Human DNA-Topoisomerases - Diagnostic and Therapeutic Implications for Cancer

Abstract

Topoisomerases constitute a family of highly conserved essential enzymes, which exist in all investigated living pro- and eukaryotic cells. They are indispensable for the control of DNA topology. Humans possess 4 types of topoisomerases, i. e. topoisomerase (topo) I, II, III and V. Topo I, a 100-kDa protein, is a member of the type-I enzyme group (type IB). Functionally, it is an ATP-independent DNA single-strand endonuclease and ligase that functions mainly during transcription but also during DNA replication. Topo II belongs to the type-II enzymes and is represented in humans by 2 highly homologous isoforms, alpha (170 kDa) and beta (180 kDa). Contrary to topo I, the 2 topo II isoforms are ATP-dependent double-strand endonucleases and ligases. Topo I and the beta-form of topo II are expressed in a proliferation-independent manner, whereas topo IIalpha is cell-cycle-regulated. Because of the crucial role of topoisomerases for the maintenance and replication of DNA during proliferation, cells become highly vulnerable when these functions are lost. Consequently, a wide range of drugs with cytostatic effects are topo inhibitors. Topo I inhibitors in clinical use belong to the camptothecin family, e. g. topotecan and irinotecan. Topo IIalpha inhibitors are constituents of most chemotherapeutic protocols and form a large heterogeneous group. It includes clinically used compounds such as the podophyllotoxin analogues etoposide and teniposide, the anthracyclines daunorubicin, doxorubicin and idarubicin, the anthracenedione mitoxantrone and amsacrine. Recently, substances with dual specificity that inhibit both topo I and topo IIalpha have been found. The clinical relevance of these new compounds remains to be established. Specific inhibitors of topo IIbeta have not been described yet. The majority of topo inhibitors interfere with the religation step in the normal action of the enzymes, which leads to a stabilisation of the so-called cleavable complex. This results in DNA single-strand breaks in the case of topo I or double-strand breaks in the case of topo II. DNA single-strand breaks due to topo I inhibition are converted into double-strand breaks in the course of DNA replication. Such topo-mediated DNA strand breaks likely induce repair or apoptosis mechanisms via p53 and/or p21(WAF1/Clip1). As a consequence, while topoisomerases are required for proliferation, proliferation is also essential for efficacious topo inhibition. The cell-cycle-dependent expression of topo IIwas also successfully used for prognostic evaluations of survival in patients with cancer. Copyright 2000 S. Karger GmbH, Freiburg