Relative mutagenicity and teratogenicity of cyclophosphamide and two of its structural analogs

In this report, cyclophosphamide was compared to two of its structural analogs, 5,5-dimethylcyclophosphamide and diethylcyclophosphamide, with respect to mutagenic and teratogenic activities. Mutagenicity was assessed using Salmonella typhimurium TA 1535; teratogenicity was assessed in Sprague-Dawley rats on day 20 of gestation after intra-amniotic drug administration on day 13. After metabolic activation, cyclophosphamide caused base substitution mutations in S. typhimurium TA 1535 and major structural defects in both intra-amniotically injected and contralateral uninjected fetuses. 5,5-Dimethylcyclophosphamide was neither mutagenic nor teratogenic. Diethylcyclophosphamide was not mutagenic but was teratogenic. However, diethylcyclophosphamide was less potent as a teratogen than cyclophosphamide and, unlike cyclophosphamide, caused malformations only in the intra-amniotically injected fetuses. Diethylcyclophosphamide does liberate acrolein after metabolic activation. If acrolein is responsible for the teratogenic effects of diethylcyclophosphamide, the other major cytotoxic metabolite of cyclophosphamide, phosphoramide mustard, may account for the difference in teratogenic potency between cyclophosphamide and diethylcyclophosphamide. These results would suggest that acrolein, although apparently not mutagenic, mediates the teratogenicity of diethylcyclophosphamide and a significant proportion of the teratogenicity of cyclophosphamide.