Alteration of EGF-receptor binding in human breast cancer cells by antineoplastic agents.
Polypeptide growth factors bind to membrane receptors on human breast cancer cells and stimulate cell proliferation, suggesting that they may be important in growth regulation. Inhibition of the stimulatory effects of these factors might result in antineoplastic activity. Since cytotoxic drugs have been shown to alter cell membrane characteristics, we have examined the effects of a variety of antitumor drugs on the binding of epidermal growth factor (EGF) to the membrane receptor of human breast cancer cells. Twenty-four standard or investigational cytotoxic drugs were screened at a concentration of one-tenth the achievable peak plasma level for their ability to inhibit binding of 125I-EGF to its receptor in MCF-7 human breast cancer cells. Although at this concentration statistically significant inhibition of binding was observed with 11 drugs, the maximum inhibition observed was only 27%. Five agents, representing classes of drugs with different modes of action, were then studied in more detail. Of these, preincubation with 5-fluorouracil, 4-hydroperoxy-cylophosphamide and doxorubicin inhibited MCF-7 colony formation in a dose-dependent manner, but these drugs had no effect on EGF-binding even at a concentration of 10 times the peak plasma level. Preincubation of cells with vinblastine and cisplatin, however, resulted in both reduced colony survival and a parallel reduction in EGF receptor binding. Membrane integrity, as measured by trypan blue exclusion, was not altered. Scatchard analysis of EGF binding demonstrated that the major effect of cisplatin was a reduction in binding affinity. We conclude that cisplatin and vinblastine at high concentrations can inhibit the binding of EGF to human breast cancer cells offering an additional possible mechanism for their antiproliferative activity.