Novel agents that potentially inhibit irinotecan-induced diarrhea

Xiaoxia Yang, Zeping Hu, Sui Yung Chan, Eli Chan, Boon Cher Goh, Wei Duan, Shufeng Zhou

Research output: Contribution to journalReview article

34 Scopus citations

Abstract

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. Late-onset 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-α (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.

Original languageEnglish (US)
Pages (from-to)1343-1358
Number of pages16
JournalCurrent Medicinal Chemistry
Volume12
Issue number11
DOIs
StatePublished - Jun 2 2005

Keywords

  • Cytochrome P450
  • Cytokine
  • Diarrhea
  • Glucuronidation
  • Irinotecan (CPT-11)
  • Metabolism
  • Toxicity
  • Transport

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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  • Cite this

    Yang, X., Hu, Z., Chan, S. Y., Chan, E., Goh, B. C., Duan, W., & Zhou, S. (2005). Novel agents that potentially inhibit irinotecan-induced diarrhea. Current Medicinal Chemistry, 12(11), 1343-1358. https://doi.org/10.2174/0929867054020972