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|Title:||A mechanistic study on reduced toxicity of irinotecan by coadministered thalidomide, a tumor necrosis factor-α inhibitor|
|Citation:||Yang, X.-X., Hu, Z.-P., Xu, A.-L., Duan, W., Zhu, Y.-Z., Huang, M., Sheu, F.-S., Zhang, Q., Bian, J.-S., Chan, E., Li, X., Wang, J.-C., Zhou, S.-F. (2006). A mechanistic study on reduced toxicity of irinotecan by coadministered thalidomide, a tumor necrosis factor-α inhibitor. Journal of Pharmacology and Experimental Therapeutics 319 (1) : 82-104. ScholarBank@NUS Repository. https://doi.org/10.1124/jpet.106.103606|
|Abstract:||Dose-limiting diarrhea and myelosuppression compromise the success of irinotecan (7-ethyl-10-[4-[1-piperidino]-1-piperidino] carbonyloxycamptothecin) (CPT-11)-based chemotherapy. A recent pilot study indicates that thalidomide attenuates the toxicity of CPT-11 in cancer patients. This study aimed to investigate whether coadministered thalidomide modulated the toxicities of CPT-11 and the underlying mechanisms using several in vivo and in vitro models. Diarrhea, intestinal lesions, cytokine expression, and intestinal epithelial apoptosis were monitored. Coadministered thalidomide (100 mg/kg i.p. for 8 days) significantly attenuated body weight loss, myelosuppression, diarrhea, and intestinal histological lesions caused by CPT-11 (60 mg/kg i.v. for 4 days). This was accompanied by inhibition of tumor necrosis factor-α, interleukins 1 and 6 and interferon-γ, and intestinal epithelial apoptosis. Coadministered thalidomide also significantly increased the systemic exposure of CPT-11 but decreased that of SN-38 (7-ethyl-10-hydroxycampothecin). It significantly reduced the biliary excretion and cecal exposure of CPT-11, SN-38, and SN-38 glucuronide. Thalidomide hydrolytic products inhibited hydrolysis of CPT-11 in rat liver microsomes but not in primary rat hepatocytes. In addition, thalidomide and its major hydrolytic products, such as phthaloyl glutamic acid (PGA), increased the intracellular accumulation of CPT-11 and SN-38 in primary rat hepatocytes. They also significantly decreased the transport of CPT-11 and SN-38 in Caco-2 and parental MDCKII cells. Thalidomide and PGA also significantly inhibited P-glycoprotein (PgP/MDR1), multidrug resistance-associated protein (MRP1)- and MRP2-mediated CPT-11 and SN-38 transport in MDCKII cells. These results provide insights into the pharmacodynamic and pharmacokinetic mechanisms for the protective effects of thalidomide against CPT-11-induced intestinal toxicity. Copyright © 2006 by The American Society for Pharmacology and Experimental Therapeutics.|
|Source Title:||Journal of Pharmacology and Experimental Therapeutics|
|Appears in Collections:||Staff Publications|
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