Sequence-specific poisons of type II DNA topoisomerases

Publisher Summary DNA topoisomerases are nuclear enzymes that regulate DNA topology during transcription, replication, and recombination processes, and are essential for the integrity of the genetic material. Mammalian DNA topoisomerase II is the cellular target of important antitumor drugs, such as intercalating agents, minor-groove binders, and others. These agents interfere with topoisomerases by forming ternary DNA-drug—enzyme complexes in which DNA strands are broken and proteinlinked. Two isoforms of type II DNA topoisomerase are present in human and murine cells. The expression of these isozymes, encoded by two distinct genes, are differentially modulated during cell proliferation and development. The initial molecular event—that is, formation of the drug-stabilized cleavable complex, is a reversible process, thus how it can ultimately lead to cell death remains a very active area of research. Irreversible double-stranded DNA breaks, generated by interaction of cleavable complexes with ongoing DNA-dependent processes, may trigger a cell death program. The chapter describes the recent advances in the molecular pharmacology of sequence-specific antitumor topoisomerase II poisons.