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Insulin potentiation therapy

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Insulin potentiation therapy (IPT) is an alternative medicine pharmacologic strategy for the chemotherapy of cancer using insulin and low-dose chemotherapy. Whilst formal studies were recognized as being required back in 1986,[1] no conventionally recognized study has been published in the subsequent 20 years.

The therapeutic approach is said to take advantage of the endogenous molecular biology of cancer cells, specifically insulin and insulin like growth factor secretion, and the interaction of these biochemicals with their specific receptors. By using insulin in conjunction with chemotherapy drugs, significantly less drug (about 10-15 % of a standard dose) can be targeted more specifically and more effectively to cancer cell populations, thus virtually eliminating dose-related side effects while claiming enhancing antineoplastic effects.

Claimed explanatory molecular biology

The proponents of IPT give the following explanation of the biology of cancer and its cells in order to understand the mechanisms of IPT, which relies upon insulin, the most integral component of IPT, having three significant actions upon cancer cells described below, as well as also dropping blood sugar levels and thus the energy source for cancer. Low blood glucose (below 60 mg/dl) also stimulates secretion of growth hormone, and growth hormone probably helps to strengthen the immune system.

Differentiation between cancer and normal cells

Insulin biologically differentiates cancer cells from normal cells based on insulin receptor concentration.

Insulin can serve to distinguish and differentiate cancer cells from healthy cells in several way. Produced in the pancreas, one of its many functions is the regulation of blood glucose levels. Chiefly, insulin activates a glucose transport protein within all cells – whether they be cancerous or healthy - which allows glucose, the energy source, to enter, thus lowering the blood glucose level.

Like anything else, cancer needs energy to grow. The growth of cancer is abnormally rapid, its sole purpose being to spread, therefore it has a voracious appetite compared to normal cells. Cancer cells have developed the ability to produce insulin and insulin-like growth factor (IGF) themselves; this way they can autonomously increase their glucose uptake.[2][3][4][5][6][7][8][9][10][11]

Being able to produce its own insulin makes cancer different from normal cells, but there is a second abnormality that insulin highlights. Every cell in the body has insulin receptors on the outer surface of its membrane - from 100-100,000 receptors per cell. But cancer cells have a much higher concentration of receptors. Breast cancer cells - for example - have six times more insulin receptors and ten times more IGF receptors per cell than normal cells. As an added boost, insulin is able to react with its own receptors and is also able to cross-react with and activate the IGF receptors on cancer cells. This means that insulin will affect cancer cells sixteen times as strongly as it effects normal tissues.[12][13][14][15][16][17][18][19][20][21][22][23] Something else to take into consideration is that ligand effect is a function of receptor concentration. In a particular tissue, the more receptors there are for a certain ligand – such as insulin – the greater the effect of that ligand on that tissue.

By activating the insulin and IGF receptors on cancer cells through the administration of insulin during an IPT treatment, the biological differences of cancer cells can be highlighted – a vital consideration for the safety of cancer chemotherapy.

Increase in cell membrane permeability

The third effect that insulin has on cancer cells is to activate enzyme activity in the cell membrane making them more permeable.

Cell membranes are largely made up of triglycerides, which are built of fatty acids. The more saturated that a fatty acid is, the higher the melting point (example: butter [a saturated fat with a higher melting point] is solid at room temperature, whereas olive oil [an unsaturated fat with a lower melting point] is a liquid). The enzyme that insulin activates is called delta-9 desaturase and the action of this enzyme is to de-saturate - to make a saturated fat into an unsaturated fat. Delta-9 desaturase - once it has been activated by insulin - de-saturates the fatty acids that make up the cell membrane of cancer cells. This fatty acid – saturated stearic acid– has a melting point of 65 °C. Stearic acid once it has been de-saturated, becomes mono-unsaturated oleic acid, which has a melting point of 5 °C. At physiologic temperatures (the temperature of the body, about 37.5 °C) tristearin – triglyceride with three stearic acids attached that composes the cancer cell membrane - is going to be more "waxy" than "oily" because of its higher melting point. This makes for a less permeable cell membrane. On the other hand, once the insulin has activated the enzyme delta-9 desaturase, the cell membrane of cancer cells is composed of triolein – the triglyceride with three oleic acids attached – with a melting point of 5 °C. This cell membrane will be more permeable at physiologic temperatures. The chemotherapy drugs are thus able to enter the cancer cells more easily because of the increased cell membrane permeability, providing the required intracellular dose intensity to kill the cancer.

Insulin is used in IPT to enhance anticancer drug cytoxicity and safety, via 1) an effect of biological differentiation based on insulin receptor concentration, 2) an effect of metabolic modification to increase the S-phase fraction in cancer cells, enhancing their susceptibility to cell-cycle phase-specific agents, and 3) a membrane permeability effect to increase the intracellular dose intensity of the drugs. Significantly less drug can thus be targeted more specifically and more effectively to cancer cells, all this occurring with a virtual elimination of the dose-related side effects.[24][25]

Supportive research

Several in-vitro studies [26] have shown how IPT works supporting the informal clinical work that has been conducted on hundreds of patients worldwide.[27]

The first clinical trial of IPT for treating breast cancer was done in Uruguay and published in 2003/04. Insulin combined with low-dose methotrexate resulted in greatly increased stable disease, and much reduced progressive disease, compared with insulin or low-dose methotrexate alone.[28]

In 2000, the National Cancer Institute's Cancer Advisory Panel on Complementary and Alternative Medicine (CAPCAM) invited Drs. Perez Garcia and Ayre to present IPT to them as part of the National Cancer Institute's (NCI's) Best Case Series program.[29] However CAPCAM have not in the eight years since undertaken any further research into IPT.

In a study on insulin treatment in cancer cachexia,[30] 138 patients, mostly with advanced stage gastrointestinal cancer, were selected at random to receive a small daily dose of insulin along with quality palliative care. The control group received the best in palliative care. The progression of cachexia was halted and even reversed in the patients receiving insulin treatment, contributing to an improved quality of life. Tumor marker measurements (CEA, CA-125, and CA 19.9) indicated that insulin did not stimulate tumor growth, and in addition, the group receiving insulin exhibited a slightly improved survival rate in comparison to the control group. Insulin significantly stimulated carbohydrate intake, decreased serum-free fatty acids, and increased whole body fat, whereas fat-free lean tissue mass was unaffected. Insulin treatment improved metabolic efficiency during exercise, but did not increase maximum exercise capacity and spontaneous physical activity.

Footnotes

  1. ^ Ayre SG, Perez Garcia y Bellon D, Perez Garcia D (1986). "Insulin potentiation therapy: a new concept in the management of chronic degenerative disease". Med. Hypotheses. 20 (2): 199–210. doi:10.1016/0306-9877(86)90126-X. PMID 3526099.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  2. ^ Zapf J., Froesch E.R. (1986). "Insulin-like growth factors/somatomedins: structure, secretion, biological actions and physiological role". Hormone Research. 24 (24): 121–130. doi:10.1159/000180551.
  3. ^ Gross G.E., Boldt D.H., Osborne C.K. (1984). "Pertubation by insulin of human breast cancer cell kinetics". Cancer Research (44): 3570–3575.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  4. ^ Cullen J.K, Yee, Sly W.S; et al. (1990). "Insulin-like growth factor receptor expression and function in human breast cancer". Cancer Research (50): 48–53. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  5. ^ Hilf R. (1981). "The actions of insulin as a hormonal factor in breast cancer. In: Pike M.C., Siiteri P.K., Welsh C.W.,eds. Hormones and Breast Cancer, Cold Spring Harbor Laboratory": 317–337. {{cite journal}}: Cite journal requires |journal= (help)
  6. ^ Goustin A.S., Leof E.B., Shipley G.D., Moses H.L. (1986). "Growth Factors and Cancer". Cancer Research: 1015–1029.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  7. ^ Rasmussen A.A., Cullen K.J. (1998). "Paracrine/autocrine regulation of breast cancer by the insulin-like growth factors". Breast Cancer Res Treat. 47 (47(3)): 219–33. doi:10.1023/A:1005903000777.
  8. ^ Holdaway I.M., Freisen H.G. (1977). "Hormone binding by human mammary carcinoma". Cancer Research (37): 1946–1952.
  9. ^ Pap V., Pezzino V., Constantino A.; et al. (1990). "Elevated insulin receptor content in human breast cancer". J Clin Invest. 86 (86): 1503–1510. doi:10.1172/JCI114868. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  10. ^ Yee D. (1998). "The insulin-like growth factors and breast cancer - revisited". Breast Cancer Res Treat. 47 (47(3)): 197–199. doi:10.1023/A:1005938615798.
  11. ^ Quinn K.A., Treston A.M., Unsworth E.J.; et al. (1996). "Insulin-like growth factor expression in human cancer cell lines". J Biol Chem (271): 11477–83. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  12. ^ Pavelik L., Pavelik K., Vuk-Pavlovic S. (1984). "Human mammary and bronchial carcinomas: in vivo and in vitro secretion of substances immunologically cross-reactive with insulin". Cancer. 53 (53(11)): 2467–2471. doi:10.1002/1097-0142(19840601)53:11<2467::AID-CNCR2820531117>3.0.CO;2-#.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  13. ^ Shames J.M., Dhurandhar N.R., Blackard W.G. (1968). "Insulin-secreting bronchial carcinoid tumor with widespread metastases". American Journal of Medicine. 44 (44): 632–637. doi:10.1016/0002-9343(68)90065-X.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  14. ^ Jaques G., Rotsch M, Wegmann C.; et al. (1988). "Production of immunoreactive insulin-like growth factor 1 and response to exogenous IGF-1 in small cell lung cancer cell lines". Exp Cell Res. 176 (176): 336–343. doi:10.1016/0014-4827(88)90335-7. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  15. ^ Nakanishi Y., Mulshine J.L., Kaspryzk P.G.; et al. (1988). "Insulin-like growth factor-1 can mediate autocrine proliferation of human small cell cancer cell lines in vitro". J Clin Invest. 82 (82): 354–359. doi:10.1172/JCI113594. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  16. ^ Wong M., Holdaway I.M. (1985). "Insulin binding by normal and neoplastic colon tissue". Int J Cancer. 35 (35): 335–341. doi:10.1002/ijc.2910350309.
  17. ^ Kiang D.T., Bauer G.E., Kennedy B.J. (1973). "Immunoassayable insulin in carcinoma of the cervix associated with hypoglycemia". Cancer. 31 (31): 801–804. doi:10.1002/1097-0142(197304)31:4<801::AID-CNCR2820310407>3.0.CO;2-J.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  18. ^ Pavelik K., Bolanca M., Vecek N.; et al. (1992). "Carcinomas of the cervix and corpus uteri in humans:stage- dependent blood levels of substance(s) immunologically cross-reactive with insulin". J Nat Cancer Inst (68): 891–894. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  19. ^ Pavelic K., Popovic M. (1981). "Insulin and glucagon secretion by renal adenocarcinoma". Cancer. 48 (48): 98–100. doi:10.1002/1097-0142(19810701)48:1<98::AID-CNCR2820480119>3.0.CO;2-A.
  20. ^ Oleesky S., Bailey I., Samos S., Bilkus D. (1962). "A fibrosarcoma with hypoglycemia and a high serum insulin level". Lancet. 280 (2): 378–380. doi:10.1016/S0140-6736(62)90231-3.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  21. ^ Pavelic K., Odavic M., Pekic B. (1982). "Correlation of substance(s) immunologically cross-reactive with insulin, glucose and growth hormone in Hodgkin's lymphoma patients". Cancer Letter. 17 (17): 81–86. doi:10.1016/0304-3835(82)90112-4.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  22. ^ Colman P.G., Harrison L.C. (1984). "Structure of insulin/insulin-like growth factor-1 receptors on the insulinoma cell, RIM-m5F". Biochem Biophys Res Commun. 124 (124): 657–662. doi:10.1016/0006-291X(84)91605-X.
  23. ^ Lee P.D.K., Rosenfeld R.G., Hintz R.L., Smith S.D. (1986). "Characterization of insulin, insulin-like growth factors I and II, and growth hormone receptors on human leukemic lymphoblasts". L Clin Endocr Metab (62): 28–35.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  24. ^ Alabaster O., Vonderharr B.K., Shafie S.M. (1981). "Metabolic modification by insulin enhances methotrexate cytoxicity in MCF-7 human breast cancer cells". Eur J Cancer Clin Oncol. 17 (17): 1223–1228. doi:10.1016/S0277-5379(81)80027-2.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  25. ^ Oster J.B., Creasey W.A. (1981). "Enhancement of cellular uptake of ellipticine by insulin preincuabation". Eur J Cancer Clin. 17 (17): 1097–1103. doi:10.1016/0014-2964(81)90294-2.
  26. ^ Hug V, Johnston D, Finders M, Hortobagyi G. (1986). "Use of growth-stimulatory hormones to improve the in vitro therapeutic index of doxorubicin for human breast tumors" (PDF). Cancer Res. 46 (1): 147–52. PMID 3509991.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  27. ^ Alabaster O, Vonderhaar B, Shafie S (1981). "Metabolic modification by insulin enhances methotrexate cytotoxicity in MCF-7 human breast cancer cells". Eur J Cancer Clin Oncol. 17 (11): 1223–8. doi:10.1016/S0277-5379(81)80027-2. PMID 7037424.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  28. ^ Lasalvia-Prisco E, Cucchi S, Vázquez J, Lasalvia-Galante E, Golomar W, Gordon W (2004). "Insulin-induced enhancement of antitumoral response to methotrexate in breast cancer patients". Cancer Chemother Pharmacol. 53 (3): 220–4. doi:10.1007/s00280-003-0716-7. PMID 14655024.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  29. ^ "Minutes of the Third Meeting". Cancer Advisory Panel for Complementary and Alternative Medicine (CAPCAM). September 18, 2000. Retrieved 2008-01-28.
  30. ^ Lundholm K, Körner U, Gunnebo L, Sixt-Ammilon P, Fouladiun M, Daneryd P, Bosaeus I (2007). "Insulin treatment in cancer cachexia: effects on survival, metabolism, and physical functioning" (PDF). Clin Cancer Res. 13 (9): 2699–706. doi:10.1158/1078-0432.CCR-06-2720. PMID 17473202.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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