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 femur 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.