INHIBITION OF THE TOPOISOMERASE-II DNA CLEAVABLE COMPLEX BY THE ORTHO-QUINONE DERIVATIVE OF THE ANTITUMOR DRUG ETOPOSIDE (VP-16)

Etoposide (VP-16) is a widely used anticancer drug whose toxicity invo lves poisoning of topoisomerase II, VP-16 undergoes enzymatic oxido-re ductive transformations in cells, resulting in the formation of the or tho-quinone derivative (VPQ) as a major product, The actions of VP-16 and VPQ on purified human topoisomerase IT have been compared, Both th e parent drug and VPQ are very efficient at trapping the tupoisomerase II-DNA cleavable complex, suggesting that methoxy groups on the E-rin g are not a prerequisite for activity, Our data also imply that VPQ ha s more effect than VP-16 on the breakage-reunion equilibrium of topois omerase II and DNA. The stronger inhibition of the religation of the s econd strand observed with VPQ suggests it interacts asymmetrically wi th the two homodimers of topoisomerase II bound to DNA. (C) 1997 Acade mic Press.