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

Topoisomerase II is the primary cellular target for a variety of antin eoplastic drugs that are active against human cancers. These drugs exe rt their cytotoxic effects by stabilizing covalent topoisomerase II-cl eaved DNA complexes that are fleeting intermediates in the catalytic c ycle of the enzyme. Despite this common feature of drug action, a numb er of mechanistic differences between drug classes have been described . These mechanistic differences (in eluding effects on DNA cleavage/re ligation, DNA strand passage, and adenosine triphosphate hydrolysis) w ere used as the basis for a series of competition experiments to deter mine whether different compounds share a common site of action on topo isomerase II or interact at distinct sites. Results of the present stu dy strongly suggest that at least four structurally disparate antineop lastic drugs, etoposide, amsacrine, genistein, and the quinolone CP-11 5,953, share an overlapping interaction domain on the enzyme.