Guide-lines in the design of new antiestrogens and cytotoxic-linked estrogens for the treatment of breast cancer.

Antiestrogens (Tamoxifen) are used for the treatment of breast cancer. However these compounds are also weak estrogens that may stimulate tumor growth. Cytotoxic-linked estrogens (Estradiol Mustard, Estracyt) are devoid of major therapeutic activity. This led to search for new antiestrogens devoid of estrogenicity and for active cytotoxic-estrogens. Hydroxylation of C-4 of triphenylethylene antiestrogens (tamoxifen, CI 628 and U 23,469) largely increases their binding affinity for the estrogen receptor (ER). Hydroxylation also increases the in vitro antitumor activity of the drugs as shown by their higher ability to inhibit the growth of the ER-positive cell line MCF-7. Triphenylethylene antiestrogens contain an aminoethoxy side chain which appears essential for their physiological activity. Removal of the chain of tamoxifen suppresses its antiestrogenicity and antitumor activity. The grafting of side chains on a weak estrogen of the gem-diphenylethylene category produces "symmetrical" antiestrogens devoid of estrogenic activity. This observation raises the question of the role played by the third phenyl ring of the triphenylethylenes since the trans-isomers of the latter display antiestrogenicity and the cis-isomers estrogenicity. Comparison of the binding affinity for ER and antitumor activity of di- and triphenylethylene antiestrogens suggests that this third phenyl ring increases the interaction with ER of the 4-phenolic group of the drugs and/or their aminoethoxy side chain. An analogue of this chain is without any biological activity suggesting that the di-(tri)pheny-lalkene structure is required for promoting the interaction of the chain with ER. New chemical structures yielding antiestrogens with antitumor activity are also reviewed. New cytotoxic estrogens designed for producing lethal damage of DNA show a low binding affinity for ER. Moreover, there is no evidence suggesting specific antitumor activity. Such activity may be more easily obtained with estrogens bearing reagents for proteins rather than DNA. The biological properties of a 2-mesylate derivative of estrone irreversibly interacting with ER supports the concept. On MCF-7 cells, the drug displays a strong antitumor activity which can only be suppressed by high, equimolar, concentrations of estradiol. It is devoid of cytotoxic activity on the ER-negative cell line Evsa-T suggesting that ER is involved in its action.