Neoadjuvant Low-Dose Chemotherapy With Insulin in Breast Carcinomas

Steven G. Ayre, Donato Perez Garcia y Bellon and Donato Perez Garcia, Jr. — European Journal of Cancer 1990; 26(11-12):1262-3

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 methotrexate 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).

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.

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