Response of Repair and Reduction Deficient Mutants to Agents Requiring Bioreduction

Abstract

The response of mammalian cells to various DNA-damaging agents is dependent upon a variety of factors including drug transport, drug metabolism and the effectiveness of cellular repair systems. Recently the availability of variant cell lines defective in various aspects of DNA repair and lines defective in certain metabolic enzyme activities has allowed the use of such cell lines to gain information on the types of lesions produced under various conditions and the enzymatic systems responsible for drug activation or inactivation. Recently there has also been a great deal of interest in a variety of agents which exhibit increased toxicity under conditions favouring bioreduction in the hope that such agents might play a role in cancer therapy because of their preferential toxicity toward hypoxic cells which are assumed to be resistant to both radiation and conventional chemotherapeutic agents. While such agents exhibit preferential toxicity to hypoxic cells, their practical use is limited by side effects which presumably arise as a result of activity in cells which are assumed to be aerobic. Consequently there is interest in the mechanisms leading to drug toxicity under both aerobic and hypoxic conditions and also in the nature of the lesions produced, and the nature of repair systems which may act to reduce drug effectiveness.