Preclinical studies with toremifene as an antitumor agent.
Toremifene is a nonsteroidal antiestrogen currently being evaluated for the treatment of breast cancer. Toremifene (10(-10)-10(-6) M) inhibited the growth of MCF-7 breast cancer cells in vitro but was ineffective against hormone-independent MDA-MB-231 cells. This activity was reproduced in vivo using the athymic mouse model. Maximal MCF-7 tumor growth was produced in athymic mice by circulating estradiol levels of approximately 200 pg/ml (from a 0.5 cm silastic capsule implanted sc). Toremifene (77 +/- 44 micrograms/day from a 2 cm silastic capsule) inhibited estradiol (0.5 cm capsule)-stimulated growth by more than 70%. No tumor growth was observed in mice treated with toremifene alone, although toremifene acted as a weak partial agonist and potent antagonist on the mouse uterus. The growth of MDA-MB-231 tumors was not influenced by either estradiol or toremifene. Toremifene (200 micrograms/day) was effective in preventing the development of 7,12-dimethylbenzanthracene-induced rat mammary tumors when given po from day 28 after carcinogen administration. The antitumor activity was reversed if the toremifene was stopped. These findings indicate toremifene is a tumoristatic agent rather than a tumoricidal agent. Clinical trials with toremifene should employ an indefinite treatment strategy to control tumor recurrence in adjuvant studies.
Robinson
S P
SP
Department of Human Oncology, University of Wisconsin Clinical Cancer Center, Madison 53792.
Parker
C J
CJ
Jordan
V C
VC
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000473:pathology; D004354:Drug Screening Assays, Antitumor; D004965:Estrogen Antagonists / Q000378:metabolism / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy; D051379:Mice; D008819:Mice, Nude; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D017312:Toremifene; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014599:Uterus / Q000187:drug effects
D000970:Antineoplastic Agents; D004965:Estrogen Antagonists; D013629:Tamoxifen; D017312:Toremifene