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Insulin, Chemotherapy, and the Mechanisms of Malignancy: 
the design and the demise of cancer. 

SGA, D.P. Garcia y Bellon, D.P. Garcia Jr

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

Published on IPTQ by permission of Donato Perez Garcia MD.

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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