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Cross-Resistance of Triphenylethylene-Type Antiestrogens but Not ICI 182,780 in Tamoxifen-Stimulated Breast Tumors Grown in Athymic Mice1

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Cross-Resistance of Triphenylethylene-Type Antiestrogens but Not ICI 182,780 in Tamoxifen-Stimulated Breast Tumors Grown in Athymic Mice1 Vol. 6, 4893–4899, December 2000 Clinical Cancer Research 4893 Cross-Resistance of Triphenylethylene-type Antiestrogens but not ICI 182,780 in Tamoxifen-stimulated Breast Tumors Grown in Athymic Mice1 Eun Sook Lee,2, 3 Jennifer MacGregor Schafer,2 MCF-7 tumor model, which implied that neither Idox nor Kathy Yao, Gale England, Ruth M. O’Regan, Tor would be effective as a second-line endocrine therapy Alexander De Los Reyes, and V. Craig Jordan4 after Tam failure and may offer no therapeutic advantages over Tam as adjuvant therapies. In contrast, ICI 182,780, a Robert H. Lurie Comprehensive Cancer Center [E. S. L., J. M. S., pure antiestrogen currently being tested as a treatment for A. D. L. R., V. C. J.], Division of Medical Oncology [R. M. O.], and Department of Surgery [G. E., K. Y.], Northwestern University breast cancer after Tam failure, had no growth-stimulatory Medical School, Chicago, Illinois 60611 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. ABSTRACT The triphenylethylene antiestrogens, idoxifene (Idox) and toremifene (Tor), are structurally related analogues of INTRODUCTION 5 tamoxifen (Tam) and were developed to improve the thera- Tam is the endocrine treatment of choice for all stages of peutic index for advanced breast cancer patients. However, ER-positive breast cancer (1, 2) and the first agent used to the issue of cross-resistance with Tam for these new agents reduce the incidence of breast cancer in high-risk women (3). is critical for clinical testing because the majority of breast Although Tam is proven to provide survival advantages after cancer patients have already received or failed adjuvant adjuvant therapy, the development of drug resistance is a po- Tam. The goal of this study was to determine the effective- tentially limiting factor to extending therapy and to enhancing ness of Idox as an antitumor agent in three models of the beneficial actions of the drug (4). Tam-stimulated breast cancer in athymic mice and compare Clearly, any new antiestrogen that is developed for breast the results with the actions of Tor and ICI 182,780 in a cancer therapy must not produce premature drug resistance and Tam-stimulated MCF-7 tumor model. We first compared must have a better toxicological profile than Tam. A new ␤ antiestrogen that has the advantage of being used for extended the activities of Tam and Idox in the 17 -estradiol (E2)- therapy (Ͼ5 years) and has fewer serious side effects than Tam stimulated MCF-7 tumor line MT2:E2. Tam and Idox re- .would have broad applications as a treatment and preventative ؍ duced E2-stimulated growth by 65–70% (week 9: P 0.0009 Thus, a new antiestrogen must be proven to be superior to Tam ؍ for Tam, P 0.0005 for Idox versus E2 alone). However, Tam (1.5 mg daily) and Idox (1.0 mg daily) both produced in the laboratory before a commitment can be made for wide- T47D breast tumors in athymic mice during 23 weeks of spread clinical testing. However, any new agent must be tested treatment (12 tumors/22 sites and 15 tumors/18 sites, respec- clinically in a population of patients with recurrent breast cancer tively). Tam and Idox stimulated tumor growth equally in who may already have been exposed to Tam during adjuvant two different Tam-stimulated MCF-7 models and in a T47D therapy. As a result, there is a high probability that the disease model. Tor was completely cross-resistant with Tam in the will already be resistant to Tam. The issue of cross-resistance for the new agent will be critical for the success of clinical testing and ultimately the advancement of the drug for testing as an adjuvant therapy. The triphenylethylene derivatives, Idox and Tor, are struc- Received 7/7/00; revised 10/13/00; accepted 10/26/00. turally related analogues of Tam and have been studied to The costs of publication of this article were defrayed in part by the improve the therapeutic index (5). Idox differs from Tam in that payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to it contains an iodine atom located at position 4. This substitution indicate this fact. affords this compound a higher affinity for the ER and higher 1 These studies were funded by NIH Specialized Program of Research metabolic stability than Tam (6, 7). There is evidence that Idox Excellence in breast cancer 1P50 CA89018-01; a grant from Smith is more effective than Tam at inhibiting both MCF-7 cell growth Kline Beecham (Philadelphia); the generous support of the Lynn Sage Breast Cancer Foundation of Northwestern Memorial Hospital; and the in vitro (8) and rat mammary tumor growth in vivo (9), and in Avon Products Foundation. addition, Idox is less likely to develop drug resistance (10, 11). 2 Both of these authors contributed equally to this work. These data resulted in the clinical testing of Idox as a breast 3 Present address: Department of General Surgery, Korea University cancer treatment; however, it remains unclear whether structural Ansan Hospital, 516 Kojan-Dong Ansan City Kyunggi-Do, 425-020 South Korea. 4 To whom requests for reprints should be addressed, at Northwestern University Medical School, Robert H. Lurie Comprehensive Cancer Center, 8258 Olson Pavilion, 303 East Chicago Avenue, Chicago, IL 60611. Phone: (312) 908-5148; Fax: (312) 908-1372; E-mail: vcjordan@ 5 The abbreviations used are: Tam, tamoxifen; ER, estrogen receptor; ␤ nwu.edu. E2,17 -estradiol; Idox, idoxifene; Tor, toremifene. Downloaded from clincancerres.aacrjournals.org on October 1, 2021. © 2000 American Association for Cancer Research. 4894 Cross-Resistance of Idoxifene Table 1 Classification of breast tumors based on hormone Hormone and Drug Treatments. Mice were divided responsiveness into groups of 10 and were treated with E2, antiestrogen, or Tumor Derived from E2-stimulated Tam-stimulated combinations. Silastic E2 capsules (0.3 or 1 cm in length) were MCF-7:Tam MCF-7 cells No Yes made as described previously (22), implanted s.c., and replaced MT2:E2 MCF-7 cells Yes No after 8–10 weeks of treatment. The 0.3-cm E2 capsule produced MT2:Tam MCF-7 cells Yes Yes a mean of 83.8 pg/ml of serum E2, whereas the 1.0-cm capsule T47D:E T47D cells Yes No 2 produced 379.5 pg/ml of serum E (23). Each was designed to T47D:Tam T47D cells Yes Yes 2 represent the E2 levels observed in post- or premenopausal women, respectively. Tam (Sigma Chemical Co., St. Louis, MO), Tor (a gift from Orion Pharmaceutical, Oula, Finland), or Idox (a gift from Smith Kline Beecham, Philadelphia, PA) were analogues of Tam with less agonist effect are effective at inhib- first dissolved in ethanol and suspended in a solution of 90% iting the growth of Tam-resistant tumors. carboxymethylcellulose (1% carboxymethylcellulose in double- Tor, a chlorinated derivative of Tam, is approved for the distilled water) and 10% polyethylene glycol 400/Tween 80 treatment of advanced breast cancer in postmenopausal women (99.5% polyethylene glycol and 0.5% Tween 80). Ethanol was (12) and has been evaluated as an adjuvant therapy (13). Tor has evaporated under nitrogen before use. Tam, Tor, or Idox was a similar pharmacological profile to Tam, but it is less potent. administered p.o. at various doses: 0.5, 1.0, or 1.5 mg/mouse/ Tor is recommended at a dose of 60 mg daily, whereas Tam is day 5 days/week. ICI 182,780, a generous gift from Zeneca recommended at a dose of 20 mg daily. The primary reason for Pharmaceuticals, was dissolved in ethanol and suspended in developing Tor was to assuage concerns about rat liver carci- peanut oil to a final concentration of 50 mg/ml. Ethanol was nogenesis with Tam (14). An investigation of the mechanism of evaporated under nitrogen. ICI 182,780 was injected s.c. at a carcinogenesis suggests that the metabolic pathways necessary dose of 5 mg/mouse once a week. to induce DNA adducts are specific to the rat (15); therefore, the Tumor Measurements. Tumor measurements were per- results from these laboratory studies may have little relevance formed weekly using Vernier calipers. The cross-sectional area for humans. was calculated using the formula: length ϫ width/4 ϫ␲. We have developed a series of human models of drug Statistical Analysis. Comparisons in mean tumor be- resistance to Tam in the laboratory that may mimic drug resist- tween the animal groups were analyzed by ANOVA at each ance to Tam in the clinic (16–19). The initial goal of this study week and followed by unpaired Student’s t test. The two tailed was to compare and contrast the effectiveness of Idox as an P of the last week of each experiment was reported using antitumor agent in the MCF-7 and T47D models of Tam- StatMost 2.5 (Datamost Corp., Salt Lake City, UT). stimulated breast cancer. Our aim was not only to test the veracity of the view (10) that Idox is not cross-resistant with Tam so that clinical testing could proceed but also to build on RESULTS our experience in predicting clinical outcomes. Where possible, An initial study was carried out to determine the dose of we have compared our findings with Tor and the pure anties- Idox equivalent to that of Tam, which has been well established trogen ICI 182,780. The pure antiestrogen is not cross-resistant in our athymic nude mice model.
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