Inhibition of DNA synthesis is a potent mechanism by which cytostatic drugs induce homologous recombination in mammalian cells

Abstract

Recombination is a process thought to be underlying genomic instability involved in carcinogenesis. This report examines the potential of cytostatic drugs to induce intrachromosomal homologous recombination. In order to address this question, the hprt gene of a well-characterized mammalian cell line was employed as a unique endogenous marker for homologous recombination. Commonly used cytostatic drugs with different mode of action were investigated in this context, i.e. bifunctional alkylating agents, inhibitors of DNA synthesis, inhibitors of topoisomerases and a spindle poison. With the exception of the spindle poison, all these drugs were found to induce homologous recombination, with clear differences in their recombination potency, which could be related to their mechanism of action. Bifunctional alkylating agents were the least efficient, whereas inhibitors of DNA synthesis were found to be the most potent inducers of homologous recombination. This raises the question whether these later drugs should be considered for adverse effects in cancer chemotheraphy.