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 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.
Osheroff
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N
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232-0146.
Corbett
A H
AH
Elsea
S H
SH
Westergaard
M
M
D000677:Amsacrine / Q000633:toxicity; D000818:Animals; D000890:Anti-Infective Agents / Q000633:toxicity; D000970:Antineoplastic Agents / Q000145:classification / Q000633:toxicity*; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004249:DNA Damage; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D005047:Etoposide / Q000633:toxicity; D024841:Fluoroquinolones; D019833:Genistein; D006801:Humans; D007529:Isoflavones / Q000633:toxicity; D008961:Models, Structural; D015363:Quinolones / Q000633:toxicity; D059005:Topoisomerase II Inhibitors
D000890:Anti-Infective Agents; D000970:Antineoplastic Agents; D024841:Fluoroquinolones; D007529:Isoflavones; D015363:Quinolones; D059005:Topoisomerase II Inhibitors; D000677:Amsacrine; C070116:CP 115953; D005047:Etoposide; D004247:DNA; D019833:Genistein; D004250:DNA Topoisomerases, Type II