Yeast Systems for Demonstrating the Targets of Anti-Topoisomerase II Agents

A key aspect of anti-topotsomerase drug action is that most antitopoisomerase drugs act by stabilizing an intermediate of the topoisomerase reaction (1 ). This intermediate consists of the enzyme covalently bound to DNA by a phosphotyrosine linkage, where the DNA strand scission has occurred, and is referred to as a covalent or cleavage complex. Complex-stabilizing topoisomerase II agents kill cells mainly because the topoisomerase :DNA covalent complex is DNA damage that interferes with DNA metabolic processes, and in mammalian cells, commits cells to apoptotic cell death (2 ) A substantial body of evidence has shown that DNA cleavage, rather than inhibition of enzyme activity is responsible for cell killing. Hence, complex-stabilizing anti-topoisomerase agents are referred to as topoisomerase poisons (1 ).