A mechanistic study on reduced toxicity of irontecan by coadministered thalidomide, a tumor necrosis factor-a inhibitor

Yang, Xiao-Xia, Hu, Ze-Ping, Xu, An-Long, Duan, Wei, Zhu, Yi-Zhun, Huang, Min, Sheu, Fwu-Shan, Zhang, Qiang, Bian, Jin-Song, Chan, Eli, Li, Xiaotian, Wang, Jian-Cheng and Zhou, Shu-Feng 2006, A mechanistic study on reduced toxicity of irontecan by coadministered thalidomide, a tumor necrosis factor-a inhibitor, Journal of pharmacology and experimental therapeutics, vol. 319, no. 1, pp. 82-104.

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Title A mechanistic study on reduced toxicity of irontecan by coadministered thalidomide, a tumor necrosis factor-a inhibitor
Formatted title Mechanistic study on reduced toxicity of irontecan by coadministered thalidomide, a tumor necrosis factor-α inhibitor
Author(s) Yang, Xiao-Xia
Hu, Ze-Ping
Xu, An-Long
Duan, Wei
Zhu, Yi-Zhun
Huang, Min
Sheu, Fwu-Shan
Zhang, Qiang
Bian, Jin-Song
Chan, Eli
Li, Xiaotian
Wang, Jian-Cheng
Zhou, Shu-Feng
Journal name Journal of pharmacology and experimental therapeutics
Volume number 319
Issue number 1
Start page 82
End page 104
Publisher American Association for Pharmacology Experimental Therapeutics
Place of publication Bethesda, Md.
Publication date 2006-06-30
ISSN 0022-3565
Summary 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-, interleukins 1 and 6 and interferon-, 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.
Language eng
Field of Research 111599 Pharmacology and Pharmaceutical Sciences not elsewhere classified
HERDC Research category C1.1 Refereed article in a scholarly journal
Copyright notice ©2006, American Association for Pharmacology Experimental Therapeutics
Persistent URL http://hdl.handle.net/10536/DRO/DU:30009155

Document type: Journal Article
Collection: School of Medicine
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