CONTRIBUTION TO THE ELUCIDATION OF THE AN TIESTROGENIC AND ANTITUMOR MECHANISM OF ACTION OF TAMOXIFEN

Our contribution to elucidation of the mechanism of action of tamoxife n can be summarized as follows: (i) hydroxylated metabolites of tamoxi fen (especially 4-hydroxytamoxifen), with high affinity for the oestro gen receptor are more potent antioestrogen and antitumoral agents than tamoxifen; they might play an important role in the in vivo antioestr ogenic and antitumoral activities of tamoxifen; (ii) the activity of t amoxifen and derivatives in vitro is closely related to their affinity for the receptor; (iii) certain oestrogen receptor properties (dissoc iation kinetics, immunoreactivity, sensitivity to specific reagents) v ary according to whether oestrogen or antioestrogen is bound to the re ceptor. These variations probably result from different ''positioning '' of oestrogen and antioestrogen at the receptor hormone-binding site . They indicate that antioestrogens may induce altered conformation an d probably defective activation of the oestrogen receptor. This could be the cause of the antioestrogenic and antitumoral effects of these c ompounds. It is now widely accepted that the oestrogen receptor is the major if not the only mediator of antioestrogenic and antitumoral eff ects of triphenylethylene antioestrogens in mammary tumor cells. These compounds efficiently promote dimerization and binding of the recepto r to target DNA. Their relative lack of oestrogenic activity could res ult from (i) their inability to activate the transactivating function of the receptor involved in transcription regulation of certain oestro gen-target genes; (ii) the accumulation of anomalous receptor forms; a nd (iii) deficient phosphorylation state of the receptor. Besides thei r conventional antioestrogenic activity, antioestrogens could also exe rt action which antagonizes the ''oestrogenic '' effects of various gr owth factors in cells expressing the oestrogen receptor. This action c ould cause antitumoral effects in the absence of oestrogens. Two main mechanisms could account for the resistance to antioestrogens in sensi tive mammary tumor cells: (i) loss of oestrogen-dependent expression o f growth factors, and (ii) change in the dominant activity of antioest rogens (antagonist --> agonist) in the cells, whose proliferation woul d be then stimulated by antioestrogens. New steroidal ''pure'' antioes trogens have been developed. These compounds seem capable of promoting dimerization and then receptor binding to target DNA. However, they c ould induce rapid and marked decreases in the oestrogen receptor conce ntration in cells, which might account for their antioestrogenic activ ity. These compounds are able to antagonize the oestrogenic effects of triphenylethylene antioestrogens and especially the growth of resista nt mammary tumors stimulated by the latter compounds. They are of grea t interest for the future treatment of mammary breast tumors expressin g the oestrogen receptor.