From fluorescence spectra to mutational spectra, a historical overview of DNA-reactive compounds

This historical survey has shown the emergence over a period of about 60 years of a coherent view of DNA-reactive carcinogens and their effects. The earliest workers, in the 'pre-Watson-Crick' era, probably thought that the mode of action of carcinogens, then largely comprising polycyclic aromatic hydrocarbons, would be revealed through a relationship to steroid hormones, and that they would have protein receptors. This may well apply, in a broad sense, to promoting agents in carcinogenesis. Demonstration of the mutagenicity of a chemical, mustard gas, shifted attention to alkylating agents as carcinogens, and to the concept of mutagens, carcinogens and cytotoxic agents as 'radiomimetic'. Alkylating carcinogens were shown to react with DNA in vitro and in vivo in ways consistent with their action as mutagens, particularly as inducers of base substitutions, GC-->AT transitions. Carcinogenic hydrocarbons were subsequently shown to react with DNA of their target tissue, mouse skin, to extents positively correlated with their carcinogenic potency. They were found to react through aralkylating metabolites to give products that can block DNA polymerase, but can also cause base substitutions of the transversion type, mainly GC-->TA. Current interest centres on correlating the observed base substitutions that activate oncogenes or inactivate tumour suppressor genes in human cancer with the nature of exogenous and endogenous mutagens and the chemistry of their reactions with DNA, in order to deduce whether specific carcinogens can be implicated in the etiology of cancers. Ancillary to these studies are determinations of carcinogen-DNA reaction products in DNA from human sources.