Breast cancer and fenretinide, an analogue of vitamin A.
Preclinical studies make fenretinide attractive for prevention and treatment of breast cancer. It inhibits mammary gland end bud formation in developing animals. Carcinogen-induced mammary cancer is suppressed by fenretinide, both at early and late stages of carcinogenesis, in young and mature rats. Fenretinide causes regression of invasive rat mammary cancer. Cytostatic activity has been demonstrated against human breast cancer cell lines. Autocrine stimulation of human breast cancer cell lines by tgf-alpha, insulin-like growth factors I and II is significantly abrogated by fenretinide. The human half-life is 24 hours. Absorption is markedly affected by meal content. Serum levels of 1 mM are achieved at doses of 200 mg/day. This dose significantly suppresses serum IGF-I levels in women. This concentration is capable of suppressing human breast cancer growth in vitro. A 3-day drug holiday is given each month in order to restore serum retinol levels. Under these circumstances, fenretinide is well tolerated. A phase III trial evaluating the efficacy of fenretinide for breast cancer prevention in high-risk women has been completed. Tamoxifen enhances the effectiveness of fenretinide in carcinogenesis models. The combination can be safely administered to women. A phase III adjuvant trial of tamoxifen, with or without fenretinide will be conducted in the United States.
Cobleigh
M A
MA
Rush-Presbyterian St. Luke's Medical Center, Chicago, IL.
D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D002986:Clinical Trials as Topic; D005260:Female; D017313:Fenretinide / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000188:drug therapy; D014407:Tumor Cells, Cultured
D017313:Fenretinide