Please use this identifier to cite or link to this item:
|Title:||A mechanistic study on reduced toxicity of irinotecan by coadministered thalidomide, a tumor necrosis factor-α inhibitor||Authors:||Yang, X.-X.
|Issue Date:||2006||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||URI:||http://scholarbank.nus.edu.sg/handle/10635/99849||ISSN:||00223565||DOI:||10.1124/jpet.106.103606|
|Appears in Collections:||Staff Publications|
Show full item record
Files in This Item:
There are no files associated with this item.
checked on Jul 21, 2019
WEB OF SCIENCETM
checked on Jul 12, 2019
checked on Jul 20, 2019
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.