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

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, arzoxif ene (Arzox; LY353381) and LY117018 in two models of Tam-stimulated tumor gr owth derived from either MCF-7 (M. M. Gottardis and V. C. Jordan, Cancer Re s., 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-r esistant with Tam. Next, using the T47D:17 beta -estradiol (E-2) model, we compared the antiestrogenic/antitumor properties of Arzox and LY117018 and determined that neither Arzox nor LY117018 caused T47D:E2 tumor growth afte r 21 weeks. In addition, we determined that long-term treatment does not re sult in failure and subsequent development of transplantable Arzox- or LYI1 7018-stimulated tumors. To establish whether Arzox and LY117018 are cross-r esistant 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 trans plantable tumors. Lastly, we showed that Arzox and LY117018 were only parti ally able to compete with postmenopausal E-2 (0.3 cm silastic capsule) in T 47D: Tam tumors. However, when T47D:E2 tumors were treated for 7 days inste ad of 5 days, both Arzox and LY117018 were more effective. Conclusions: Arzox is not cross-resistant with Tam in the T47D athymic mous e model but does exhibit cross-resistance in the MCF-7 model.