Irinotecan Action Pathway

Irinotecan is a topoisomerase I inhibitor used in the treatment of cancer. It is hydrolyzed by esterases in the liver, intestine, and cytoplasm into the active metabolite SN-38, which binds to and inhibits the function of topoisomerase I. Topoisomerase I unwinds DNA by making transient single strand breaks that relieves the torsion of supercoiled DNA. In the unwound form, DNA can serve as a template for DNA replication as well as transcription. In the normal state, this effect is transient and the breaks DNA are quickly religated by topoisomerase I itself. SN-38 binding, however, inhibits religation and stabilizes the DNA-topoisomerase I complex in the cleaved DNA form, ultimately leading to breaks in both DNA chains and cell death.