Cancer Treatment Reports October 1976 [antikvár]

Antiestrogenic and Antitumor Properties of Tamoxifen in Laboratory Animals1 V. Craig Jordan2-' * SUMMARY This paper reviews the antiestrogenic and antitumor properties of tamoxifen (NSC-180973; ICI-46474) in the rat. In classic tests for antiestrogenic activity, tamoxifen inhibits the actions of estradiol in the rat uterus and vagina. At the cellular level, tamoxifen inhibits estrogen binding to cytoplasmic estrogen receptors, but although estrogen-receptor units are translocated to the nucleus DNA synthesis does not occur. It is suggested that tamoxifen competes for estrogen receptors in the cytoplasm and the false messenger units block the nuclear acceptors which are normally activated by estradiol-estrogen receptor complexes thereby provoking DNA synthesis. Tamoxifen inhibits the growth of some 7,12-dimethylbenz(a)anthracene-induced rat mammary tumors whereas others continue to grow. Estrogen-stimulated rises in plasma prolactin are only partially inhibited by tamoxifen although at the tumor level, tamoxifen completely blocks estrogen binding. There is a linear correlation (P < 0.01) between estrogen-receptor levels in tumor biopsies before therapy and tumor responses to 3 weeks of tamoxifen treatment (50 /xg/day), ie, tumors with low levels of estrogen receptors do not respond to therapy whereas tumors with higher levels of estrogen receptors regress. It is suggested that tamoxifen antagonizes the actions of estrogen at the tumor level by blocking the estrogen-receptor mechanism thereby producing tumor regression. Therefore, estrogen-receptor measurements in tumor biopsies before therapy may be a useful predictive test for the tumor response to tamoxifen treatment. [Cancer Treat Rep 60:1409-1419, 1976] Harper and Walpole (1,2) first described the contrasting biologic activities of tamoxifen [trans-l-(p-l3-dimethylaminoethoxyphenyl)-l,2-diphenylbut-l-ene] and its cis isomer, ICI-47,699 (fig 1). In the rat, 'Supported by AID contract CSD 2837; by contract N01-CB-43967 from the Division of Cancer Biology and Diagnosis, National Cancer Institute, National Institutes of Health, Department of Health, Education, and Welfare; by ICI United States, Inc; arid by grants from the Yorkshire Cancer Research Campaign and ICI Ltd (Pharmaceuticals Division) in England. department of Pharmacology, Leeds University School of Medicine, England. 3I would like to thank Suzanne Koerner and Carol Roberson for their assistance in the studies undertaken at the Worcester Foundation for Experimental Biology, Shrewsbury, Mass, and Margaret M. Collins, C. J. Dix, Lynne J. Dowse, T. Jaspan, G. Prestwich, Linda Rowsby, and P. A. Rylett at Leeds University, England, for their invaluable assistance. *Reprint requests to: V. Craig Jordan, PhD, Department of Pharmacology, Leeds University School of Medicine, Leeds LS2 9NL, England. tamoxifen is antiestrogenic since it will inhibit estrogen-stimulated rises in uterine wet weight and inhibit vaginal cornification, whereas ICI-47,699 is a full estrogen and does not antagonize the actions of estradiol. By comparison, tamoxifen is a full estrogen in the mouse with ICI-47,699 being somewhat less potent (3). Of interest though, is the observation that the administration of large doses of tamoxifen to ovariectomized mice causes the vagina to cornify for a few days but then the vagina enters a prolonged diestrus when the tissue is unable to bind or respond to exogenous estradiol (4). In this paper the antiestrogenic properties of tamoxifen in the rat will be illustrated and a theory for the mechanism of action of the compound at the cellular level will be discussed. Since tamoxifen has a spectrum of activity in the control of human breast cancer (5,6), it was considered important to examine the antitumor properties of the compound Cancer Treatment Reports Vol. 60, No. 10, October 1976 1409