The anti-tumor 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, 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.
Eliason
J F
JF
Nippon Roche Research Center, Department of Oncology, Kanagawa Prefecture, Japan.
Inoue
T
T
Kubota
A
A
Horii
I
I
Hartmann
D
D
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001853:Bone Marrow / Q000187:drug effects*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000633:toxicity*; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012176:Retinoids / Q000008:administration & dosage / Q000494:pharmacology*
D000970:Antineoplastic Agents; D009025:Morpholines; D012176:Retinoids; C081137:mofarotene; D005472:Fluorouracil