DNA topoisomerases are enzymes that disentangle the topological problems that arise in double-stranded DNA by the generation of either single or double strand breaks. Topoisomerases are ubiquitous enzymes, exsist in all living organisms. Type I topoisomerase cuts one strand of a DNA double helix, relaxation occurs, and then the cut strand is reannealed. Type II topoisomerase cuts both strands of one DNA double helix, pass another unbroken DNA helix through it, and then reanneal the cut strands. What’s more, biological functions of TOP2 isoforms are modulated by a variety of protein-protein interactions. Some of these interactions may affect enzyme activity, stability and localization.

In humans, topoisomerase II is a chemotherapy target. In prokaryotes, gyrase is an antibacterial target. Mammalian cells have two topoisomerase II (TOP2) isoforms: type IIA and type IIB topoisomerases, which possess similar structure and mechanisms. Type II topoisomerases play an important role in other processes such as transcription. Specifically, type IIA topoisomerase is essential for all cells, and is essential for separating replicated chromosomes. And type IIB topoisomerase is essential for normal development.

CP-67015 is a antibiotic and potent topoisomerase II inhibitor.

CP-67015, a potent topoisomerase II inhibitor, is a positive direct-acting mutagen in mammalian cells with both gene and chromosomal level effects. Importantly, CP-67015 interferes with a DNA replicative/repair process, perhaps by alteration of one or more DNA polymerase activities. In vitro cytogenetic studies showed strong clastogenic activity in human lymphocytes and in CHO cells. Besides, CP-67015 is also a quinolone antibiotic. It inhibits supercoiling activity of prokaryotic DNA gyrase, with 100% inhibition. In vivo, CP-67015 induces chromosome damage in mouse bone marrow cells.

Taken together, CP-67015 is a direct-acting mutagen in mammalian cells with both gene and chromosomal level effects.

[1]. Nitiss JL. Nat Rev Cancer. 2009 May;9(5):338-50.