Tamoxifen aziridine (TA), an antiestrogen-based affinity label for the estrogen receptor, is highly selective and efficient in its covalent binding to the estrogen receptor (Katzenellenbogen et al., J. biol. Chem. 258 (1983) 3487-3495). Thus, it was of interest to investigate the biological character and potency of this compound and, in particular, to determine if the irreversible attachment of this tamoxifen-derived compound to the estrogen receptor would result in enhanced antiestrogenic properties or in unusual biological activity. The effect of tamoxifen aziridine and tamoxifen (Tam), the parent compound which is an antiestrogen that binds reversibly to the estrogen receptor, were compared with respect to their effects on uterine growth, growth of dimethylbenzanthracene (DMBA)-induced mammary tumors in rats, and proliferation and plasminogen activator activity of MCF-7 human breast cancer cells. In immature (day 20) rats, Tam and TA behaved as weak estrogen agonists and estrogen antagonists in that Tam or TA alone increased uterine weight to levels lower than that evoked by estradiol (E 2 ), and both were able to suppress the stimulation of uterine weight evoked by E 2 . Administration of Tam and TA via Alzet minipumps (25 or 200 μg/rat/day) to mature rats bearing DMBA-induced mammary tumors resulted in marked regression and/or disappearance of most tumors. Uterine weights were also suppressed in these mature rats by Tam and TA. Tam was slightly more potent than TA in evoking tumor regression and in suppressing uterine weights in these in vivo studies. In MCF-7 human breast cancer cells in culture, Tam and TA suppressed cell proliferation and evoked no increase in plasminogen activator activity by themselves, while being very effective in preventing plasminogen activator activity stimulation by E 2 . Thus, TA displayed a bioactivity profile similar to that of Tam, the reversibly binding ligand, in vitro and in vivo. The covalent attachment of TA to the receptor does not, therefore, markedly alter the biological character or potency of the antiestrogen receptor complex.
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