Defining functional drug-interaction domains on topoisomerase II by exploiting mechanistic differences between drug classes.

Osheroff N, Corbett AH, Elsea SH, Westergaard M
Cancer Chemother Pharmacol. 1994 34 Suppl: S19-25

PMID: 8070023 · DOI:10.1007/BF00684859

Topoisomerase II is the primary cellular target for a variety of antineoplastic drugs that are active against human cancers. These drugs exert their cytotoxic effects by stabilizing covalent topoisomerase II-cleaved DNA complexes that are fleeting intermediates in the catalytic cycle of the enzyme. Despite this common feature of drug action, a number of mechanistic differences between drug classes have been described. These mechanistic differences (including effects on DNA cleavage/religation, DNA strand passage, and adenosine triphosphate hydrolysis) were used as the basis for a series of competition experiments to determine whether different compounds share a common site of action on topoisomerase II or interact at distinct sites. Results of the present study strongly suggest that at least four structurally disparate antineoplastic drugs, etoposide, amsacrine, genistein, and the quinolone CP-115,953, share an overlapping interaction domain on the enzyme.

MeSH Terms (15)

Amsacrine Animals Anti-Infective Agents Antineoplastic Agents DNA DNA Damage DNA Topoisomerases, Type II Etoposide Fluoroquinolones Genistein Humans Isoflavones Models, Structural Quinolones Topoisomerase II Inhibitors

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