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A-Ring Substituted Estrogens as Inhibitors of the MXT Transplantable Mammary Ductal Carcinoma¹

Department of Biochemistry [S. C. B.] and Internal Medicine [J. P. H., T. C.], Wayne State University School of Medicine, and Department of Chemistry [J. P. H., D. O.], Michigan Cancer Foundation, Detroit, Michigan 48201

A-ring substituted estrogens have been examined as growth inhibitors of the hormone dependent MXT murine mammary tumor. Certain of these estrogen analogues inhibited the growth of newly implanted as well as established MXT tumors when administered either by s.c. or i.p. injections or by intubation. These compounds were nontoxic over a broad range of active levels. Amino and nitro groups, introduced at position-4 of estrone 3-methyl ether were particularly carcinostatic, a property not shared by 4-bromoestrone 3-methyl ether. In addition tumor inhibition was greatly diminished by placing the nitro group at the other ortho position (i.e., carbon-2). Evidence indicates that the A-ring substituted estrogens may function as growth inhibitors via the estrogen receptor mechanism in the case of 4-nitro- and 4-aminoestrone. The 3-methyl ethers of these compounds also blocked tumor growth, possibly through in vivo dealkylation leading to the free phenolic A-ring substituted estrogens. On the other hand, A-ring substituted 3-deoxyestrogens (particularly 4-nitro- and 4-aminoestratrien-17ß-ol), which do not bind to receptor, were also excellent inhibitors of hormone dependent MXT breast tumors and therefore must express their activity by mechanisms other than that mediated by receptor. The A-ring substituted estrogens are unlike tamoxifen and diethylstilbestrol which (a) display toxicity at optimum inhibitory doses and (b) are inactive or marginally active in rodent breast cancer models.

¹ Supported by NIH grant CA-37387 from the National Cancer Institute and in part by the Ben Kasle Trust for Cancer Research and an institutional grant to the Michigan Cancer Foundation from the United Foundation of Greater Detroit. Reported in part at the 20th and 21st Annual Meetings of the American Association for Cancer Research, Toronto, Canada, May 1984 and Houston, TX, May 1985, respectively.

² To whom requests for reprints should be addressed, at Department of Biochemistry, Wayne State University School of Medicine, 540 Canfield, Detroit, MI 48201.

Received 9/30/86. Revised 2/ 4/87. Accepted 6/ 5/87.