Comparative effects of ASTA Z 7557 (INN mafosfamide) and cyclophosphamide on hematopoiesis in mice

Abstract

Acute effects of ASTA Z 7557 and Cyclophosphamide (Cy) on pluripotential (CFU-S), granulocytic (CFU-C), early erythroid (BFU-E) and late erythroid (CFU-E) progenitor cells in the bone marrow, as well as on RBC and WBC, were compared in F1 (CBA X C 57 BL) female mice. Dose-survival curves of both agents for CFU-S and CFU-C were found to be exponential, indicating that the effects of the drugs have no cell cycle dependency. At equimolar doses, marrow CFU-S and CFU-C contents appeared to decrease more rapidly with increasing doses of ASTA Z 7557 than with those of Cy. After a single dose of 200 mg/kg of each drug ( = 50% LD10), there was greater initial suppression of CFU-S, CFU-C, BFU-E and CFU-E in the Cy-treated animals than in ASTA Z 7557-treated mice. In both groups, however, the WBC had their nadir on Day 3 after treatment, followed by a return to normal by Day 8. In ASTA Z 7557-treated animals, the recovery of CFU-S, CFU-C and BFU-E was also completed by Day 8 after treatment. In Cy-treated mice, however, complete recovery of these cells was achieved on Day 15. Results indicate quantitative rather than qualitative differences between the marrow toxicities of ASTA Z 7557 and Cy in mice. Quantitative differences could be due to different pharmacokinetic properties of the agents, since Cy is excreted in partially unmetabolized form, and it might be that this inactive part of the agent grew increasing drug doses.