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Influence of cyclophosphamide and 4-ketocyclophosphamide on mouse limb development.

Many studies have been performed on the in vivo teratogenicity of cyclophosphamide, and there is uncertainty whether the parent compound or P-450 generated alkylating metabolite(s) is the proximal teratogen(s). We have examined the influence of cyclophosphamide and a metabolite, 4-ketocyclophosphamide, on mouse limb development. Pregnant mice were injected with 10, 15 or 20 mg/kg of cyclophosphamide on days 9 to 11 of gestation. Hindlimb buds were maximally sensitive to 20 mg/kg of cyclophosphamide at 9 A.M. on day 11, and the predominant malformations formed were preaxial ectrodactyly and hemimelia. Hindlimb buds of the same gestational age exposed to cyclophosphamide in vitro responded identically to controls in morphology and uptake of 3H-thymidine and 35SO4. Exposure to 4-ketocyclophosphamide in culture, however, resulted in the formation of limbs with a "hemimelic" appearance and distal limb reduction, and with reduced uptake of 3H-thymidine and 35SO4. These findings support the position that the P-450 generated metabolite(s), and not the parent compound, is the proximal teratogen(s).