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Clinical Cancer Research Vol. 6, 4893-4899, December 2000
© 2000 American Association for Cancer Research

Experimental Therapeutics, Preclinical Pharmacology

Cross-Resistance of Triphenylethylene-type Antiestrogens but not ICI 182,780 in Tamoxifen-stimulated Breast Tumors Grown in Athymic Mice1

Eun Sook Lee2, 3, Jennifer MacGregor Schafer2, Kathy Yao, Gale England, Ruth M. O’Regan, Alexander De Los Reyes and V. Craig Jordan4

Robert H. Lurie Comprehensive Cancer Center [E. S. L., J. M. S., A. D. L. R., V. C. J.], Division of Medical Oncology [R. M. O.], and Department of Surgery [G. E., K. Y.], Northwestern University Medical School, Chicago, Illinois 60611

The triphenylethylene antiestrogens, idoxifene (Idox) and toremifene (Tor), are structurally related analogues of tamoxifen (Tam) and were developed to improve the therapeutic index for advanced breast cancer patients. However, the issue of cross-resistance with Tam for these new agents is critical for clinical testing because the majority of breast cancer patients have already received or failed adjuvant Tam. The goal of this study was to determine the effectiveness of Idox as an antitumor agent in three models of Tam-stimulated breast cancer in athymic mice and compare the results with the actions of Tor and ICI 182,780 in a Tam-stimulated MCF-7 tumor model. We first compared the activities of Tam and Idox in the 17ß-estradiol (E2)-stimulated MCF-7 tumor line MT2:E2. Tam and Idox reduced E2-stimulated growth by 65–70% (week 9: P = 0.0009 for Tam, P = 0.0005 for Idox versus E2 alone). However, Tam (1.5 mg daily) and Idox (1.0 mg daily) both produced T47D breast tumors in athymic mice during 23 weeks of treatment (12 tumors/22 sites and 15 tumors/18 sites, respectively). Tam and Idox stimulated tumor growth equally in two different Tam-stimulated MCF-7 models and in a T47D model. Tor was completely cross-resistant with Tam in the MCF-7 tumor model, which implied that neither Idox nor Tor would be effective as a second-line endocrine therapy after Tam failure and may offer no therapeutic advantages over Tam as adjuvant therapies. In contrast, ICI 182,780, a pure antiestrogen currently being tested as a treatment for breast cancer after Tam failure, had no growth-stimulatory effect on the MCF-7 Tam-stimulated breast tumor line. This agent may provide an advantage as an adjuvant therapy and increase the time to treatment failure.




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