Molecular aspects of carcinogenesis. Part B

Abstract

Nitrogen mustards represent a major group of alkylating agents that are used in the chemotherapy of cancer. It is commonly accepted that they exert their cytotoxic effects by their ability to produce interstrand crosslinks in DNA. The main target site of the two identical alkylating moieties is the N-7 position of guanine. By a Maxam-Gilbert-type reaction it is possible to identify "hot spots" for alkylation by nitrogen mustards. Analysis of data obtained reveal the importance of the DNA context for efficient alkylation. For most of~ the compounds the highest reactivity is observed ila regions of G clusters, while in the neighbourhood of cytosine residues alkylation is reduced. As a consequence intrastrand rather than interstrand crosslinks would be the major DNA lesions resulting from exposure to those agents. In contrast, uracil mustard and quinacrine mustard differ from the other nitrogen mustards with respect to their alkylaltion specificity. Although both of them, like the other compounds, preferentially react with the N-7 of D-guanosine, their efficiency is determined by specific interactions with the DNA. In the case of uracil mustard this causes a sequence preference for 5'-Y-G-C-3', and it should thus be superior at producing interstrand crosslinks. Since the substituent attached to the alkylating group of the drug can alter the DNA sequence preference for the reaction it may be possible to design new agents to optimise the selectivity of reaction with critical DNA sequences.