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DNA Cross-Linking and Single-Strand Breaks Induced by Teratogenic Concentrations of 4-Hydroperoxycyclophosphamide and Phosphoramide Mustard in Postimplantation Rat Embryos¹

Department of Pediatrics, University of Washington, Seattle, Washington 98195

Postimplantation rat embryos (Day 10) were exposed in vitro to teratogenic concentrations of 4-hydroperoxycyclophosphamide, an activated form of cyclophosphamide, and phosphoramide mustard, the major teratogenic metabolite of cyclophosphamide. Following a 5-h exposure to these agents, drug-induced DNA damage was assessed by alkaline elution. Both drugs induced detectable DNA cross-linking at teratogenic concentrations. Alkaline elution combined with proteinase K digestion indicated that approximately half of the DNA cross-linking was DNA-DNA cross-linking and the other half was DNA-protein cross-linking. In addition to DNA cross-linking, phosphoromide mustard produced DNA strand breaks and/or alkaline labile sites. However, 4-hydroperoxycyclo-phosphamide did not produce detectable DNA strand breaks or alkaline labile sites. Our data also indicate that the induction of abnormal morphogenesis by 4-hydroperoxycyclophosphamide and phosphoramide mustard is correlated with drug-induced DNA cross-linking.

¹ Supported by NIH Grant HD 16287.

Received 2/24/87. Revised 6/16/87. Accepted 7/15/87.

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