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. 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-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.
Keywords: irinotecan (cpt), metabolism, cytochrome p, glucuronidation, transport, toxicity, diarrhea, cytokine
Current Medicinal Chemistry
Title: Novel Agents that Potentially Inhibit Irinotecan-Induced Diarrhea
Volume: 12 Issue: 11
Author(s): Xiaoxia Yang, Zeping Hu, Sui Yung Chan, Eli Chan, Boon Cher Goh, Wei Duan and Shufeng Zhou
Affiliation:
Keywords: irinotecan (cpt), metabolism, cytochrome p, glucuronidation, transport, toxicity, diarrhea, cytokine
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. 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-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.
Export Options
About this article
Cite this article as:
Yang Xiaoxia, Hu Zeping, Chan Yung Sui, Chan Eli, Goh Cher Boon, Duan Wei and Zhou Shufeng, Novel Agents that Potentially Inhibit Irinotecan-Induced Diarrhea, Current Medicinal Chemistry 2005; 12 (11) . https://dx.doi.org/10.2174/0929867054020972
DOI https://dx.doi.org/10.2174/0929867054020972 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
Call for Papers in Thematic Issues
Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.
The broad spectrum of the issue will provide a comprehensive overview of emerging trends, novel therapeutic interventions, and translational insights that impact modern medicine. The primary focus will be diseases of global concern, including cancer, chronic pain, metabolic disorders, and autoimmune conditions, providing a broad overview of the advancements in ...read more
Approaches to the treatment of chronic inflammation
Chronic inflammation is a hallmark of numerous diseases, significantly impacting global health. Although chronic inflammation is a hot topic, not much has been written about approaches to its treatment. This thematic issue aims to showcase the latest advancements in chronic inflammation treatment and foster discussion on future directions in this ...read more
Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications
The Special Issue covers the results of the studies on cellular and molecular mechanisms of non-infectious inflammatory diseases, in particular, autoimmune rheumatic diseases, atherosclerotic cardiovascular disease and other age-related disorders such as type II diabetes, cancer, neurodegenerative disorders, etc. Review and research articles as well as methodology papers that summarize ...read more
Chalcogen-modified nucleic acid analogues
Chalcogen-modified nucleosides, nucleotides and oligonucleotides have been of great interest to scientific research for many years. The replacement of oxygen in the nucleobase, sugar or phosphate backbone by chalcogen atoms (sulfur, selenium, tellurium) gives these biomolecules unique properties resulting from their altered physical and chemical properties. The continuing interest in ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Use of BNP and CRP as Biomarkers in Assessing Cardiovascular Disease:Diagnosis Versus Risk
Current Vascular Pharmacology Neuroprotective Mechanisms as Treatment Strategy in Alzheimers disease
Current Medicinal Chemistry - Central Nervous System Agents Pathogenesis in Childhood Idiopathic Nephrotic Syndrome: An Update of Patchwork
Current Pediatric Reviews Immunomodulatory Drugs (IMiDs™): A New Treatment Option for Myelodysplastic Syndromes
Current Pharmaceutical Biotechnology Diet Bioactive Compounds: Implications for Oxidative Stress and Inflammation in the Vascular System
Endocrine, Metabolic & Immune Disorders - Drug Targets Cannabinoid System in Neurodegeneration: New Perspectives in Alzheimers Disease
Mini-Reviews in Medicinal Chemistry A Role for Leptin in the Systemic Inflammatory Response Syndrome (SIRS) and in Immune Response
Current Drug Targets - Inflammation & Allergy AKT Signaling in Regulating Angiogenesis
Current Cancer Drug Targets Non-Analgesic Effects of Opioids: Opioids and the Endocrine System
Current Pharmaceutical Design Oxidative Bioactivation and Toxicity of Leflunomide in Immortalized Human Hepatocytes and Kinetics of the Non-Enzymatic to Its Major etabolitie, A77 1726
Drug Metabolism Letters Psychosocial Vulnerability and Early Life Adversity as Risk Factors for Central Sensitivity Syndromes
Current Rheumatology Reviews Biomechanical Stress-induced Signaling in Smooth Muscle Cells: An Update
Current Vascular Pharmacology Validity of Oxygen-Ozone Therapy as Integrated Medication Form in Chronic Inflammatory Diseases
Cardiovascular & Hematological Disorders-Drug Targets Protective Role of Melatonin in Liver Damage
Current Pharmaceutical Design Targeting the NF-κB pathway in prostate cancer: a promising therapeutic approach?
Current Drug Targets Electroporation Advances in Large Animals
Current Gene Therapy Paclitaxel Resistance: Molecular Mechanisms and Pharmacologic Manipulation
Current Cancer Drug Targets Molecular Dynamics as a Tool in Rational Drug Design: Current Status and Some Major Applications
Current Computer-Aided Drug Design The Shape of the Messenger: Using Protein Structure Information to Design Novel Cytokine-based Therapeutics
Current Pharmaceutical Design Screening of SLE-susceptible SNPs in One Chinese Family with Systemic Lupus Erythematosus
Current Bioinformatics