New aspects in the development of cytotoxic-linked estrogens for the control of breast neoplasia.

The interest of cytotoxic-linked estrogens as therapeutical drugs for controlling the growth of breast cancers relies on their potential binding to estrogen receptors (ER) in these cancers. 14, 15-alpha and beta epoxide derivatives of estradiol-17 alpha and 17 beta were investigated for their ER binding affinity and their cytotoxic activities on the MCF-7 and Evsa-T cell lines. 14, 15 alpha and beta-epoxides of estradiol 17 alpha as well as the 14, 15 alpha epoxide of estradiol 17 beta bound to ER. No compound revealed any cytotoxicity on the cell lines. A 11 beta-aziridine derivative of estrone showed significant binding activity to ER. Concentrations of 10(-7) and 10(-8) M of this compound act stimulating on the growth of MCF-7 cell line. 10(-6) M is slightly inhibitory. There is no effect on Evsa-T cells. Binitrogen mustard derivatives of hexestrol and diethylstilbestrol displayed a very low binding activity whereas mononitrogen mustards of estrone showed a significant binding activity. At concentrations of 10(-6) M all mustard compounds inhibited the growth of MCF-7 cell line. The inhibitory influence of the mononitrogen mustards were higher than those of the binitrogen mustards. With regard to the Evsa-T cells only mononitrogen mustard displayed a growth inhibiting effect.