showing
tremendous promise: Interleukin-12, pentosan polysulfate, platelet factor 4,
thalidomide, and TNP. Angiostatin and Endostatin, two fairly new entries in the
antiangiogenic family of drugs, ave produced remarkable results in animal
experiments.Also, tetrathiomolybdate (TM), a pharmaceutical employed to lower
serum and tissue copper levels in persons suffering from Wilson's
Disease, has shown promise in effecting angiogenesis
in Phase I clinical trials involving patients with Metastatic cancer (Clin Cancer Res., 2000 Jan;
(1):1-10)
[Also: Garlic raises endogenous nitric oxide levels, which has an antiangiogenic effect. Published research indicates that garlic boosts the activity of NO synthase, but not owed to its high content of arginine nor to the phytochemical allicin (22, 23)].
Calmative Botanic Formula Plus Auto-suggestion, Cognitive Therapy,
Biofeedback or other Stress-Attenuating Measures
Cancer patients typically present with substantially levated serum free fatty acid and amino acid levels. This is due, in part, to cancer treatment (and response) related fears and anxiety. These powerful emotions trigger adrenal hormone release - the physiological effects of which include activation of adipocyte lipase (resulting in mobilization of free fatty acids) and partial inhibition of protein synthesis, i.e., the plasma amino acids which are normally (readily) utilized by nonmalignant cells for protein synthesis are only partially used resulting in an increase in the availability of amino acids to meet tumor cell metabolic needs.
It is vitally important, therefore, to provide the
cancer patient with anxiolytic phytomedicines or pharmaceuticals plus
supportive psychological therapy (or biofeedback) to minimize fear and
anxiety-related stress [Or provide a referral to a qualified psychologist,
psychiatrist, or other health care professional who can design a comprehensive
stress management program]. Stress can also be attenuated by sexual release in
patients interested in and capable of engaging in same. In my own clinical
experience (informed by published animal and human trials), an extract of Gotu
Kola (Centella asiatica), Kava Kava
Root (Piper methysticum), Valerian
Root (Valeriana officinalis) or
Passion Flower (Passiflora incarnata)
is usually quite effective. One of the more potent anxiolytic/calmative
formulas I have employed in ameliorating stress in cancer patients is a
Traditional Chinese drug called the Zizyphus Combination [Suan-Tsao-Jen-Tang].
In a comparative double blind study, the Zizyphus Combination [250 mgs. TID per
os] were fully comparable to those of diazepam [2 mgs. TID per os].
There was one crucial difference between the two: When taken at bedtime, the Zizyphus Combination did not leave patients drowsy or otherwise impaired upon rising (24).
35% of caloric intake should be in the form of protein (Emphasis on nonplant protein
sources. This should be sufficient to maintain nitrogen balance.) NOTE:
Patients with kidney disease or other serious health conditions should consult
their primary care physician concerning the adviseability of consuming high
protein meals.
Protein with a high "biologic value", i.e., a mix of all the essential amino acids (plus a high proportion of omega 3 fatty acids. Ideally: A 4:1 ratio of omega 3 to omega 6 fatty acids.) Emphasis: Cold water fish.
Approximately 35% of the patient's caloric intake is
to come from complex carbohydrates. However, beans, bread, potatoes, and all
grains should be eaten rarely, if at all.
These foods were introduced only recently (Neolithic period) and the emerging
consensus among many experts in evolutionary nutrition is that our bodies do
not benefit (in the long run) from reliance of such foods.
Raw and
steamed vegetables and fruits should comprize the bulk of the patient’s
carbohydrate intake.
Dietary and supplemental forms of fat should provide 20-30% of (daily) calories. Example: A 70 kg. man will require approximately 2,000 calories/day - 400 calories (44 grams - 20% level) of which should come from fats (Primarily omega-3 rich fatty acid sources/supplement).
Caveat:
The use of fish oils is contraindicated for patients on blood thinners or who
are diabetic.
Caloric and nitrogen intake should be calculated with a mind to meeting the patient's essential metabolic requirements. Allowances must be made, of course, for the increase in metabolic rate wrought by use of exogenous thyroid plus the patient's daily level of physical activity.
Protein
or nitrogen (N) requirements to maintain nitrogen balance can be estimated by
calculating nitrogen losses:
Total N
loss (gm/d) = Nurine + Nstool + Nskin.
Where
Nurine = Range of 1.3-1.7 gm/d
Average
estimated from urinary urea N (mg/d) x daily urine volume (dl) divided by 0.8.
Nstool =
1-2 gm/d
Nskin =
0.3 gm/d
Normal
total N loss = Range of 2.9-5.9 (Mean 4.4) gm/d
Protein
estimated as follows:
N(g) x 6.5
= Protein (grams)
From Internal Medicine, Diagnosis & Therapy
(1988-1989). Edited by Jay H. Stein, M.D., Appleton & Lange, pp. 246-7.
The diet should include plenty of potassium-rich foods. High magnesium foods and drinking water are to be eschewed. The rationale is simple: Increases in potassium ion concentration stimulate the secretion of insulin (Desirable in terms of treatment objectives). Magnesium is inhibitory (25).
The emphasis should be on fruit and protein. The
consumption of fruit after rising is consonant with primate dietary patterns
[Patterns virtually all "higher" primates became adapted to over the
millenia]. In the case of chimpanzees (Pan
troglodytes), our evolutionary siblings (99% identical genome), fruits are
consumed early in the morning thereby providing fructose and other sugars
needed to replenish fasting serum glucose levels. Interestingly, neuropeptide Y
- which stimulates carbohydrate craving - peaks during the early part of the
day. This lend support to the view that the general primate metabolic machinery
has been conserved throughout the course of hominoid and hominid evolution. For
a detailed exploration of diets that are consonant with our species' evolved
nature, peruse The Paleolithic Presciption (1988) and/or visit the
Paleolithic Diet Page at http://www.panix.com/~paleodiet/
Prior
to: 250 mgs. L-hydroxycitrate (20 minutes before the meal)
500 mgs.
quercitin (See note below)
With:
10-30 drops Lavendula oil mixed into fruit juice or water.
After: 2-3 grams concentrated garlic or 5-15 units insulin suspension [Isophane] injected i.m. approximately 30-45 minutes following the A.M. meal. If insulin is used, a glucometer or other method must be employed (by the patient or caregiver) to measure his or her serum glucose level - and monitor same at regular intervals throughout the day. If hypoglycemia occurs, the patient should consume a sucrose rich candy or beverage (26).
1/2 to 1
grain thyroid
Antiangiogenic
drug or liquid shark cartilage
[Dosage depends on the nature of the drug or supplement used, e.g.,
thalidomide, liquid shark cartilage, an extract or preparation consisting
largely of the antiangiogenic proteins, etc.]
Botanic
or pharmaceutical calmative (If needed)
NOTE: As quercitin is very poorly absorbed in the human gut, it is recommended that patients take a more bioavailable form such as water soluble quercitin hydrate or "activated" quercitin [Activated quercitin is a combination of quercitin and bromelin and magnesium ascorbate. According to literature published by a major "activated" quercitin manufacturer/distributor, Threshold Enterprises Ltd. (Source Naturals brand), various clinical studies have demonstrated that vitamin C improves the absorption of quercitin]. Interestingly, the marriage of ascorbate with quercitin packs its own therapeutic punch. To whit: A quercitin-ascorbate blend inhibited HBT squamous cell carcinoma cells in one study (27).
The
emphasis should be on complex carbohydrates and protein.
Prior
to: 250 mgs. L-hydroxycitrate [20 minutes prior to meal]
500 mgs.
quercitin
With:
10-30 drops Lavendula oil mixed into fruit juice or water
After:
If Isophane insulin was not used in the AM, 2-3 grams concentrated garlic.
1/2 to 1
grain thyroid
Omega-3
fatty acid supplement*
Botanic
or pharmaceutical calmative
Antiangiogenic
drug or liquid shark cartilage [See AM
Meal entry]
Melatonin
Complex
carbohydrates and protein foods are emphasized.
Prior
to: 250 mg. L-hydroxycitrate (20 minutes before meal.)
With:
10-30 drops Lavendula oil mixed into water or fruit juice/
After:
If Isophane insulin was not used in the A.M., 2-3 grams concentrated garlic.
Omega 3
fatty acid supplement*
* If
dietary omega 3 fatty acid intake meets the patient's daily intake level (in
grams), there is no need to take an omega 3 fatty acid supplement.
SPECIAL NOTE - For patients who cannot readily obtain sufficient omega-3 fatty acids through the diet: In my experience, patients often find that the most convenient way way of getting supplemental fats is to mix and consume omega-3 rich Flaxseed oil with low fat or non-fat cottage cheese or small quantities of reduced fat peanut or soy butter.
Botanic
or pharmaceutical calmative
Antiantiogenic
drug or liquid shark cartilage [See AM
Meal entry]
Melatonin
(Before retiring)
Low Dose Gamma Radiation Used in Tandem with Lipoxygenase Inhibitors
A recent addition to the Metabolic Oncolytic Regimen is low dose radiotherapy (in tumors
types with a demonstrated susceptibility to same) coupled with the use of
lipoxygenase inhibiting pharmaceuticals or natural substances. This combination
was first suggested to the author by in
vitro research carried out at the Institute of Biophysics in Czechoslovakia
(Academy of Sciences of the Czech Republic). Researchers at the Institute found
that when human carcinoma HS578T and monoblastoid U937 cell lines were treated
with the lipoxygenase inhibitors norhydroguaiaretic (NDGA) and escultein - then
exposed to low dose gamma radiation (1GY) - (3H)-thymidine incorporation and
cell proliferation was suppressed [NOTE: Quercitin compromises lipoxygenase activities
both in vitro and in vivo. The cyclooxygenase inhibitor piroxicam had no effect
(28)].
Additional Supporting Evidence: German scientists treated mice with Lewis cell lung cancer with various combinations of i.p. administered collagenase, cyclooxygenase, and lipoxygenase inhibitors plus radiation. The most effective modulation of tumor growth (2.8 - 3.3. fold increaes in tumor growth delay) was seen in animals treated with a combination of moncycline (collagenase inhibitor)/suldinac (cyclooxygenase inhibitor) plus radiation and phenidone (Lipoxygenase inhibitor)/suldinac plus radiation (29).
NDGA (Nordihydroguariaretic
acid): A General Lipoxygenase Inhibitor and ATP Depleting Agent
NDGA, a chemical compound present in the botanical Larrea tridentata (Chaparral) - once
widely used in various folk treatments for cancer - has shown efficacy in
inducing tumor cell lysis in numerous in
vitro studies. In one laboratory experiment, NDGA and a 12-LOX selective
inhibitor brought about rapid and dose-dependent apoptosis of serum cultured
W256 cells (as well as other tumor cell lines including leukemia) (30). In
another study, NDGA inhibited an ATP sensitive osmolyte channel in hepatoma
cell line HepG2 by virtue of its ability to deplete ATP (31). These properties
make NDGA a compound worth further investigation, especially in terms of its
efficacy when used in tandem with novel cancer treatment approaches such as the
Metabolic Oncolytic Regimen.
CAUTIONARY NOTE: Readers and physicians are
discouraged from utilizing either Larrea
tridentata or purified NDGA in conjunction with the Metabolic Oncolytic Regimen (or any other cancer treatment). During
1992-4 eighteen cases of hepatoxicity were reported to the F.D.A. involving
Chaparral ingestion. Thirteen cases did show clear evidence of liver toxicity
including cholestatic hepatitis (4 persons) with progression to cirrhosis. Two
of the thirteen developed fulminant liver failure that required liver
transplantation (32).
However, there is a newly patented nontoxic extract of
Larrea tridentata which should be
available on the market shortly (U.S. Patent # 6,039,955, March 21, 2000). It
would be entirely approrpiate for cancer patients to use this species of NDGA.
The use of lipoxygenase inhibitors and low dose radiation is a relatively new
area of medical research and to-date has primarily involved cell cultures.
However, the rationale for employing both (where appropriate) is scientifically
credible and consonate with extant knowledge of tumor cell biology. As radiotherapy
is used quite effectively in the management and even eradication of some solid
tumors, patients who elect to undergo the Metabolic
Oncolytic Regimen - in combination with radiotherapy - would be well
advised to discuss the use of a lipoxygenase inhibitor with his/her oncologist.
Admittedly, this is one of the more tenuous component
of the MOR. However, as this paper
represents a synthesis of what has been utilized in clinical practice - with
the hypothetical but promising - I would be remiss not to include it.
Compounds Whose Effects on Various Metabolic Pathways Should Complement
the Activity of the Therapeutic Agents Cited Previously
Orange Peel Oil (Limonene source); azaleic acid (Evidence indicates it interferes with vital biological processes in tumor cell mitochondria) (33); Tirapazamine (3-amino-1,2,4-neozotrizine 1,4 dioxide) - a pharmaceutical that is specifically cytotoxic to hypoxic cancer cells (34). Developed by J. Martin Brown et al at Stanford Medical School, tirapazimine has completed Phase I/ II clinical trials at various centers (1997). The results were encouraging in some forms of cancer, but it is far too early to know if the drug will produce statistically significant increases in survival); Amionoglutethimide – an anxioloytic agent viz its ability to lower adrenal levels. Various studies have shown that this drug blocks adrenal steroidogenesis by inhibiting desmolase conversion to pregnenolone (35); penylacetate phenylacetylglutamine (The end metabolite of this compound is structually similar to glutamine – a preferred metabolic substrate in some tumors. It blocks the uptake of glutamine through ASC amino acid transporter) (36). Also: thrombospondin, various metalloproteinase inhibitors and interferons, transforming growth factor beta, and platelet factor 4 (PF4).
Hyperthermia lowers tissue pH and thus should adroitly
complement the Metabolic Oncolytic
Regimen (At least in cases
involving relatively superficial solid tumors). Interestingly, quercitin
is a hyperthermic sensitizer by virtue of its ability to block lactic acid
transport and heat protein synthesis. Normally tumors develop thermoresistance
via the production of heat shock protein. Quercitin helps circumvent this
process and thus leave the tumor susceptible to hyperthermia therapy [In
cervical carcinoma cells, quercitin did not exert cytotoxic effects at normal
body temperatures, but did potentiate hyperthermia-induced toxicity at 41
degrees Centigrade (105.8 degrees Fahrenheit) (37) ]. If local or regional
heating of a tumor is not feasible owed to disseminated malignancy, whole body
hyperthermia can be induced. One method which has demonstrated efficacy in a
randomized double blind trial at Memorial Sloan Kettering is Mixed Bacterial
Vaccine (Coley's) (38). Another is to employ a hyperthermia chamber such as he
Aquatherm unit being utlized at the University of Wisconsin (The UW Hospital
& Clinic Hyperthermia Project website is: http://www.medicine.wisc.edu/sections/medonc/wbh).
The
following are two admittedly very theoretical approachs to inducing intratumor
hyperthermia sufficient to effect tumor cell lysis.
1) Ferritin-mediated
electromagnetic hyperthermia
In a paper published in the journal Medical Hypotheses [(2000) 54(2),
177-179)], the authors suggest that an alternating magnetic field no greater
than ~ 100 KHz (kilohertz) should induce heating of intracellular ferritin
sufficient to lyse tumor cells without adversely effecting normal tissues and
cells. The iron core in ferritin is
strongly paramagnetic and thus can be utilized to produce heat via the Brown
and Neel effects (respectively). Since ferritin is often found at higher levels
in neoplastic cells than normal ones, this makes achieving hyperthermia by way
of an externally applied high frequency magnetic field very probable.
Japanese, German, and other researchers have published many papers indicating that intracellular hyperthermia sufficent to achieve cell lysis is possible employing magnetite cationic liposomes and other 'magnetic fluids.' (39,40). The ferritin mediated approach, while different from the aforementioned, retains many features in common and should be explored in the laboratory and in well controlled clinical trials.
A possible permutation to this approach which occurred
to the author is this: Introduce magnetotactic bacterial vectors in vivo which have been genetically engineered or artifically
selected to seek out and bind to specific tumor cell antigens. If achievable,
the magnetotactic bacteria might provide sufficient iron once inside tumor
cells to make achieving eletromagnetic heating more certain.
NOTE: Interestingly, there is published animal studies
indicating that hyperthermia used in tandem with glucose administration
enhances the tumor lysing impact of the former (41, 42). As the Metabolic Oncolytic Regimen is geared,
in part, to boost intratumor glucose levels (thus raising the rate of lactate
synthesis), the use of the MOR in
combintion with hyperthermia is logically compelling.
It should be noted that researchers at Jefferson Medical College found that i.v. and iv. plus oral glucose effectively lowered tumor extracellular pH in 17 nondiabetic cancer patients at Henan Tumor Hospital. These scientists were looking into boosting tumor acidification as a potential thermoradiosensitizer (43).
2)
While dwelling on the
merit of inducing electromagnetic intracellular heating using 'magnetic fluids'
and/or ferritin, it occurred to me that iron
and cobalt phthalocyanines might be exploited to achieve sufficient
intracellular hyperthermia to lyse tumor cells.
The phthalocyanines are being employed in photodynamic oncolytic therapy (research) with varying degrees of success. Since these compounds are selectively retained by tumors, resist photochemical and chemical breakdown, are essentially non-toxic, and can be synthesized readily with a neutron-activated nuclide (boron compounds) and as conjugates with epidermal growth factor (thus making tumor cell targeting more contain), they are very attractive to cancer researchers (44).
Setting aside the photodynamic use aspect, there is the electromagnetic heating potential of the iron and cobalt-bearing phthalocyanines (PCs) to consider. As mentioned above (#1), iron is very paramagnetic. Cobalt, while less responsive to a magnetic field than iron, might still be of merit in instances where use of iron might boost tumor growth in micrometasteses which are strongly suspected to exist but not confirmable using extant detection technology.
Cautionary note: Copper plays a role in angiogenesis and thus may be
contraindicated save as a heroic measure, especially in patients on
tetrathiomolybdate (TM).
In his
patent application, Dr. Clarence D. Cone, Jr., reported that partial to
complete oncolysis was achieved in patients with a variety of cancers. Here is
a sampling:
Female
age 52 Tongue
Male age
57 Throat
Male age
70 Stomach
Female
age 47 Cecum
Female
age 54 Colon
Male age
45 Breast
Female
age 57 Ovary
Female
age 60 Uterus
Male age
65 Kidney
Male age
59 Prostate
Male age
49 Pancreas
Male age
49 Lymphoma
Male age
47 Melanoma
Female
age 48 Basal Cell (skin)
Male age
66 Leukemia
Male age
50 Bone Sarcoma
Select
Case histories:
Female, age 57. Diagnosed with infiltrating ductal cell carcinoma of the breast (Terminal inflammatory stage). Multiple biopsied specimens confirmed diagnosis. Prior treatments: Surgery, radiotherapy (4000 rads), intensive chemotherapy (Mitoxin). Treated using the Cone regimen: By day 20 the tumor was reduced 70%. By day 75 the patient was reported to be in good psychological condition and active while remaining on the regimen (Phase II).
Female, age 54. Diagnosed with advanced colon adenocarcinoma, extenstive liver metastases. Confirmed by multiple biopsied specimens and ultrasound scans. Classified as inoperable. Had no standard cancer treatments. By day 16 on the Cone regimen the tumor was reduced by 87.5%. By day 12 of Phase II treatment the tumor was reduced 83.5% [The starting size of the tumor in Phase II was bigger than in Phase I. It is not known whether the tumor grew during the resting interval between treatment phases. Note: There is no resting or non-treatment phase in my version of the Cone metabolic therapy - author].
Male, age 57. Diagnosed with epidermoid carcinoma of the larynx, metastasized to the left neck. Confirmed by multiple biopsied specimens, CT scans and xerograms. No standard cancer treatments undertaken. By day 13 on the regimen the tumor was reduced by 88%. After the resting interval and at the start of Phase II, the tumor grew back to 4 cms. By day 13 the tumor was non-palpable.
Male, age 59. Diagnosed with (moderately differentiated) Metastatic adenocarcinoma of the prostate. Confirmed by multiple biopsied specimens, cytoscopy and bone scans. Treated prior to undergoing the Cone regimen with laetrile, vitamin A, oral enzymes, hormone therapy, and surgery (TURP). By Day 22 of Phase I the patient was asymptomatic. At the start of Phase II the prostate was enlarged and very hard. By day fifteen the patient was in excellent condition and asymptomatic. Prostate size was reduced to normal.
Two select but representative cases of patients who utilized the Metabolic Oncolytic Regimen
Male, age 59. Diagnosed with squamous cell carcinoma
(4 cm. tumor - lower lobe - left lung. Metastases to the lymph nodes and
mediastinum. Diagnosis confirmed by CT scan, biopsied specimens, and endoscopic
examination of the tumor. Classified as inoperable and terminal, the patient
elected to forego conventional treatment and undergo the Metabolic Oncolytic Regimen.
By the 26th day on the Regimen, lymph nodes were no longer palpable and tumor in left lung was 95% obliterated. Patient achieved full remission and is now 7+ years post-diagnosis.
Female, age 38. Diagnosed with oral cancer (squamous
cell) with metastases to the larynx and both lungs. Diagnosis confirmed by
multiple biopsied specimens. Patient declined surgery, chemo- therapy and
radiotherapy, as these offered little but hope of cure. After receiving
material on the Metabolic Oncolytic
Regimen, patient chose to undergo same (Her oncologist agreed to supervise
her treatment and monitor her progress or lack thereof). By the 43rd on the Regimen, tumors at all cites were
reduced an average of 78%. By day 91, no evidence of cancer could be detected
by biopsy or CT scan. Patient has been in remission for 10+ years to-date.
In at least some instances the dramatic responses seen
in patients who had standard therapies prior to commencing either the Cone
therapy or the Metabolic Oncolytic
Regimen are probably due (in large part) to same. What is interesting is
that there were good responses, i.e., partial and total remission, in patients
who had no standard cancer therapy prior to undergoing the Cone regimen and my
permutation (respectively).
The Metabolic
Oncolytic Regimen is still very much in its earliest developmental stages
(1988-present). It must be stated that there were treatment failures on the
Cone therapy and among patients on my version. This is not unexpected, as no
cancer therapy - standard or non-standard - always effects tumor lysis (Partial
or complete). Biomedical researchers
and research-oriented naturopathic, osteopathic and allopathic physicians are
invited to acquaint themselves with and employ this species of metabolic
therapy in the treatment of various solid tumors.
Since this is admittedly a very experimental approach to effecting oncolysis, it is hoped that
the MOR will be used either as an
adjunctive measure in tandem with more established oncolytic methods or, in the
case of end stage cancer patients, as a heroic measure possibly employed in
concert with other promising therapeutic agents or techniques.
I would urge those who use the MOR diligently accrue and freely communicate their findings and
observations with me (and any interested researcher or clinician). If the data
provided indicates a statistically significant response in one or more types of
cancer, i.e., average survival times greater than rates reported of other
therapies on such databases as SEERS, etc., justification will exist to pursue
funding of a more formal clinical investigation.
Update & Reiterated Request: Feedback from
1997-present from physicians who have utilized the MOR has been disappointingly scant. It is hoped that those who
elect to utilize the MOR in treating
patients with solid tumors will do follow-up and report treatment failures and
successes to me by e-mail or regular mail (contact addresses below)
Dr. Anthony G. Payne was an instructor at Teikyo University of Science & Technology (Toyko, Japan) until late 1999. In early 2000 he became an instructor at the Minami-Atami ALS School, Atami-shi, Japan.
Payne's original paper on the Metabolic Oncolytic Regimen, which appeared in the Townsend
Letter for Doctors (December 1996), earned him 2 medals in medicine and an
honorary M.D. degree in recognition of its therapeutic potential [Open
International University's 1997 Royal Order of Physicians Gold Medal in
Medicine and Scientist of the Year].
Dr.
Payne and his wife, Sachi, reside in the Tokyo area of Japan.
Payne
can be reached most readily by e-mail at mailto:ExpatriateWizard@japan.co.jp.
Dr. Payne's
mailing address is Tanokura 2F, 1017-1 Shimotaga, Atami-shi, Shizuoka,
413-0102, Japan.
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Original
paper copyright 1996 by Dr. Anthony G. Payne. All rights reserved.
Revised edition
copyright 2001 by Dr. Anthony G.Payne. All rights reserved.
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