This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Schafer, J. M. Articles by Jordan, V. C. Search for Related Content PubMed PubMed Citation Articles by Schafer, J. M. Articles by Jordan, V. C.

Analysis of Cross-Resistance of the Selective Estrogen Receptor Modulators Arzoxifene (LY353381) and LY117018 in Tamoxifen-stimulated Breast Cancer Xenografts¹

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

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:17ß-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.

This article has been cited by other articles:

				D. Nonclercq, F. Journe, I. Laios, C. Chaboteaux, R.-A. Toillon, G. Leclercq, and G. Laurent Effect of nuclear export inhibition on estrogen receptor regulation in breast cancer cells J. Mol. Endocrinol., August 1, 2007; 39(2): 105 - 118. [Abstract] [Full Text] [PDF]

				L. Wu and I. F. Tannock Effect of the Selective Estrogen Receptor Modulator Arzoxifene on Repopulation of Hormone-Responsive Breast Cancer Xenografts between Courses of Chemotherapy Clin. Cancer Res., November 15, 2005; 11(22): 8195 - 8200. [Abstract] [Full Text] [PDF]

				C. J. Fabian and B. F. Kimler Selective Estrogen-Receptor Modulators for Primary Prevention of Breast Cancer J. Clin. Oncol., March 10, 2005; 23(8): 1644 - 1655. [Full Text] [PDF]

				C. Osipo, H. Liu, K. Meeke, and V. C. Jordan The Consequences of Exhaustive Antiestrogen Therapy in Breast Cancer: Estrogen-Induced Tumor Cell Death Experimental Biology and Medicine, September 1, 2004; 229(8): 722 - 731. [Abstract] [Full Text] [PDF]

				C. J. Fabian, B. F. Kimler, J. Anderson, O. W. Tawfik, M. S. Mayo, W. E. Burak Jr., J. A. O'Shaughnessy, K. S. Albain, D. M. Hyams, G. T. Budd, et al. Breast Cancer Chemoprevention Phase I Evaluation of Biomarker Modulation by Arzoxifene, a Third Generation Selective Estrogen Receptor Modulator Clin. Cancer Res., August 15, 2004; 10(16): 5403 - 5417. [Abstract] [Full Text] [PDF]

				H. Liu, E.-S. Lee, C. Gajdos, S. T. Pearce, B. Chen, C. Osipo, J. Loweth, K. McKian, A. De Los Reyes, L. Wing, et al. Apoptotic Action of 17{beta}-Estradiol in Raloxifene-Resistant MCF-7 Cells In Vitro and In Vivo J Natl Cancer Inst, November 5, 2003; 95(21): 1586 - 1597. [Abstract] [Full Text] [PDF]

				S. Detre, S. Riddler, J. Salter, R. A'Hern, M. Dowsett, and S. R. D. Johnston Comparison of the Selective Estrogen Receptor Modulator Arzoxifene (LY353381) with Tamoxifen on Tumor Growth and Biomarker Expression in an MCF-7 Human Breast Cancer Xenograft Model Cancer Res., October 1, 2003; 63(19): 6516 - 6522. [Abstract] [Full Text] [PDF]

				A. Buzdar, J. A. O'Shaughnessy, D. J. Booser, J. E. Pippen Jr., S. E. Jones, P. N. Munster, P. Peterson, A. S. Melemed, E. Winer, and C. Hudis Phase II, Randomized, Double-Blind Study of Two Dose Levels of Arzoxifene in Patients With Locally Advanced or Metastatic Breast Cancer J. Clin. Oncol., March 15, 2003; 21(6): 1007 - 1014. [Abstract] [Full Text] [PDF]

				T. Bachleitner-Hofmann, B. Pichler-Gebhard, M. Rudas, M. Gnant, S. Taucher, D. Kandioler, E. Janschek, P. Dubsky, S. Roka, E. Sporn, et al. Pattern of Hormone Receptor Status of Secondary Contralateral Breast Cancers in Patients Receiving Adjuvant Tamoxifen Clin. Cancer Res., November 1, 2002; 8(11): 3427 - 3432. [Abstract] [Full Text] [PDF]

				R. C. Dardes, R. M. O'Regan, C. Gajdos, S. P. Robinson, D. Bentrem, A. De Los Reyes, and V. C. Jordan Effects of a New Clinically Relevant Antiestrogen (GW5638) Related to Tamoxifen on Breast and Endometrial Cancer Growth in Vivo Clin. Cancer Res., June 1, 2002; 8(6): 1995 - 2001. [Abstract] [Full Text] [PDF]

				M. B. Sporn Hobson's Choice and the Need for Combinations of New Agents for the Prevention and Treatment of Breast Cancer J Natl Cancer Inst, February 20, 2002; 94(4): 242 - 243. [Full Text] [PDF]

				R. M. O'Regan, C. Gajdos, R. C. Dardes, A. De Los Reyes, W. Park, A. W. Rademaker, and V. C. Jordan Effects of Raloxifene After Tamoxifen on Breast and Endometrial Tumor Growth in Athymic Mice J Natl Cancer Inst, February 20, 2002; 94(4): 274 - 283. [Abstract] [Full Text] [PDF]

				N. Suh, A. L. Glasebrook, A. D. Palkowitz, H. U. Bryant, L. L. Burris, J. J. Starling, H. L. Pearce, C. Williams, C. Peer, Y. Wang, et al. Arzoxifene, a New Selective Estrogen Receptor Modulator for Chemoprevention of Experimental Breast Cancer Cancer Res., December 1, 2001; 61(23): 8412 - 8415. [Abstract] [Full Text] [PDF]

				R. C. Dardes, D. Bentrem, R. M. O'Regan, J. M. Schafer, and V. C. Jordan Effects of the New Selective Estrogen Receptor Modulator LY353381.HCl (Arzoxifene) on Human Endometrial Cancer Growth in Athymic Mice Clin. Cancer Res., December 1, 2001; 7(12): 4149 - 4155. [Abstract] [Full Text] [PDF]