DNA-topoisomerase inhibitors

Abstract

The topology of DNA is regulated by DNA-topoisomerase enzymes, which induce either transient DNA single-strand breaks (topoisomerase I) or DNA double-strand breaks (topoisomerase II). The action of several anticancer drugs, eg, DNA intercalating agents (ie, anthracyclines, anthracenediones, anthrapyrazoles, amsacrines, and ellipticines) and epipodophyllotoxins, appears to be mediated by the enzyme topoisomerase II alpha. The action of camptothecins is mediated by topoisomerase I. All of these drugs cause the induction of DNA enzyme complexes. Some new topoisomerase inhibitors have instead the ability to inhibit the catalytic activity of the enzyme without inducing the formation of complexes. Inhibition of transcription and DNA replication have been implicated as the most likely mechanisms of cytotoxicity. The drugs stimulate DNA cleavage with a certain degree of sequence specificity, which is typical for each drug or class of drugs. The differences in the location of the cleavage sites may explain the different pharmacologic effects of the various topoisomerase inhibitors. Cellular resistance to topoisomerase inhibitors is due to decreased intracellular drug retention (eg, overexpression of P-170), to a decreased level of topoisomerase enzymes, or to mutations that reduce the drug sensitivity of the enzymes. Synergistic activity of the combination of topoisomerase I and topoisomerase II inhibitors or of topoisomerase inhibitors and radiotherapy has been found to be highly dependent on the sequence used.