Analysis of cross-resistance of the selective estrogen receptor modulators arzoxifene (LY353381) and LY117018 in tamoxifen-stimulated breast cancer xenografts

Jennifer MacGregor Schafer, Eun Sook Lee, Rita C. Dardes, David Bentrem, Ruth M. O’Regan, Alexander de Los Reyes, V. Craig Jordan

Research output: Contribution to journalArticle

46 Scopus citations

Abstract

Purpose: Cross-resistance is the primary issue facing the evaluation of new antiestrogens to treat metastatic breast cancer because they may be tested, initially, in populations of patients that have failed long-term adjuvant tamoxifen (Tam) therapy. Experimental Design: We have tested the benzothiophene derivatives, arzoxifene (Arzox; LY353381) and LY117018 in two models of Tam-stimulated tumor growth derived from either MCF-7 (M. M. Gottardis and V. C. Jordan, Cancer Res., 48: 5183-5187, 1988) or T47D (J. MacGregor Schafer et al., Clin. Cancer Res., 6: 4373-4380, 2000) breast cancer cells. Results: Using the MCF-7:Tam model, we found that both Arzox and LY117018 (1.5 mg/day) resulted in tumor growth and, therefore, were partially cross-resistant with Tam. Next, using the T47D:17β-estradiol (E2) model, we compared the antiestrogenic/antitumor properties of Arzox and LY117018 and determined that neither Arzox nor LY117018 caused T47D:E2 tumor growth after 21 weeks. In addition, we determined that long-term treatment does not result in failure and subsequent development of transplantable Arzox- or LY117018-stimulated tumors. To establish whether Arzox and LY117018 are cross-resistant in T47D: Tam tumors, mice were treated with Arzox or LY117018 (1.5 mg/day), and, again, we found that neither resulted in the growth of transplantable tumors. Lastly, we showed that Arzox and LY117018 were only partially able to compete with postmenopausal E2 (0.3 cm silastic capsule) in T47D: Tam tumors. However, when T47D:E2 tumors were treated for 7 days instead of 5 days, both Arzox and LY117018 were more effective. Conclusions: Arzox is not cross-resistant with Tam in the T47D athymic mouse model but does exhibit cross-resistance in the MCF-7 model.

Original languageEnglish (US)
Pages (from-to)2505-2512
Number of pages8
JournalClinical Cancer Research
Volume7
Issue number8
StatePublished - Jan 1 2001

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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