We have evaluated the estrogen antagonist and agonist actions of antiestrogens in ovarian-dependent and autonomous rat mammary tumors, and in human MCF-7 breast cancer cells. Two of the antiestrogens (CI628 and U23,469), which we have prepared in high specific activity radiolabeled form, are metabolized during their action in vivo to demethylated forms that are preferentially localized in the nucleus and have a higher receptor affinity. Antiestrogens elicit regression of 90% of DMBA-induced tumors and during tumor regression, estrogen receptors are mainly localized in the nucleus and the level of prolactin receptors is diminished. Antiestrogens also markedly diminish the growth rate of the ovarian-autonomous but estrogen-sensitive R3230AC mammary tumor. Our studies indicate differences in the responses of tumor enzymes (glucose-6-phosphate dehydrogenase, malic enzyme, peroxidase) to estradiol and antiestrogen. Utilizing the high affinity tritium-labeled CI628 metabolite, CI628M, we find the antiestrogen-receptor complex to be similar to that of the estradiol-receptor complex in many ways, but to differ in its sedimentation properties and in its binding to DNA-cellulose. These may be suggestive of differences in chromatin interaction that may underlie the antagonist character of antiestrogens.
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