Analysis of Cross-Resistance of the Selective Estrogen Receptor Modulators Arzoxifene (LY353381) and LY117018 in Tamoxifen-stimulated Breast Cancer Xenografts

• Published in: Clinical cancer research 2001-08, Vol.7 (8), p.2505-2512
• Main Authors: SCHAFER, Jennifer Macgregor, LEE, Eun-Sook, DARDES, Rita C, BENTREM, David, O'REGAN, Ruth M, DE LOS REYES, Alexander, JORDAN, V. Craig
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; Chemotherapy; Drug Resistance, Neoplasm; Estradiol - therapeutic use; Female; Humans; Medical sciences; Mice; Mice, Nude; Pharmacology. Drug treatments; Piperidines - pharmacology; Pyrrolidines - pharmacology; Selective Estrogen Receptor Modulators - pharmacology; Tamoxifen - therapeutic use; Thiophenes - pharmacology; Time Factors; Treatment Outcome; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
• ISSN: 1078-0432; 1557-3265

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 (E 2 ) model, we compared the antiestrogenic/antitumor properties of Arzox and LY117018 and determined that neither Arzox nor LY117018 caused T47D:E 2 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 E 2 (0.3 cm silastic capsule) in T47D:Tam tumors. However, when T47D:E 2 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.