Emerging DNA topisomerase inhibitors as anticancer drugs.
Drugs that inhibit or poison the function of topoisomerase (topo) enzymes are one of the mainstays of cancer chemotherapy, and include some of the most widely used anticancer drugs. A major effort is going into improving the broad deficiencies of established agents: for topo I inhibitors, this includes better lactone stability than for camptothecin; for topo II inhibitors lower cardiotoxicity than for existing anthracycline/anthraquinone analogues and for both classes, ways to counteract cell efflux mechanisms. At the same time, new types of structures are also being explored and developed. This review covers 24 drugs (6 topo I inhibitors, 12 topo II inhibitors and 6 dual topo I/II inhibitors) at various stages of clinical development. Although many of the latter class are at an early stage of development, despite a lack of detailed structural biology on the target enzymes, the research area is vigorous and has the potential to open up specific new drug design approaches.
Denny
William A
WA
Auckland Cancer Society Research Centre, Shool of Medical Sciences, University of Auckland, New Zealand. b.denny@auckland.ac.nz
D000328:Adult; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D002648:Child; D002986:Clinical Trials as Topic; D004273:DNA, Neoplasm / Q000378:metabolism; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015394:Molecular Structure; D015337:Multicenter Studies as Topic; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors