Teratogenicity and Neonatal Toxicity of Ifosfamide in Mice 1

Abstract

Summary

Ifosfamide (IFA) is a structural analog of cyclophosphamide (CP), an alkylating agent which causes perinatal toxicity in mice. The purpose of this study was to examine the teratogenicity and neonatal toxicity of IFA in Swiss Webster mice. IFA, 0, 5, 10 and 20 mg/kg ip, was given to pregnant mice on Day 11 of gestation and teratogenic effects were determined on Day 19. In other experiments, IFA, 45 mg/kg sc, was given to 1 day old mice and growth and development were followed for 49 days. Plasma levels of IFA and CP alkylating metabolites were determined in adult mice given doses of 100 mg/kg ip. IFA, 20 mg/kg, significantly increased resorption rate to 81.2 ± 5.6% and 10 and 20 mg/kg IFA significantly reduced fetal body weight to 82.5 and 48.6% of controls, respectively. IFA, 20 mg/kg, significantly increased the incidence of open eyes, internal and external hydrocephalus, micro-melia, adactyly, syndactyly, microcaudate, kinky tail, microphakia, kidney ectopia, hydronephrosis, missing or non-ossified skull bones, sternbrae, vertebrae and long bones. IFA, 5 mg/kg, significantly increased the incidence of supernumerary ribs. IFA administration to 1 day old mice significantly reduced mean body weight to 73.2% of controls and the ratio of tail length to body length from 0.97 to 0.86 after 49 days. Mortality was not increased. The levels of plasma alkylating metabolites in adult mice after IFA were significantly less than after CP. Neonatal toxicity induced by IFA resembled that of CP, while the teratogenic response to IFA, although qualitatively similar to CP, was quantitatively different.