DNA sequence specificity of antitumor agents. Oncogenes as possible targets for cancer therapy.

Abstract

An examination of the DNA sequence specificity of guanine-N7 alkylation for nitrogen mustards and chlorethylnitrosoureas revealed that large variations in alkylation intensities existed among different guanines in the DNA sequence. The most striking finding was that most agents reacted preferentially at runs of G's, the degree of preference being much greater than would be expected from the number of G's alone. This correlated with the molecular electrostatic potential induced at the guanine-N7 position by the nearest neighbor base pairs. Uracil and quinacrine mustards, however, showed distinctly different reaction patterns from other mustards and a detailed examination has led to structural hypotheses to account for the differences. Certain regions of the genome including regions in some oncogenes and the Epstein-Barr virus have unusually high GC contents (greater than 80% GC) which suggests that the antitumor effectiveness of alkylating agents may in part be due to selective reaction at certain regions in the genome. In fact certain mustards have been shown to exhibit enhanced reactivities with such regions in DNA fragments derived from the c-H-ras oncogene. The above findings point to the possibility of design of alkylating agents to optimise the selectivity of reaction with critical DNA regions. An alternative approach presently under investigation has emerged from an understanding of the characteristics of the sequence specific interaction of the natural oligopeptide antibiotics netropsin and distamycin in the minor groove of DNA. This has led to the synthesis of novel agents (lexitropsins) in which the binding specificity can be shifted from (AT)n in (GC)n in a predictable fashion. Thus the rational design of DNA sequence specific vectors linked to DNA reactive groups, such as alkylating or cleaving agents, could enable DNA damage to be delivered selectively to predetermined critical sites on the genome.