Deoxyribonucleic acid crosslinking by 4-hydroperoxycyclophosphamide in cyclophosphamide-sensitive and -resistant...

4-Hydroperoxycyclophosphamide, a synthetic, activated form of cyclophosphamide, has been used to study DNA crosslinking in L1210 cell lines sensitive and resistant to cyclophosphamide. The time course of crosslink appearance and the proportion of inter-strand to DNA-protein crosslinks support the belief that phosphoramide mustard is the ultimate alkylating agent derived from cyclophosphamide. Cell survival and DNA crosslinking studies with a cyclophosphamide-resistant L1210 cell line indicate that resistance is associated with a failure of 4-hydroperoxycyclophosphamide to produce DNA crosslinks. The ability to reverse this situation by exposure of resistant cells to disulfiram points to a role of aldehyde dehydrogenase in this mechanism of cyclophosphamide resistance.