The anti‐tumor arotinoid RO 40‐8757 protects bone marrow from the toxic effects of 5‐fluorouracil

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Abstract
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, significantly enhanced the reduction in tumor burden and tumor number. In order to determine if Ro 40-8757 had a protective effect on 5-FU-treated animals, several studies were performed with non-tumor-bearing mice. The 5-FU was given once a week for 3 weeks at a dose that was lethal only after the third administration. When this treatment was combined with Ro 40-8757 given 5 times/week, approximately 50% of the mice survived. Examination of the progenitor cell contents of femura and spleens of treated mice indicated that the protective effect of Ro 40-8757 was manifested at the primitive hemopoietic progenitor cell level. Studies with murine bone marrow cells and human breast-cancer cell lines in vitro demonstrated that there was no interaction between the 2 drugs at the cellular level, indicating that the arotinoid does not enhance the ability of cells to metabolize 5-FU. This protective effect of the arotinoid makes it a useful potential partner for combination therapy with 5-FU.