14 Anticancer Drugs That Convert DNA Topoisomerases into DNA Damaging Agents

Abstract

I. INTRODUCTION
The importance of DNA topoisomerases as molecular targets in clinical pharmacology has become increasingly evident (for review, see Ross 1985; Chen and Liu 1986; Bodley and Liu 1988; Drlica and Franco 1988; Liu 1989). Topoisomerases change the topology of DNA by two fundamentally different mechanisms. Type-I DNA topoisomerases transiently break one strand of the duplex DNA, whereas type-II DNA topoisomerases transiently break both DNA strands during each catalytic cycle. Although the catalytic activity of topoisomerases is important for many DNA functions, topoisomerase-targeting therapeutic agents exert their therapeutic action not through inhibition of the catalytic activity of topoisomerases but through a mechanism involving DNA damage. So far, all known topoisomerase-targeting therapeutics specifically and reversibly block the DNA rejoining step of topoisomerases, resulting in the trapping of a covalent enzyme/DNA intermediate termed the cleavable complex (for review, see Liu 1989). The cleavable complex can be irreversibly converted to topoisomerase-linked DNA breaks upon addition of a strong protein denaturant. This type of “DNA lesion” differs from other types of covalent DNA modifications in its reversibility: The lesion disappears upon removal of the inhibitors.

According to this proposed mechanism of drug action, DNA can be viewed as the cotarget of this class of topoisomerase inhibitors. Because many of the cellular effects of these therapeutics are due to their “DNA damaging” effects rather than their inhibition of enzyme activities, this class of topoisomerase inhibitors can be viewed as “topoisomerase poisons” (Kreuzer and Cozzarelli 1979; Liu 1989).

The potential of topoisomerase poisons in clinical...