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COPYRIGHT 2001 The Townsend Letter Group
Background
The Metabolic Oncolytic Regimen is based on the seminal work of former NASA scientist Clarence Cone, Jr., PhD. 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.
Abstract
The Metabolic Oncolytic Regimen is based on an approach to achieving lysis in solid tumors pioneered by Clarence Cone, Jr., PhD (NASA, retired). Dr. Cone's novel therapy, which is reflected in patents granted various versions of same [US 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 bioflavonoid 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 principal 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).
Tumor Cell Biology
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 underway early on in tumorigenesis. As we cannot presently circumvent this process, the principal 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 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...
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