Novel agents that potentially inhibit irinotecan-induced diarrhea

Yang, Xiaoxia, Hu, Zeping, Chan, Sui Y., Chan, Eli, Goh, Boon C.h.e.r, Duan, Wei and Zhou, Shufeng 2005, Novel agents that potentially inhibit irinotecan-induced diarrhea, Current medicinal chemistry, vol. 12, no. 11, pp. 763-771.

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Title Novel agents that potentially inhibit irinotecan-induced diarrhea
Author(s) Yang, Xiaoxia
Hu, Zeping
Chan, Sui Y.
Chan, Eli
Goh, Boon C.h.e.r
Duan, Wei
Zhou, Shufeng
Journal name Current medicinal chemistry
Volume number 12
Issue number 11
Start page 763
End page 771
Publisher Bentham Science Publishers Ltd
Place of publication Hilversum, The Netherlands
Publication date 2005-06
ISSN 0929-8673
1875-533X
Keyword(s) Irinotecan (CPT-11)
metabolism
cytochrome P450
glucuronidation
transport
toxicity
diarrhea
cytokine
Summary Irinotecan (CPT-11, 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin) has exhibited clinical activities against a broad spectrum of carcinomas by inhibiting DNA topoisomerase I (Topo I). However, severe and unpredictable dosing-limiting toxicities (mainly myelosuppression and severe diarrhea) hinder its clinical use. The latter consists of early and late-onset diarrhea, occurring within 24 hr or ≥ 24 hr after CPT-11 administration, respectively. This review highlights novel agents potentially inhibiting CPT-11-induced diarrhea, which are designed and tested under guidance of disposition pathways and potential toxicity mechanisms. Early-onset diarrhea is observed immediately after CPT-11 infusion and probably due to the inhibition of acetylcholinesterase activity, which can be eliminated by administration of atropine. Lateonset diarrhea appears to be associated with intestinal exposure to SN-38 (7-ethyl-10-hydroxycamptothecin), the major active metabolite of CPT-11, which may bind to Topo I and induce apoptosis of intestinal epithelia, leading to the disturbance in the absorptive and secretory functions of mucosa. CPT-11 and SN-38 may also stimulate the production of pro-inflammatory cytokines and prostaglandins (PGs), thus inducing the secretion of Na+ and Cl-. Early treatment of severe late-onset diarrhea with oral high-dose loperamide has decreased patient morbidity. Extensive studies have been conducted to identify other potential agents to ameliorate diarrhea in preclinical and clinical models. These include intestinal alkalizing agents, oral antibiotics, enzyme inducers, P-glycoprotein (PgP) inhibitors, cyclooxygenase-2 (COX-2) inhibitors, tumor necrosis factor-agr (TNF-α) inhibitors, or blockers of biliary excretion of SN-38. Further studies are needed to identify the molecular targets associated with CPT-11 toxicity and safe and effective agents for alleviating CPT-11-induced diarrhea.
Language eng
Field of Research 111502 Clinical Pharmacology and Therapeutics
Socio Economic Objective 860899 Human Pharmaceutical Products not elsewhere classified
HERDC Research category C1.1 Refereed article in a scholarly journal
ERA Research output type C Journal article
Copyright notice ©2005, Bentham Science Publishers Ltd.
Persistent URL http://hdl.handle.net/10536/DRO/DU:30009195

Document type: Journal Article
Collection: School of Medicine
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