IPT and the Mechanisms of Malignancy

Insulin, Chemotherapy and the Mechanisms of Malignancy: The Design and the Demise of Cancer

S.G. Ayre, D.P. Garcia y Bellon, D.P. Garcia Jr

Medical Hypotheses (2000) 55(4), 330-334

SUMMARY
The endogenous molecular biology of cancer cells involves autocrine and paracrine secretion of insulin and insulin-like growth-factors I and II, which subserve energy production and growth stimulation, respectively, in these cells. These activities confer on cancer its malignant potential, working as they do autonomously, free from higher levels of integrated control. Taking advantage of cancer’s mechanisms of malignancy by employing exogenous insulin as a biologic response modifier, it is possible to potentiate the cytotoxic effects of chemotherapeutic agents for improved treatment of cancer. A synergy between certain membrane and metabolic effects of insulin on cancer cell molecular biology increases anticancer drug efficacy, and it does so with reduced doses of the drugs, enhancing their safety. This treatment strategy has been applied abroad over the last five decades with very promising clinical results.

INTRODUCTION
Cancer: hoist by one’s own petard

I used to believe that a petard was some sort of medieval weapon with a big rounded blade and a smaller pointed affair sticking out of the other end, all mounted atop a longish wooden shaft. Spanish, I thought. Thus, to me, getting hoist by one’s own petard meant getting stuck in the rear-end with the pointy end while menacing the enemy with the thing during the heat of battle. I recently had occasion to question the veracity of this particular concept, so I went to the books and looked it up. I discovered instead that a petard was a large and powerful explosive charge meant to be placed before the main gate in the wall surrounding a city under siege. The idea was to have the petard blow open the city gates, allowing hordes of marauders to then run into the besieged city to do primitive things there.

With this new understanding, the phenomenon of being “hoist by one’s own petard” now conjures up for me the image of some poor fellow – the unfortunate victim of some faulty lightning fast fuse – flying face first through the air, rather quickly and on an upward trajectory, back arched, head and legs trailing, arms too, still clutching in one hand one of those Spanish petard things. (Letting go of old concepts is hard).

The definition of the idiom “hoist by one’s own petard” is given as “caught by the very device one had contrived to hurt another”(1). This definition most appropriately characterizes the situation with cancer and its mechanisms of malignancy when these are viewed in relation to an innovative chemohormonal protocol called Insulin Potentiation Therapy (IPT) (2,3). In this approach, cancer’s very devices designed to kill the host are, in turn, used to more safely and effectively kill the cancer via the controlled administration of exogenous insulin plus lowered doses of conventional anticancer medications. Developed empirically in the early 1930’s by one Donato Perez Garcia, Sr., M.D., of Mexico City, the scientific significance of this neoadjuvant chemohormonal protocol can now be more clearly substantiated intellectually in the light of advances in our understanding of the molecular biology of malignant neoplasia.

INSULIN AND THE MECHANISMS OF MALIGNANCY
The mechanisms of malignancy in solid tumors are related to expression of information within the host genome encoding the biosynthesis of insulin and the insulin-like growth factors I & II (IGFs). There are numerous reports identifying the synthesis and secretion of insulin and the IGFs in cancers of the breast (4-19), lung (19-22), colon (23,24), melanoma (24), cervix (24-26), renal cell carcinoma (27), fibrosarcoma (28), Hodgkin’s lymphoma (29), insulinoma (30), as well as in one hematologic malignancy, lymphoblastic leukemia (28). The specific receptors for these ligands have likewise been well characterized on the cell membranes of these cancers (6,14,15,23,24,32,33). It is recognized that there are other growth factors that contribute in regulating tumor growth, such as epidermal growth factor (EGF), transforming growth factor-alpha (TGF-a), transforming growth factor-beta (TGF-b), and platelet-derived growth factor (PDGF) [32,34]. Of all of these growth factors, the IGFs have been reported to be the most potent growth-promoting mitogens in breast cancer cells [35].

The majority of citations relative to insulin and the IGFs included here come from studies on breast cancer cells. This is because the majority of funding and research on the molecular biology of cancer has been concentrated in this particular area. As cited above, several cancer cell lines derived from other tissues have likewise been found to possess this complement within their own molecular biology. In addition, positive clinical results from the Mexican experience involve other tumors apart from just cancers of the breast. Therefore, for the purposes of discussing IPT and cancer, the published findings on the mechanisms of malignancy specific to breast cancer are herein extrapolated to include malignant tumors in general.

Sporn and Todaro also discuss these mechanisms in general relation to cancer, affirming that the secretion of insulin and the IGFs in human cancer cells, together with elaboration of the specific receptors for these ligands, confer on the cells an autocrine and/or paracrine capability, resulting in their malignant transformation (36). Zapf and Froesch make this similar and more fully descriptive affirmation: “This combination of insulin and the IGFs operates autonomously at the cellular level within tumors, and this operation is free from any higher level of integrated control. The two work together in an autocrine and/or paracrine manner and in a complementary fashion, with the IGFs being the major anabolic hormones responsible for mediating messages about growth in the tumor, while insulin regulates and provides the fuel for these processes (4).” Consistent with the expressed opinions of these authors, and because of our clinical observations with the practice of IPT, it is our judgment that the workings of insulin and its related compounds are central to the mechanisms of malignancy in human cancer.

INSULIN AND CANCER CHEMOTHERAPY
Insulin has been shown to increase the cytotoxic effect of methotrexate in MCF-7 human breast cancer cells (HBCC), in vitro, by a factor of up to ten thousand (37). In another in vitro study, preincubation of MDA-MB-231 HBCC with insulin resulted in an increased intercellular accumulation of the DNA intercalating agent, ellipticine, with a concomitant increase in cytotoxicity (38). The authors in the first study attributed the effect to metabolic modification within the cancer cells, rendering them more sensitive to the effects of the methotrexate. However, in a related study it was shown that “insulin has significant effects on the intramembrane methotrexate transport system of MCF-7 HBCC. Enhanced cytotoxicity may be related to an increased capacity of the cells to accumulate free intracellular methotrexate. Insulin-induced changes in cellular lipid synthesis and perhaps in membrane lipid profile could result in changes in membrane fluidity and enhanced methotrexate transport (39).”

We propose that both the membrane and the metabolic modifications cited here play a role in IPT’s enhancing cancer chemotherapy, and we further propose that the insulin potentiation described above for methotrexate and ellipticine operates for other drugs as well. Supporting this latter proposition, we have published a report demonstrating a forty- percent increase in the brain uptake index of azidothymidine in rat brain using insulin (40). It bears mentioning here that the capillary endothelium of the blood-brain barrier is well supplied with insulin receptors (41).

As for the mechanisms of insulin’s membrane effect in IPT, the hormone has a potent effect to activate delta-9 desaturase enzyme activity (42). This causes alterations in cellular lipid synthesis – specifically, the transformation of saturated stearic acid with its melting point of 68oC, to the unsaturated compound oleic acid with a melting point of only 5oC. At physiologic temperatures of 20oC, such a biochemical transformation would certainly cause an increase in membrane fluidity and, thereby, in membrane permeability (43,44), as proposed above (39). Other hypotheses proposed for this membrane effect include drug adsorption onto glucose molecules with transmembrane transport then occurring via the insulin-activated glucose transport protein, or a similar adsorption of drug molecules onto insulin with the resulting chimeric drug-insulin complex being internalized into the cell by a process of receptor-mediated endocytosis (45-48).

With regard to the metabolic modification of cancer cells attributed to insulin, there are several factors involved here. The cross-reaction of insulin with IGF receptors on cancer cell membranes increases the S-phase fraction in tumors, (9) rendering the cells more susceptible to the cytotoxic effects of anticancer drugs. Significant for this proposition about IPT is a report that supraphysiologic doses of insulin, such as are administered in this protocol, can fully replace the growth requirement for IGF-I in defined media through this cross-reaction process (49). The degree of insulin’s effect to promote cellular growth here is significant. In vitro, after the addition of insulin to an asynchronous population of breast cancer cells, the S-phase fraction increased to 66% compared to only 37% in the controls (5). Given the pharmacokinetics of the anticancer drugs, particularly the cell-cycle phase specific agents, such an increase in the S-phase fraction would have a significant effect to enhance anticancer drug cytotoxicity.

Of some interest is another example of metabolic modification discussed in two obscure reports of complete cancer remissions produced by insulin-induced hypoglycemia alone – without any chemotherapy at all (50,51). These cases involved protocols very different from our own with respect to doses and timing of insulin administration, and the control of the hypoglycemia. One of the authors here posited that an accumulated hyperoxidation of the blood was responsible for the remissions. This accumulation was thought to be due to decreased oxygen needs for metabolizing glucose on account of the decreased amount of glucose in the blood. From the classical work of Warburg, it is known that cancer cell metabolism relies on the anaerobic degradation of glucose (52). Perhaps the increased tissue oxygen tension, in combination with a lowered blood glucose concentration, sufficiently perturbed cancer cell metabolism to producing the observed lethal effects. Whether these phenomena may play a role to enhance anticancer drug cytotoxicity in IPT is not known, but the possibilities are interesting.

Another important facet of IPT is the selectivity it provides in differentiating between cells of normal versus cancerous tissues. Autoradiographic studies demonstrate that insulin binds dominantly to tumor cells rather than to fat and fibrous tissue within tumors (14). Breast cancer cell membranes have been found to have an average of seven times more insulin receptors (15) and ten times more IGF receptors (6) than normal breast and other tissues within the host. As it is logical to affirm that ligand effect is a function of receptor concentration, insulin’s action as a biological response modifier would thus predominately target cancer cells, with a relative sparing of host normal tissues.

We consider that this “smart bomb” phenomenon plays a central role in both the increased safety to the host, as well as increased efficacy against the cancer. The lowered doses of anticancer drugs work better due to the membrane effect that leads to the increased intracellular dose intensity. These lower systemic drug doses – but actually higher intracellular ones within cancer cells – will then more effectively damage the cancer cells via insulin’s powerful metabolic effect on them. Extending the safety of chemotherapy in IPT, insulin’s membrane and metabolic effects will tend to be relatively selective for cancer cells on account of their richer complement of receptors, avoiding an intensity of chemotherapy effects in normal tissues.

As may be seen from the list of citations, a great deal of scientific interest has been focused on studying insulin and its related compounds in cancer over the last two decades. Having discovered how cancer cells worked, remaining true to its allopathic orientation medicine set about finding ways to block these mechanisms – but to little avail. No safe and selective way could be found to do this on account of the ubiquitous role insulin plays in normal human physiology. In spite of this apparent dead end, there was one report in the literature from this era that discussed an alternative notion, one recapitulating some of our own thoughts and ideas about actually applying a hormone – insulin – as a therapeutic adjunct, rather than attempting to block it. In this article discussing breast cancer and the effects of estrogen, it was proffered that “Drugs are most effective in cycling populations of cells.. and.. hormonal manipulations directed towards regulating cell growth, rather than producing cell death, combined with chemotherapy, should be more effective in increasing cure rates in mammary carcinomas” (53).

In clinical applications of IPT, pharmacologic doses of insulin – 0.4 units per kilogram body weight (Humalog, Lilly) – are administered to manipulate the endogenous mechanisms of malignancy in cancer cells via the mechanisms described. Naturally, insulin delivery is done in conjunction with glucose monitoring and appropriate hypertonic glucose administration. Drug potentiation results from an insulin-induced increase in transmembrane passage and intracellular accumulation of drug, along with a recruitment of cells into S-phase of the cell replicative cycle by cross-reaction of insulin with IGF receptors. A synergy between these two effects of insulin and the pharmacokinetics of anticancer drug therapy greatly enhances cytotoxicity, particularly for the cell cycle phase-specific anticancer drugs.

As well as improved efficacy, this regimen also increases safety because of the lower total doses that may be effectively used, with corresponding reduced drug side effects. Typically, reductions of seventy-five to ninety percent of the usual and customary doses of anticancer medication are given, employing combinations of chemotherapy agents standard for the diagnosis and stage of the particular disease. Augmenting both elements of safety and efficacy here is IPT’s “smart bomb” effect caused by the relative selectivity of insulin action on cancer cells, as compared to normal somatic cells, due to the excess of insulin and IGF receptors on their cell membranes.

Anecdotally, after many years of clinical experience using the potentiation of chemotherapy with insulin, it appears the method is both safe and effective. In addition, IPT has shown that chemotherapy may be used as a primary and exclusive modality in the medical management of several solid tumor malignancies.

CONCLUSION
Insulin Potentiation Therapy is an empirically derived innovation for which good scientific evidence now exists to affirm its formulation. Being consistent with the natural biology of cancer cells, the operative mechanisms in IPT make it an ideal process for the medical treatment of cancer. In its turn, IPT strongly affirms the appropriateness of chemotherapy in cancer management, creating the possibility of expanding the scope of application for chemotherapy as primary treatment for certain malignancies. These are two important affirmations. First, the strong anecdotal and supporting scientific evidence for IPT makes this a potential boon for the medical profession to be able to manage cancer more effectively. Second, relying as it does on chemotherapy there is little that is truly “alternative” about Insulin Potentiation Therapy, a similar boon for important sectors of the medical industry that provide us with the tools for treating cancer.

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Insulin, Chemotherapy and the Mechanisms of Malignancy: The Design and the Demise of Cancer S.G. Ayre, D.P. Garcia y Bellon, D.P. Garcia Jr Medical Hypotheses (2000) 55(4), 330-334 SUMMARY The endogenous molecular biology of cancer cells involves autocrine and paracrine secretion of insulin and insulin-like growth-factors I and II, which subserve energy production and growth…
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