Tobin Peter J, Dodds Helen M, Clarke Stephen, Schnitzler Margaret, Rivory Laurent P
Department of Pharmacology, University of Sydney, New South Wales, Australia.
Oncol Rep. 2003 Nov-Dec;10(6):1977-9.
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 beta-glucuronidase. The purpose of this study was to examine the role of carboxylesterases and beta-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 beta-glucuronidase activities were found to be lower in tumour tissues compared to matched normal colon mucosa samples. In colorectal tumour, beta-glucuronidase and carboxylesterase-mediated SN-38 production rates were comparable at clinically relevant concentrations of SN-38G and CPT-11, respectively. Therefore, tumour beta-glucuronidase may play a significant role in the exposure of tumours to SN-38 in vivo, particularly during prolonged infusions of CPT-11.
伊立替康（CPT-11）是一种用于治疗转移性结直肠癌的前体药物。它通过羧酸酯酶被激活成为拓扑异构酶毒物SN-38。随后，SN-38被代谢为其无活性的葡糖醛酸苷SN-38G，然而，SN-38G可被β-葡糖醛酸酶重新激活为SN-38。本研究的目的是探讨羧酸酯酶和β-葡糖醛酸酶在人结直肠肿瘤体外生成SN-38中的作用。通过高效液相色谱法测定人结直肠肿瘤匀浆中CPT-11和SN-38G生成SN-38的情况。与匹配的正常结肠黏膜样本相比，发现肿瘤组织中的羧酸酯酶和β-葡糖醛酸酶活性较低。在结直肠肿瘤中，分别在临床相关浓度的SN-38G和CPT-11下，β-葡糖醛酸酶和羧酸酯酶介导的SN-38生成率相当。因此，肿瘤β-葡糖醛酸酶可能在体内肿瘤暴露于SN-38中发挥重要作用，尤其是在长时间输注CPT-11期间。
