Bacteriophage T4, a model system for understanding the mechanism of type II topoisomerase inhibitors

Abstract

Bacteriophage T4 provides a simple model system for analyzing the mechanism of action of antitumor agents that inhibit DNA topoisomerases. The phage-encoded type II topoisomerase is sensitive to many of the same antitumor agents that inhibit mammalian type II topoisomerase, including m-AMSA, ellipticines, mitoxantrone and epipodophyllotoxins. Results from the T4 model system provided a convincing demonstration that topoisomerase is the physiological drug target and strong evidence that the drug-induced cleavage complex is important for cytotoxicity. The detailed molecular steps involved in cytotoxicity, and the mechanism of recombinational repair of inhibitor-induced DNA damage, are currently being analyzed using this model system. Studies with the T4 topoisomerase have also provided compelling evidence that topoisomerase inhibitors interact with DNA at the active site of the enzyme, with each class of inhibitor favoring a different subset of cleavage sites based on DNA sequence. Finally, analysis of drug-resistance mutations in the T4 topoisomerase have implicated certain regions of the protein in drug interaction and provided a strong link between the mechanism of action of the antibacterial quinolones, which inhibit DNA gyrase, and the various antitumor agents, which inhibit mammalian type II topoisomerase.