Topoisomerase enzymes as drug targets.
DNA topoisomerases catalyze changes in the topology of DNA. Recently, other functions have also been reported for these enzymes. For example, topoisomerase I participates in transcription by RNA polymerases I, II, and III, and also has a kinase activity. Topoisomerase I binds directly to at least two helicases, nucleolin and SV40 T antigen, and mechanistic studies show that T antigen alters the function of topoisomerase I. Additional protein and nucleotide interactions for both topoisomerases I and II suggest that each protein is multifunctional. It may be that the multifunctional nature of these enzymes is the basis for the antitumor activity seen with inhibitors of these enzymes. Clinical trials with combinations of CPT-11 and 5-fluorouracil for the treatment of colon cancer, and preclinical studies with CPT-11 and vincristine are particularly encouraging. Protracted schedules of administration of topoisomerase inhibitors will likely have greater antitumor effect than more concentrated, higher dose exposures, but a systematic determination of optimal schedules of administration is needed.
Guichard
S M
SM
Laboratoire de Pharmacologie, Institut Claudius Regaud, Toulouse, France.
Danks
M K
MK
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D004264:DNA Topoisomerases, Type I / Q000378:metabolism / Q000502:physiology*; D004250:DNA Topoisomerases, Type II / Q000378:metabolism / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II