Mutagenic damage to mammalian cells by therapeutic alkylating agents

Cytotoxic alkylating agents used as therapeutics include nitrogen mustards, ethyleneimines, alkyl sulfonates, nitrosoureas and triazenes. Their reactivity with DNA, RNA and proteins can cause cell death. Side-effects of treatment include tissue toxicity and secondary malignancies, likely due to the genetic damage induced. The full mutagenic potential of alkylating agents may only be realised after they undergo metabolic activation, principally by cytochromes P450. Mutagenicity is related to the ability of alkylating agents to form crosslinks and/or transfer an alkyl group to form monoadducts in DNA. The most frequent location of adducts in the DNA is at guanines. Expressed mutations involve different base substitutions, including all types of transitions and transversions. The mutational spectra of alkylating agents on mammalian cells is distinct from that induced in bacterial cells, reflecting the different codon usage by bacteria and differences in DNA repair and replication enzymes. Mutations are induced by busulfan, chlorambucil (CAB), cyclophosphamide (CP, or its metabolite), dacarbazine, mechlorethamine, melphalan, mitomycin-C (MMC), nitrosoureas and thiotepa. Although dose-dependent, the relationship is not always linear. The molarities at which alkylating agents induce cell killing and mutations vary over three orders of magnitude. The mutagenic efficiency, of alkylating agents also varies, with some agents inducing three times more mutations for equivalent cell killing. The induction of micronuclei, sister chromatid exchanges, or chromosome aberrations is variable, but has been observed for CP, CAB, MMC, melphalan and triethylenemelamine. There is insufficient information to determine whether any synergistic effects of alkylating agents used in combination will influence the cytotoxic and mutagenic damage equally. Understanding the potential synergy of alkylating agents at the cellular and molecular level should allow improvement of the therapeutic efficacy of alkylating agents without increasing the unwanted mutation induction.