Considerations in the design and evaluation of cytotoxic estrogens

The estrogen receptor that is present in many breast tumors provides a mechanism for the concentration of estrogens. Hence, it should be possible to effect a selective, receptor-mediated killing of estrogen receptor-rich tumor cells with a suitable cytotoxic estrogen derivative. Because the dose per cell that can be delivered by a receptor-mediated process is limited by the capacity of the estrogen receptor system (ca. 1,000-10,000 molecules per cell), the cytotoxic moiety of these derivatives needs to be directed at a target where an effective cell kill can be achieved with this limited dose; DNA appears to be the most suitable target. The estrogen derivatives that contain DNA-alkylating and cross-linking groups and retain high affinity for the estrogen receptor should be carried selectively to the nucleus. There, it is hoped that they would react with DNA with reasonable efficiency. Definitive tests of receptor-mediated cytotoxicity in vitro could be performed in cultures of human breast tumor cells that are receptor positive (e.g., MCF-7) or receptor negative (e.g., MDA-MB-231). These tests would involve comparison of the potency of the cytotoxic estrogens with that of cytotoxic control compounds, both in the presence and absence of estradiol, in order to correct for possible differences in the sensitivity of the different cell lines to cytotoxic agents and to metabolic effects of estradiol. These agents would then be tested in experimental mammary tumor systems in the rat. Our current understanding of the characteristics of estrogen receptor binding, and the availability of suitable systems for studying these agents in vitro and in vivo, make a definitive test of selective cytotoxicity, mediated by the estrogen receptor, a timely and sensible endeavor.