Cross-resistance of triphenylethylene-type antiestrogens but not ICI 182,780 in tamoxifen-stimulated breast tumors grown in athymic mice

The triphenylethylene antiestrogens, idoxifene (Idox) and toremifene (Tor), are structurally related analogues of tamoxifen (Tam) and were developed t o improve the therapeutic index for advanced breast cancer patients. Howeve r, the issue of cross-resistance with Tam for these new agents is critical for clinical testing because the majority of breast cancer patients have al ready received or failed adjuvant Tam, The goal of this study was to determ ine the effectiveness of Idox as an antitumor agent in three models of Tam- stimulated breast cancer in athymic mice and compare the results with the a ctions of Tor and ICI 182,780 in a Tam-stimulated MCF-7 tumor model. We fir st compared the activities of Tam and Idox in the 17 beta -estradiol (E-2)- stimulated MCF-7 tumor line MT2:E-2. Tam and Idox reduced E-2-stimulated gr owth by 65-70% (week 9: P = 0.0009 for Tam, P = 0.0005 for Idox versus E-2 alone). However, Tam (1.5 mg daily) and Idox (1.0 mg daily) both produced T 47D breast tumors in athymic mice during 23 weeks of treatment (12 tumors/2 2 sites and 15 tumors/18 sites, respectively). Tam and Idox stimulated tumo r growth equally in two different Tam-stimulated MCF-7 models and in a T47D model. Tor was completely cross-resistant with Tam in the MCF-7 tumor mode l, which implied that neither Idox nor Tor would be effective as a second-l ine endocrine therapy after Tam failure and mag offer no therapeutic advant ages over Tam as adjuvant therapies. In contrast, ICI 182,780, a pure antie strogen currently being tested as a treatment for breast cancer after Tam f ailure, had no growth-stimulatory 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.