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Antitumor Activities and Estrogen Receptor Interactions of the Metabolites of the Antiestrogens CI628 and U23,469 in the 7,12-Dimethylbenz(a)anthracene-induced Rat Mammary Tumor System¹

Department of Physiology and Biophysics, University of Illinois, and School of Basic Medical Sciences, University of Illinois College of Medicine, Urbana, Illinois 61801

This study compares the antitumor activities of the nonsteroidal antiestrogens -{p-[2-(1-pyrrolidino)ethoxy]phenyl}-4-methoxy-'-nitrostilbene (CI628) and cis-{3-[p-(1,2,3,4-tetrahydro-6-methoxy-2-phenyl-1-naphthyl)phenoxy]-1,2-propanediol} (U23,469) with their demethylated metabolite forms in the dimethylbenz(a)anthracene-induced rat mammary tumor system. Since these demethylated forms are generated during the action of the parent antiestrogens in vivo and are selectively accumulated in the nuclear estrogen receptor fraction in preference to the parent compound, we investigated whether direct administration of the metabolites might prove more effective than administration of the parent antiestrogens in eliciting tumor regression. We have therefore compared the potencies of the parent antiestrogens and their demethylated forms -{p-[2-(1-pyrrolidino)ethoxy]phenyl}-4-hydroxy-'-nitrostilbene (CI628M) and cis-{3-[p-(1,2,3,4-tetrahydro-6-hydroxy-2-phenyl-1-naphthyl)-phenoxy]-1,2-propanediol} (U23,469M) in stimulating the regression of established dimethylbenz(a)anthracene-induced mammary tumors; and we have monitored the effects of these antiestrogens on estrogen receptors and the enzyme peroxidase as a specific marker for estrogen action in mammary tumors and in uteri of tumor-bearing animals.

In mammary tumor cytosol in vitro, the antiestrogens competed with [³H]estradiol for binding to estrogen receptor with affinities of 113% (CI628M), 5% (CI628), 31% (U23,469M), and 0.6% (U23,469), where the affinity of estradiol is considered to be 100%. However, all four antiestrogens were equally effective as antagonists of tumor growth in vivo. Administration of 25 or 100 µg daily of either parent (CI628 and U23,469) or the demethylated (CI628M and U23,469M) antiestrogens was able to elicit the regression of the majority of dimethylbenz(a)anthracene tumors, while low doses (2.5 µg/day) of any of these four compounds had no effect on tumor growth. The 25- and 100-µg doses of antiestrogens markedly reduced tumor cytoplasmic estrogen receptor levels, but they failed to elevate significantly tumor peroxidase activity. Uterine weights were significantly decreased below the diestrus controls following treatment with 25- or 100-µg daily dosages of the antiestrogens; and these treatments resulted in the nuclear localization of approximately 80% of total estrogen receptors. Uterine peroxidase activity, which was high in diestrus control females, was dramatically reduced to 5 to 25% by the intermediate- or high-dose levels of the antiestrogens.

These results indicate that, although the demethylated antiestrogens have a 20- to 50-fold enhanced affinity for the mammary tumor estrogen receptor in vitro as compared to their parent compound in vivo, where the parent compounds are rapidly converted to the demethylated metabolites, both forms are equally potent antitumor and antiuterotrophic agents. These high-affinity antiestrogens should be excellent ligands for experiments designed to elucidate the mechanism of antiestrogen action in breast cancer.

¹ Supported by USPHS NIH Grants CA 18119 from the National Cancer Institute and HD 06726 from the National Institute of Child Health and Human Development.

² To whom requests for reprints should be addressed.

Received 9/10/80. Accepted 12/29/80.

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