Use of Antitopoisomerase Drugs to Study the Mechanisms of Induction of Chromosomal Damage

Abstract

There are different approaches to study the mechanisms of formation of chromosomal aberrations. One, which has been quite successful, is the use of agents which induce specific damage to DNA that can be followed in its evolution to produce chromosomal aberrations. Another approach consists of using agents that affect different cellular functions (i.e. DNA synthesis and repair) which are required to overcome the damage induced at the DNA level. The difficulties encountered in this type of method are the lack of agents whose target or mechanism of action inside the cell are well established. Among the quite few agents whose targets are well known, are the inhibitors of DNA topoisomerases which appear to be a promising tool to be used to understand the mechanisms of production of chromosomal damage and their kinetics. DNA topoisomerases are enzymes that are involved in DNA replication, recombination, chromatid segregation and transcription (for a review see Wang 1985; D’Arpa and Liu 1989). These enzymes catalyse the interconversions between topological isomers of DNA. DNA topoisomerase I (Topo I) breaks and rejoins one strand of the DNA double helix, whereas DNA topoisomerase II (Topo II) catalyzes the breakage and rejoining of both DNA strands. These enzymes produce transient DNA breaks through which other DNA strands can pass. A covalent protein-DNA intermediate during each cycle of strand breakage and reunion is formed (Zwelling et al. 1981). This protein-DNA intermediate has been termed the “cleavable complex”.