Irinotecan (CPT-11) is a prodrug that is used to treat metastatic colorectal cancer. It is activated to the topoisomerase poison SN-38 by carboxylesterases. SN-38 is subsequently metabolised to its inactive glucuronide, SN-38G, which can however be reactivated to SN-38 by β-glucuronidase. The purpose of this study was to examine the role of carboxylesterases and β-glucuronidase in the in vitro production of SN-38 in human colorectal tumours. The production of SN-38 from CPT-11 and SN-38G was measured by HPLC in human colorectal tumour homogenates. Carboxylesterase and β-glucuronidase activities were found to be lower in tumour tissues compared to matched normal colon mucosa samples. In colorectal tumour, β-glucuronidase and carboxylesterase-mediated SN-38 production rates were comparable at clinically relevant concentrations of SN-38G and CPT-11, respectively. Therefore, tumour β-glucuronidase may play a significant role in the exposure of tumours to SN-38 in vivo, particularly during prolonged infusions of CPT-11.

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