A HYPOTHESIS AND A SPECIAL EXPERIMENTAL METABOLIC THERAPY IN THE TREATMENT OF VARIOUS SOLID TUMORS

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http://www.redflagsweekly.com/extra/2003_aug12.html

 

 

August 12, 2003

 

A HYPOTHESIS AND A SPECIAL EXPERIMENTAL METABOLIC THERAPY IN THE TREATMENT OF

VARIOUS SOLID TUMORS

 

(The Revised Metabolic Oncolytic Regimen for Effecting Lysis in Solid Tumors)

 

By Anthony G. Payne, N.M.D., Ph.D., M.D. (hon.)

 

SCTI Research & Development Laboratory, 1064 Calle Negocio #B, San Clemente, CA.

92673. Phone: 949-248-7034. FAX: 949-388-3441. E-mail:

anthony

 

 

 

Background

 

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.

 

 

 

Acknowledgments

 

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).

 

 

 

Summary

 

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 prodigious quantities of lactic acid. This is achieved

using a specific dietary regimen plus various synthetic and natural drugs ,

e.g,., the bioflavinoid quercetin 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 deficit 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;

 

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.

 

 

 

Limonene

 

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.

 

 

 

L-Hydroxycitrate

 

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.

 

 

 

Melatonin

 

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/)

 

 

 

Thyroid

 

Exogenous thyroid hormone should contribute to the achievement 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 proposed experimentally 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)

 

 

 

 

 

Quercetin

 

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 quercetin-induced lactic acidosis in

(glycolytic) tumor cells may bring about pH-endonuclease activity that leads to

tumor cell die off.

 

NOTE: Quercetin 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; © 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). [Quercetin 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 , 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 elevated 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).

 

 

 

DIETARY GUIDELINES

 

Protein

 

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.

 

 

 

Carbohydrates

 

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 comprise the bulk of the patient’s

carbohydrate intake.

 

 

 

Fats

 

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

 

AM MEAL

 

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 millennia]. 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 Prescription (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. quercetin (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 quercetin is very poorly absorbed in the human gut, it is recommended

that patients take a more bioavailable form such as water soluble quercetin

hydrate or " activated " quercetin [Activated quercetin is a combination of

quercetin and bromelin and magnesium ascorbate. According to literature

published by a major " activated " quercetin manufacturer/distributor, Threshold

Enterprises Ltd. (Source Naturals brand), various clinical studies have

demonstrated that vitamin C improves the absorption of quercetin].

Interestingly, the marriage of ascorbate with quercetin packs its own

therapeutic punch. To whit: A quercetin-ascorbate blend inhibited HBT squamous

cell carcinoma cells in one study (27).

 

 

 

MID-DAY MEAL

 

The emphasis should be on complex carbohydrates and protein.

 

Prior to: 250 mgs. L-hydroxycitrate [20 minutes prior to meal]

 

500 mgs. quercetin

 

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

 

 

 

PM MEAL

 

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 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: Quercetin 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 increases 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, quercetin 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.

Quercetin helps circumvent this process and thus leave the tumor susceptible to

hyperthermia therapy [in cervical carcinoma cells, quercetin 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 utilized at the University of

Wisconsin.

 

 

 

Two Novel Theoretical Methods of Inducing Intratumor Hyperthermia

 

The following are two admittedly very theoretical approaches 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 artificially 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 electromagnetic heating more

certain.

 

NOTE: Interestingly, there are 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 combination 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 certain), 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 .

 

 

 

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.

 

 

 

Comments

 

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).

 

 

 

Concluding Remarks

 

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 affects 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 Information

 

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 may be reached at SCTI Research & Development Laboratory, 1064 Calle

Negocio #B, San Clemente, CA. 92673. Phone: 949-248-7034. FAX: 949-388-3441.

E-mail: anthony

 

 

 

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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.