Changes in DNA Supercoiling Status of Cells Treated with Antineoplastic Drugs

Abstract

Many antineoplastic drugs have recently been found to exert their cytotoxic effects by interfering with DNA metabolism through the poisoning of DNA topoisomerases. DNA topoisomerases are ubiquitous nuclear enzymes that, as their name implies, are involved in the regulation of DNA topology. These enzymes have been found to play key roles in virtually every aspect of nucleic acid metabolism by regulating localized changes in DNA supercoiling. At least two forms of DNA topoisomerases exist in eukaryotic cells: form I, which relaxes DNA supercoils through the breakage and reunion of a single DNA strand; and form II, which passes an intact DNA double helix through an enzyme mediated double-strand break. Topoisomerase poisons act by stabilizing topoisomerase-mediated strand breaks. These protein-linked single- and double-strand breaks disrupt DNA metabolism in two ways: (1) by abolishing control over DNA supercoiling dynamics, and (2) by physically hindering the processes of transcription and replication due to the presence of bulky protein-DNA adducts. To understand the mechanism of cell killing by topoisomerase poison-induced strand break induction, the nature of the lesion must be considered in the context of genomic ultrastructural organization.