Anthony G. Payne, N.M.D., Ph.D., M.D. (hon.)
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).
Body of Paper
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).
The Hypoxic Cells’ Dependence on Anaerobic Processes
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;
(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)].
Essential Fatty Acids
(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 patients 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 DAILY ONCOLYTIC REGIMEN
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)
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: A Useful Therapeutic Adjunct
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.
Two Novel Theoretical Methods of Inducing Intratumor Hyperthermia
The following are two admittedly very theoretical approachs to inducing intratumor hyperthermia sufficient to effect tumor cell lysis.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).
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).
Clinical Efficacy – Cone Metabolic Method
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)
Author Background Contact InformationDr. 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.
- Racker et al, Science, 1981, # 209, pp. 263.
- Spencer, TL et al, Biochem. J. 1976, # 154, pg. 405.
- Belt JA et al, Biochem., 1979, # 18, pg. 3506.
- Alberta B et al, Molecular Biology of the Cell 2/e, Garland Publishing, NY. 1989.
- ‘Anticancer Agents in Orange Peel Oil’, Cancer Watch, June 2, 1993, Vol. 2.
- Watson J et al, Biol. Biochem., Vol. # 135, pp. 209-217.
- Lowenstein JM, ‘Effect of (-)-hydroxycitrate on fatty acid synthesis by rat liver in vivo’, J. Biol. Chem., 1971; 246(3):629-32
- Sauer LA, Dauchy RT, and Blask DE. ‘A novel mechanism for the regulation of tumor growth in vivo: situ’. Proc. Amer. Assoc. Cancer Res. 37:224, 1996
- Bever, BO and Zahand, GR. ‘Plants and Oral Hypoglycemic Action’, Qtrly. J. Crude Drug Res., 1979, #17, pp. 139-196
- Review of Physiological Chemistry, Lange Medical Publications, 1973, 14/e, pg. 489.
- ‘Quercitin Interacts with Calmodulin, A Calcium Regulatory Protein’, Experimentia, 1984, 40:184-185.
- Perez-Sala D., Callado-Escobar D, and Mollinedo, F. ‘Intracellular akalinization suppresses lovastatin-induced apoptosis in HL-60 cells through activation of a pH-dependent endonuclease’ , J. Biol. Chem., 270:6235-6242, 1995.
- Oho, K and Nakane, H. ‘Mechanisms of inhibition of various cellular DNA and RNA polymerases by several flavinoids’. J. Biochem. 108: 609-661, 1990.
- Ghosh J, Meyers CE. Biochem. Biophys. Res. Commun., 1997 June 18, Vol. # 235, pp. 418-423
- Review of Physiological Chemistry, op cit, pg.288.
- ‘Angiogenesis and its inhibitors’, Cancer Watch, Vol. 3, Nov. 1994, pg. 169.
- Tang GD, Honn J., J. Cell Physiol., August 1997, Vol. 172, pp. 155-170.
- ‘From Ideas To Trials: The Story Behind Lane’s Shark Cartilage’, Altern Ther., Vol. 1, #5, Nov. 1995, pg. 26
- Holt, Stephen. ‘Nutraceuticals Angiogenesis’, Altern Complem. Ther., June/July 1995, pg. 244.
- Pipili-Synetos E, Skkoula E, Haralabopoulos G, Andriopoulou P, Persisteris P, Maragoudakis ME. ‘Evidence that nitric Oxide is an endogenous antiangiogenic mediator’, British J. Pharmacol., 1994
- Das I, Hirani J and Sooranna S. ‘Arginine is not responsible for the activation of nitric oxide synthase by garlic’ . J. Ethnophamacol., 1996 July 26, Vol. # 53, pp. 5-9.
- ‘From Idea to Trials: The Story Behind Lane’s Shark Cartilage’, op cit, pg. 443.
- ‘Suan-Tsao-Jen-Tang v. Diazepam: A Controlled Double Blind Study in Anxiety’, Internl. J. of Clin. Pharmacol., Ther. Toxicol., 24(12): 6, pp. 49-50, 1986.
- Review of Physiological Chemistry, op cit, pg. 443.
- Kandaswami C, Perkins E, Solonivk DS, Drzewiecki G, and Middleton, Jr., E, ‘Ascorbic acid-enhanced antiproliferative effect of flavinoids on squamous cell carcinoma in vitro’, Anticancer Drugs 4:91-96, 1993.
- Hofmanova J, Musilova E, and Kozubik A. ‘ Suppression of human cancer cell proliferation by lipoxygenase inhibitors and gamma-radiation in vitro’, Gen. Physio. Biophys. 15: 317-331, August 1996.
- Teicher BA, Korbutt TT, Menon K, Holden SA, and Ara G. ‘Cyclooxygenase and lipoxygenase inhibitors as modulators of cancer therapies’, Cancer Chemother. Pharmacol., 33: 512-522, 1994.
- Tang DG et al, J. Cell Physiol., Vol. # 172, pp. 155-170, op cit
- Ballatori N and Wang W, Amer. J. Physiol., May 1997, Vol. # 272, pp. C1429- C1436.
- Sheik NM, Philen RM and Love LA. ‘Chaparral-associated hepatotoxicity’, Arch. Interl. Med., 1997 April 28, 157(8); 913-919.
- Picardo M et al, ‘Activity of azaleic acid on cultures of lymphoma and leukemia- derived cell lines, normal resting stimulated lymphocytes and 3T3 fibroblasts’, Biochem. Pharmacol., 1985, 34:1653-1658.
- Brown JM, ‘SR 4233 (Tirapazamine): A new anticancer drug exploiting hypoxia in solid tumours’, Review, Lancet, 1993: 1163-1170.
- Cocconi G, ‘First generation aromatase inhibitors: Aminoglutethimine and testolactone’, Breast Cancer Res. Treatment, 30: 57-60, 1994.
- Soltysiak-Ppawluczuk, D and Burzynski, SR, ‘Cellular accumulation of antineoplaston A2S1 in human hepatoma cells’, Cancer Lett., 107-112, 1995.
- Pontigi P, Rotella GB, Sabuto A, and Curto FC, ‘Hyperthermia in cancer and AIDS: An updated survey’, J. Environ. Toxicol. Oncol., 15 (2-4), 89-97, 1996.
- Johnston, B. ‘Clinical effects of Coley’s toxin. 1. Controlled study. 2. A seven year study’. Cancer Chem. Reports 21:19-68, August 1962
- Mitsumori M, Hiraoka M, Shibata T, Okuno Y, Nagata Y, Nishimura Y, Abe M, Hasegawa M, Nagae H, Ebisawa Y, ‘ Targeted hyperthermia using derxtran magnetite complex: a new treatment modality for liver tumors,’ Hepatogastroenterology 1996 Nov-Dec; 43(12): 1431-7.
- Yanase M, Shinkai M, Honda H, Wakabayashi T, Yoshida J, Kobayashi T, ‘Intracellular hyperthermia for cancer using magnetite cationic liposomes: ex vivo study,’ Jpn J. Cancer Res Jul;88 (7): 630-2.
- Akagi K, Aoki Y, Nasu R, Nagata K, Itagaki Y, Sawada S, ‘Enhancement of antitumor effects of hyperthermia with glucose administration in murine mammary carcinoma,’ Oncol Res; 6(3): 593-6 1999.
- Leeper DB, Engin K, Thistlethwaite AJ, Hitchon HD, Dover JD, Li DJ, Tupchong L, ‘Human tumor extracellular pH as a function of blood glucose concentration,’ Int J Radiat Oncol Biol Phys 1994 March 1;28(4):935-43.
- Lepper DB, Engin K, Wang JH, Cater JR, Li DJ, ‘Effect of i.v. versus combinaed i.v. plus oral glucose on human tumour extracellular pH for potential sensitization to thermoradiotherapy,’ Int J Hyperthermia 1998 May-June; 14(3): 257-69.
- Lutsenko SV, Feldman NB, Finakova GV, Posypanova GA, Severin SE, Skyrabin KG, Kirpichnikov MP, Lukyanets EA, Vorozhtsov GN, ‘Targeting phthalocyanines to tumor cells using epidermal growth factor conjugates, ‘ Tumour Biol 1999 Jul-Aug; 20 (4): 218-24.