Chapter 24. DNA Topoisomerases as Therapeutic Targets in Cancer Chemotherapy

Recent findings have shown that a large number or clinically important anticancer drugs affect the breakage-rejoining reaction of mammalian DNA topoisomerase II by trapping a covalent enzyme-DNA cleavable complex to the mechanism of cell killing by anticancer drugs. DNA topoisomerase may be a key component in the regulation of chromatin conformation and cell proliferation. DNA topoisomerases are enzymes that control the topology of DNA. They are involved in DNA replication, RNA transcription and recombination. Based on their mechanism of action, DNA topoisomerases have been categorized into two types. Type I and type II DNA topoisomerases catalyze the topological changes in DNA by transiently breaking one strand or two strands of the DNA helix, respectively. The most characteristic reaction of a type I DNA topoisomerase is the relaxation of super-helical DNA, The type II topoisomerases can catalyze the passing of two DNA segments those can lead to a number of topoisomerization reactions of DNA such as super-coiling/relaxation, knotting/unknotting, and catenation/decatenation. Recent studies suggest that mammalian DNA topoisomerases is highly regulated by the growth state of cells. The antitumor activity of topoisomerase II —targeting anticancer drugs may well be determined at least in part by the differential regulation of topoisomerase II in neoplastic cells. This chapter discusses protein-linked DNA breaks induced by a number of antitumor drugs. Adriamycin, an anthracycline, has been one of the most important anticancer drugs to use as because of its mode of DNA binding, adriamycin interferes with many DNA functions such as replication and transcription. The chapter also discusses evidence that DNA Tonoisomerase II is the drug target responsible for protein-linked DNA breaks, drug-induced DNA cleavage on cellular chromatin in cultured mammalian cells and mechanism of cell killing.