DNA-DAMAGE AND MUTAGENESIS INDUCED BY NITROGEN MUSTARDS

The nitrogen mustards are bifunctional alkylating agents which, althou gh used extensively in cancer chemotherapy, are themselves highly carc inogenic. All nitrogen mustards induce monofunctional guanine-N7 adduc ts, as well as interstrand N7-N7 crosslinks involving the two guanines in GNC.GNC (5' --> 3'/5' --> 3') sequences. In addition, the aromatic mustards melphalan and chlorambucil also induce substantial alkylatio n at adenine N3, while cyclophosphamide forms phosphotriesters with re latively high frequency. Nitrogen mustards are genotoxic in virtually every assay, and produce a wide array of mutations, including base sub stitutions at both G.C and A.T base pairs, intragenic as well as multi locus deletions, and chromosomal rearrangements. Mutational spectra ge nerated by these agents in various model systems vary widely, and no s ingle lesion has been implicated as being primarily responsible for mu stard-induced mutagenesis. On the contrary, adducts of both adenine an d guanine, and monofunctional as well as bifunctional adducts, appear to be involved. Further, it is still not known which types of mutation are responsible for mustard-induced cancers, since no genes have yet been identified which are consistently altered in these malignancies.