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Department of Oncology, Wyeth Research, 401 North Middle Town Road, Pearl River, New York, New York 10965, USA

(Requests for offprints should be addressed to Y Zhang; Email: zhangy{at}wyeth.com)

(Current address of T Annable is Kalypsys, 10420 Wateridge Circle, San Diego, CA 92121, USA)
(Current address of P Frost is ImClone Systems Incorporated, 180 Varick Street, New York, NY 10014, USA)
(Current address of L M Greenberger is Cancer Therapeutics Research, Johnson & Johnson Pharmaceutical Research, OMP Building, Room B354B, 1000 Route 202, Raritan, NJ, USA)

The effect of combinations of a mammalian target of rapamycin (mTOR) inhibitor, temsirolimus, and an estrogen receptor- (ER) antagonist, ERA-923, on breast carcinoma in culture and in a xenograft model has been studied. Phase III trials are underway using temsirolimus for several cancers. ERA-923 was studied in a phase I trial for tamoxifen refractory metastatic breast cancer and was shown to have good safety profiles. Combination of noninhibitory doses of temsirolimus with suboptimal doses of ERA-923 synergistically inhibited the growth of MCF-7 cells. Synergy was found across a wide range of doses and could also be achieved by combining temsirolimus with other antiestrogens such as raloxifene and 4-hydroxytamoxifen. In vivo combination of temsirolimus and ERA-923 at certain doses and schedules completely inhibited tumor growth, while individual agents were only partially effective. Although the mechanism underlying the synergism remains to be understood, the results were associated with the ability of temsirolimus to block the transcriptional activity mediated by ER as well as an increase in G1 arrest when it was combined with ERA-923. Results demonstrated for the first time that the combination of temsirolimus and a pure antiestrogen has excellent anticancer activity in preclinical models and, therefore, may have clinical use in treating hormone-dependent tumors.

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