Effect of the Selective Estrogen Receptor Modulator Arzoxifene on Repopulation of Hormone-Responsive Breast Cancer Xenografts between Courses of Chemotherapy

Abstract

Selective inhibition of repopulation of clonogenic tumor cells between courses of chemotherapy has potential to improve the effectiveness of treatment. Here we study arzoxifene, a short-acting selective estrogen receptor modulator, for its potential to inhibit repopulation in estrogen-dependent human breast cancer MCF-7 xenografts between courses of chemotherapy. Proliferation of tumor cells was evaluated by cyclin D1 expression and uptake of 5-bromo-2'-deoxyuridine. Arzoxifene decreased cell proliferation in xenografts. To model adjuvant treatment of human breast cancer, MCF-7 cells were injected s.c. into nude mice and four groups of mice received the following treatments beginning after implantation: (a) control (vehicle solution); (b) arzoxifene alone, 5 days per week by oral gavage for 3 weeks; (c) 5-fluorouracil (5-FU) or paclitaxel i.p. weekly, for 3 doses; and (d) arzoxifene following each cycle of chemotherapy. The incidence of tumors with volume > or =50 mm(3) was determined as a function of time. MCF-7 xenografts developed in 100% of control mice by 4 weeks after implantation. Paclitaxel or 5-FU alone had minor effects to delay the appearance of xenografts whereas arzoxifene alone caused longer delay. Combined treatment with arzoxifene given between cycles of 5-FU or paclitaxel had substantial effects, with approximately 50% tumor incidence by 5 weeks. Our results indicate that arzoxifene can inhibit repopulation of hormone-responsive MCF-7 breast cancer xenografts when given between courses of chemotherapy. The scheduling of short-acting hormonal agents between courses of adjuvant chemotherapy for human breast cancer has potential to improve the outcome of treatment.