Long-term carcinogenicity of cyclophosphamide in two mouse strains with different spontaneous leukemia incidence

The aim of the present study was to investigate to what extent the induction of leukemia by the carcinogenic agent cyclophosphamide (CPA) might be influenced by the genetic predisposition. CPA was s.c. administered at 26 mg/kg and 13 mg/kg weekly for lifetime to AKR mice which are genetically predisposed to develop leukemias, and to NMRI mice, that exhibit a low spontaneous leukemia rate. CPA dose-dependently increased the median life span in AKR mice by 27% and 76% (P less than 0.001), and decreased the incidence in leukemias by 17% and 37% (P less than 0.01), respectively. In NMRI mice, CPA significantly increased the incidence of leukemias by 46% at the low dose (P less than 0.02) and 26% at the high dose (P less than 0.03), respectively. The apparently parallel observations of the lower leukemia incidences following the higher CPA-dosage in both strains probably are related to different mechanisms of action: in the susceptible, genetically determined AKR mice the therapeutic effect of CPA prevailed its carcinogenic potential and the genetic host factors whereas in the resistant NMRI mice the cytotoxic efficacy of CPA reduced its carcinogenicity at the higher dosage.