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 involves poisoning of topoisomerase II. VP-16 undergoes enzymatic oxido-reductive transformations in cells, resulting in the formation of the ortho-quinone derivative (VPQ) as a major product. The actions of VP-16 and VPQ on purified human topoisomerase II have been compared. Both the parent drug and VPQ are very efficient at trapping the topoisomerase II-DNA cleavable complex, suggesting that methoxy groups on the E-ring are not a prerequisite for activity. Our data also imply that VPQ has more effect than VP-16 on the breakage-reunion equilibrium of topoisomerase II and DNA. The stronger inhibition of the religation of the second strand observed with VPQ suggests it interacts asymmetrically with the two homodimers of topoisomerase II bound to DNA.