BREAST-CANCER AND FENRETINIDE, AN ANALOG OF VITAMIN-A

Preclinical studies make fenretinide attractive for prevention and tre atment of breast cancer. It inhibits mammary gland end bud formation i n developing animals. Carcinogen-induced mammary cancer is suppressed by fenretinide, both at early and late stages of carcinogenesis, in yo ung and mature rats. Fenretinide causes regression of invasive rat mam mary cancer. Cytostatic activity has been demonstrated against human b reast cancer cell lines. Autocrine stimulation of human breast cancer cell lines by tgf-alpha, insulin-like growth factors I and II is signi ficantly abrogated by fenretinide. The human half-life is 24 hours. Ab sorption is markedly affected by meal content. Serum levels of 1 mM ar e achieved at doses of 200 mg/day. This dose significantly suppresses serum IGF-I levels in women. This concentration is capable of suppress ing human breast cancer growth in vitro. A 3-day drug holiday is given each month in order to restore serum retinol levels. Under these circ umstances, 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 fen retinide in carcinogenesis models. The combination can be safely admin istered to women. A phase III adjuvant trial of tamoxifen, with or wit hout fenretinide will be conducted in the United States.