Carcinogen-induced rat mammary

Toremifene (Fareston , chlorotamoxifen Figure 5.15) has been thoroughly investigated in the laboratory [269-272] and has antitumor activity in carcinogen-induced rat mammary cancer, but is less potent than tamoxifen [272-274]. Toremifene has been tested extensively in phase I—III clinical trials [275-278] and has been approved for use in postmenopausal women with metastatic breast cancer [279]. As predicted from the reduced potency in animal studies, the dose required for activity is 60 mg of toremifene daily (tamoxifen is used at 20 mg daily). The side-effects are similar to those of tamoxifen and, as with tamoxifen, the responses are observed in ER-positive tumors. However, because adjuvant therapy with tamoxifen is standard throughout the world, issues of cross-resistance of tamoxifen and toremifene are important considerations for the use of toremifene in recurrent breast cancer. Laboratory studies by Osborne et al. [280] have demonstrated that toremifene-stimulated tumors can develop from MCF-7 breast cancer cells transplanted into athymic mice. Toremifene is cross-resistant with tamoxifen in tamoxifen-stimulated breast cancer in the laboratory [281]. Similarly, cross-over clinical trials demonstrate that there is little possibility of a second response to toremifene after tamoxifen failure [282, 283]. 

Idoxifene inhibits the growth of carcinogen-induced rat mammary tumors [293] and MCF-7 tumors grown in athymic mice [294, 295]. When compared to tamoxifen, idoxifene appears to have more antagonistic and less agonistic effects on ER in laboratory studies. Also, idoxifene has been reported to develop acquired antiestrogen resistance more slowly than tamoxifen [294]. However, there appears to be crossresistance in laboratory models of tamoxifen-stimulated growth [281]. 

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