title: Therapeutic targeting of CPT-11 induced diarrhea: a case for prophylaxis.
abstract: CPT-11 (irinotecan), a DNA topoisomerase I inhibitor is one of the main treatments for colorectal cancer. The main dose limiting toxicities are neutropenia and late onset diarrhea. Though neutropenia is manageable, CPT-11 induced diarrhea is frequently severe, resulting in hospitalizations, dose reductions or omissions leading to ineffective treatment administration. Many potential agents have been tested in preclinical and clinical studies to prevent or ameliorate CPT-11 induced late onset diarrhea. It is predicted that prophylaxis of CPT-11 induced diarrhea will reduce sub-therapeutic dosing as well as hospitalizations and will eventually lead to dose escalations resulting in better response rates. This article reviews various experimental agents and strategies employed to prevent this debilitating toxicity. Covered topics include schedule/dose modification, intestinal alkalization, structural/chemical modification, genetic testing, anti-diarrheal therapies, transporter (ABCB1, ABCC2, BCRP2) inhibitors, enzyme (β-glucuronidase, UGT1A1, CYP3A4, carboxylesterase, COX-2) inducers and inhibitors, probiotics, antibiotics, adsorbing agents, cytokine and growth factor activators and inhibitors and other miscellaneous agents.
authors.affiliation: Internal Medicine, St. Barnabas Hospital, Bronx, NY 10457, USA.
authors.forename: Umang
authors.initials: U
authors.lastname: Swami
authors.forename: Sanjay
authors.initials: S
authors.lastname: Goel
authors.forename: Sridhar
authors.initials: S
authors.lastname: Mani
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy; D003967:Diarrhea / Q000139:chemically induced* / Q000517:prevention & control; D004305:Dose-Response Relationship, Drug; D006760:Hospitalization; D006801:Humans; D000077146:Irinotecan; D058990:Molecular Targeted Therapy; D000089762:Multidrug Resistance-Associated Protein 2; D012720:Severity of Illness Index; D059004:Topoisomerase I Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use
chemical_list: C000715087:ABCC2 protein, human; D000972:Antineoplastic Agents, Phytogenic; D000089762:Multidrug Resistance-Associated Protein 2; D059004:Topoisomerase I Inhibitors; D000077146:Irinotecan; D002166:Camptothecin