DNA topoisomerases in cancer therapy

DNA topoisomerases I and II are nuclear enzymes which modify DNA topology by their ability to break and reseal one or both strands in concert. Each of these enzymes has important functions in DNA replication, and very likely in other genetic processes as well. In addition, each can serve as a cancer chemotherapy target. The plant alkaloid camptothecin traps DNA topoisomerase I in a form which is covalently linked to DNA. Presumably this action is the basis for its anti-tumor effect, although this has not been conclusively demonstrated. The evidence for DNA topoisomerase II as a target for intercalating agents and epipodophyllotoxins is more formidable. Each of these classes of agents traps the enzyme on DNA in a structure referred to as a 'cleavable complex'. Illicit recombination events, as well as induction of an 'SOS-like' response analogous to that found in bacteria, have been suggested as possible mechanisms for cell death following cleavable complex formation. Development of new agents directed at topoisomerase II will depend heavily on understanding the nature of the interaction between the drug, enzyme and DNA. Hypotheses are presented in this paper on this interaction. Intracellular content of topoisomerase II is linked to the ability of the cell to enter a G0-like state, and the inability of malignant cells to undergo such a change may provide part of the basis for therapeutic selectivity. The ability to modulate topoisomerase II levels may provide an opportunity for therapeutic intervention.