THE ANTITUMOR AROTINOID RO-40-8757 PROTECTS BONE-MARROW FROM THE TOXIC EFFECTS OF 5-FLUOROURACIL

Combination therapy with 5-fluorouracil (5-FU) and the arotinoid Ro 40 -8757 (mofarotene) of established chemically induced mammary tumors in rats was examined. The cytotoxic drug was administered weekly and Ro 40-8757 was given daily. The dose of Ro 40-8757 used in this study did not have an effect on tumor burden but, in combination with 5-FU, sig nificantly enhanced the reduction in tumor burden and tumor number. In order to determine if Ro 40-8757 had a protective effect on 5-FU-trea ted animals, several studies were performed with non-tumor-bearing mic e. The 5-FU was given once a week for 3 weeks at a dose that was letha l only after the third administration. When this treatment was combine d with Ro 40-8757 given 5 times/week, approximately 50% of the mice su rvived. Examination of the progenitor cell contents of femura and sple ens of treated mice indicated that the protective effect of Ro 40-8757 was manifested at the primitive hemopoietic progenitor cell level. St udies with murine bone marrow cells and human breast-cancer cell lines in vitro demonstrated that there was no interaction between the 2 dru gs at the cellular level, indicating that the arotinoid does not enhan ce the ability of cells to metabolize 5-FU. This protective effect of the arotinoid makes it a useful potential partner for combination ther apy with 5-FU. (C) 1994 Wiley-Liss, Inc.