DNA topoisomerases as anticancer drug targets: from the laboratory to the clinic.
DNA topoisomerases play important roles in basic cellular biology. Recently they have been identified as the molecular targets of a variety of pharmaceutical agents. Some of the drugs that target the topoisomerases are anticancer drugs. These anticancer drugs work by a novel mechanism of action. They inhibit the topoisomerase molecule from religating DNA strands after cleavage. This leaves a cell with DNA breaks, which if not repaired, become lethal. In other words, these drugs convert the topoisomerase molecule into a DNA damaging agent. This is a stoichiometric relationship. Each anticancer drug molecule has the potential of interacting with one topoisomerase molecule to cause one DNA lesion. The clinical implication of this mechanism of drug action is that sensitivity to topoisomerase targeting drugs should be dependent on high topoisomerase levels. This is clearly true in laboratory systems. With new developments in in situ immunohistochemistry, topoisomerase expression can now be easily estimated in human cancers. From this information, it may be possible to predict the sensitivity or resistance of human cancers to topoisomerase targeting anticancer drugs.
Holden
J A
JA
Department of Pathology, University of Utah, Salt Lake City 84132, USA. joe.holden@path.med.utah.edu
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002986:Clinical Trials as Topic; D004249:DNA Damage; D004260:DNA Repair; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D059003:Topoisomerase Inhibitors
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D059003:Topoisomerase Inhibitors