A structure-function analysis of DNA topoisomerase II inhibitors

DNA topoisomerases are ubiquitous enzymes that catalyze the interconversion of different topological forms of DNA. Topoisomerases are expressed at higher levels in logarithmically growing cells than in quiescent cells. Possibly, this enables differentiation between cancer and normal cells making this enzyme an attractive target for therapeutic intervention. Different types of topoisomerases, the mechanism of interconversion of DNA topological states, and structural requirements for cytotoxic poisons and catalytic inhibitors of these enzymes are discussed. Intercalative and non-intercalative cleavage complex poisons as well as the direct catalytic inhibitors provide for at least three different molecular modes of action, but future research is certain to show that additional mechanistic subdivions will be necessary to more completely characterize the cytotoxic mechanisms of these drugs