Breast Carcinoma Treated by a Regimen of Low-Dose Chemotherapy and insulin: Report of Four Cases and Pharmacokinetic Considerations
Published on IPTQ with permission of Donato Perez Garcia, M.D.
We report four cases of breast carcinoma (infiltrating ductal type, stages II to IV) treated abroad with an innovative approach using insulin as a pharmacologic adjunct to a protocol of low-dose combination cyclophosphamide, methotrexate, and 5-fluorouracil (CMF). On a weekly basis, patients received 5 days of oral and 2 days (Monday, Thursday) of parenteral chemotherapy, the latter administered together with 0.1 to 0.2 units/kg of regular insulin (mean treatment, 8 weeks).
Significant improvements were seen in the clinical course of each patient through reduction in size or disappearance of the primary, regression of metastases, changes in laboratory and radiologic parameters, and improvements in Karnofsky scores. The regimen. was tolerated by all four patients, without dose-related side effects.
Insulin enhances the transmembrane transport of drugs. Experiments with MCF-7 human breast cancer cells in vitro have shown a 10,000-fold increase in the cytotoxic effect of methotrexate with insulin, and an in vivo experiment with rats has demonstrated an insulin-induced increase in passage through the blood-brain barrier of zidovudine (AZ'!).
These effects may be mediated through insulin receptors, possibly via coupling with the process of receptor-mediated endocytosis. Cell membrane-derived second messengers of insulin may also play a role in altering the mechanics of membrane transport.
Metabolic modification of cancer cell metabolism by insulin could account for some of the observed potentiation of drug effect Insulin stimulates DNA and RNA synthesis through direct interaction with its receptors on nuclear membranes, and it may produce a similar effect via cross-reaction with IGF1 receptors. Such actions would serve to augment anticancer drug cytotoxicity, particularly for the cell cycle-specific agents (methotrexate, 5-fluorouracil).
The clinical experiences reported here are uncontrolled and anecdotal. We encourage investigation in the United States of the observed insulin potentiation effect on anticancer chemotherapy through in vitro and in vivo basic scientific research and, if warranted, properly controlled clinical trials.