A comparison of the antitumor activity of two triarylcyclopropyl antiestrogens (compounds 4d and 5c) on human breast cancer cells in culture

Compound 4d ((E)- and (Z)-1,1-Dlchloro-2-[4-(benzyloxy)-phonyl]2,3-ble(4-methoxyphenyl) cyclopropane) and compound 5c ((2>1,1-Dlchloro-2-[4-(bonzyloxy)-phenyl]-2-(4-mothoxyphenyl)-3-phenylcyclopropane) are two members of a novel series of triarylcyclopropyl compounds which have been shown to be pure antiestro-gana. In the present study, the antiproliferative activity of 4d and 5c was examined on estrogen receptor (ER)-posltlve MCF-7 and ER-negatlva MDA-MB-231 human breast cancer cells and A-549 human lung cancer cells. Compound 4d Inhibited the growth of MCF-7 cells In a dose-related manner over a concentration range of 10 to 10∼6 M while compound 5c Inhibited MCF-7 cell growth in a dose-related manner over a concentration range of 10 to 10 M. Further, neither compound altered the growth of MDA-MB-231 or A-549 cells. Co-adminiatratlon of estradiol reversed the antiproliferative activity of 4d but not 5c on MCF-7 cells. Both compounds bound specifically to ER in MCF-7 cells; however, the relative binding activity of 4d was five times greater than estradiol and 5000 times greater than 5c. The influence of 4d and 5c on the cell surface morphology of MCF-7 and MDA-MB-231 cells was studied using scanning electron microacopy. Both compounds, at a concentration of 10 M, reduced the density of microvilli on MCF-7 cells, which was reversed by co-admlnlatration of estradiol (10 M). These compounds did not altar the cell surface morphology of ER-negatlve MDA-MB-231 cells. In conclusion, the results of this study indicate that compound 4d la mora potent than 5c as an Inhibitor of breast cancer cell proliferation and suggest that a polar methoxy group on the ± phenyl ring of compound 4d contributes to ER binding and ER-medlated antitumor activity. Further, these results suggeet that one or both of these compounds may be highly effective in the treatment of estrogen-dependent breast cancer.