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Neoadjuvant Low-dose Chemotherapy with Insulin in Breast Carcinomas

SGA, Donato Perez Garcia y Bellon and Donato Perez Garcia, Jr
European Journal of Cancer 1990; 26(11-12):1262-3

Published on IPTQ by permission from Donato Perez Garcia, M.D.

WE HAVE developed a neoadjuvant chemohormonal therapy for breast carcinomas without surgery or radiotherapy. Cyclophosphamide, methotrexate, and 5-fluorouracil are administered, with insulin as a biological response modifier to potentiate anticancer drug effects [1]. This regimen affords maximum breast conservation and minimum patient discomfort.

Breast malignancies are histologically verified by fine needle biopsy. Insulin/chemotherapy cycles are repeated twice a week for 3 weeks, and then weekly for another 3—6 weeks depending on clinical findings. Fasting subjects receive insulin (0.3 U/kg) and, at onset of hypoglycaemia, cyclophosphamide 8 mg/rn2, methotrexate 3 mg/rn2, and 5-fluorouracil 50 mg/rn2 with 50% hypertonic glucose, intravenously. On non-treatment days, patients are given oral cyclophosphamide 50 mg and rnethotrexate 2.5 mg.

A 32-year-old woman found a lump in her right breast in November 1988. Xeromammography confirmed the presence of a lesion (Fig. 1), and a biopsy revealed an infiltrating ductal adenocarcinoma. After 8 weeks of chemohormonal therapy, the breast mass was no longer palpable. A xeromammogram at 3 months showed no evidence of tumour (Fig. 1).

Insulin and insulin-like growth factor-1 (IGF-1) have been identified as autocrine and/or paracrine growth factors in human breast cancer cells [2—4]. We administer pharmacological doses of insulin to manipulate membrane and metabolic activities of these endogenous growth-promoting mechanisms, thereby potentiating anticancer drug effects. Drug potentiation results from an insulin-induced increase in the transmembrane passage of anticancer drugs in human breast cancer cells [5, 6], and a recruitment of cell populations into S-phase of the replicative cycle by cross-reaction of insulin with IGF-1 receptors [7]. The cell-killing effects of anticancer drugs, particularly the chemotherapy agents specific for cell cycle phase, are greatly augmented [8]. Therefore, ideal pharmacokinetic circumstances for the chemotherapy of breast cancer are created. As well as improved efficacy, this regimen increases safety because of lower total doses administered and reduced side-effects.

Chemohormonal therapy with oestrogen has shown promising results in preliminary trials [9]. However, insulin and chemotherapy is more efficacious, as not only can insulin mimic oestrogen’s cell-recruiting effects in oestrogen receptor positive human breast cancer cells [10], but insulin also stimulates recruitment in oestrogen receptor negative cells. Unlike oestrogen, insulin can increase the transmembrane passage and intracellular accumulation of anticancer drugs. The administration of low-dose anticancer drug therapy with insulin can produce complete and long-term regression of tumour masses in treated subjects. Therapy is tolerated without adverse effect and in our case produced excellent cosmetic results.

Fig. 1. Patient 1: xeromammogram on 3 February (left) 
and 15 June (right) 1989.

1. SGA, Perez Garcia y Bellon D, Perez Garcia D Jr. Insulin potentiation therapy: a new concept in the management of chronic degenerative disease. Med Hypotheses 1986,20, 199—210.

2. Hilf R. The actions of insulin as a hormonal factor in breast cancer. In: Pike MC, Siiteri PK, Welsch CW, eds. Hormones and Breast Cancer. Cold Spring Harbor, Cold Spring Harbor Laboratory, 1981, 317—337.

3. Lippman ME, Dickson RB, Kasid A, et al. Autocrine and paracrine growth regulation of human breast cancer. J Steroid Biochem 1986, 24, 147—154.

4. Cullen JK, Yee D, Sly WS, et al. Insulin-like growth factor receptor expression and function in human breast cancer. Cancer Res 1990, 50,48—53.

5. Alabaster 0, Vonderhaar BK, Shafie SM. Metabolic modification by insulin enhances methotrexate cytotoxicity in MCF-7 human breast cancer cells. Eur J Cancer Clin Oncol 1981, 17, 1223—1228.

6. Oster JB, Creasey WA. Enhancement of cellular uptake of ellipticine by insulin preincubation. Eur 3 Cancer Clin Oncol 1981, 17, 1097—1103.

7. Van Wyk JJ, Graves DC, Casella SJ, Jacobs S. Evidence from monoclonal antibody studies that insulin stimulates deoxyribonucleic acid synthesis through the type 1 somatomedin receptor. 3 Clin Endocrinol Metab 1985, 61,639—643.

8. Shackney SE, Cell kinetics and cancer chemotherapy. In: Calabresi

P, Schein PS, Rosenberg SA, eds. Medical Oncology: Basic Principles and Clinical Management of Cancer, New York, Macmillan, 1985, 41—60.

9. Paridaens R, Klijn JGM, Julien JP, et al. Chemotherapy with estrogenic recruitment in breast cancer: experimental background and clinical studies conducted by the EORTC breast cancer cooperative group. Eur J Cancer Clin Oncol 1986,22,728.

10. Van der Burg B, de Laat SW, van Zoelen EJJ. Mitogenic stimulation of human breast cancer cells in a growth-factor defined medium: synergistic action of insulin and estrogens. In: Brescani F, King RJB, Lippman ME, Raynaud JP, eds. Progress in Cancer Research and Therapy, vol. 35: Hormones and Cancer 3. New York, Raven Press, 1988,231—233.

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