Excision of DNA adducts of nitrogen mustards by bacterial and mammalian 3-methyladenine-DNA glycosylases

Abstract

Nitrogen mustards are among the DNA alkylating agents most widely used in chemotherapy. The homogeneous Escherichia coli AlKA protein (3-methyladenine DNA glycosylase II) is shown to excise damaged guanine and adenine bases from DNA modified by mechlorethamine, uracil mustard, phenylalanine mustard and chlorambucil, and less efficiently acridine mustard adducts. Homogeneous recombinant human and rat 3-methyladenine-DNA glycosylases excise adducts formed by nitrogen mustards less efficiently than the AlKA protein. In addition to the in vitro excision of adducts, the AlKA protein eliminates cytotoxic mechlorethamine adducts from DNA in vivo.