DEFINING FUNCTIONAL DRUG-INTERACTION DOMAINS ON TOPOISOMERASE-II BY EXPLOITING MECHANISTIC DIFFERENCES BETWEEN DRUG CLASSES

作者：OSHEROFF N^*; CORBETT AH; ELSEA SH; WESTERGAARD M

来源：Cancer Chemotherapy and Pharmacology, 1994, 34: S19-S25.

DOI：10.1007/BF00684859

• DRUG-INTERACTION DOMAINS
• TOPOISOMERASE II
• DNA STRAND-BREAK
• DNA STRAND-PASSAGE

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 (in eluding 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.

• 出版日期1994-8