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Figure 1. Irinotecan, the active metabolite, SN-38, and its glucuronide (A), and formation of inhibitory complex of Top1-DNA-SN-38 much more potent than irinotecan (B). In liver, irinotecan is bioactivated through hydrolysis catalyzed by carboxylesterases to be converted into SN-38, an active metabolite of irinotecan. SN-38 undergoes glucuronide conjugation to be SN-38 glucuronide by a UDP-glucuronosyltransferase, UGT1A1, for the detoxification pathway. SN-38 glucuronide is hydrolyzed by b-glucuronidase after being excreted in the gut. In the tumor cells, SN-38 can target the Top1-DNA covalent reaction intermediates and reversibly stabilize the Top1-DNA-SN-38 complex. As illustrated in (B), the collision of the DNA replication fork, together with this ternary complex formation, ultimately results in lethal and irreversible double-strand breaks^[4]. Top1: Topoisomerase I.