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.

Progress and problems with the use of suicide genes for targeted cancer therapy

“…In an interesting approach, Metz et al (2013), engineered secretary form of CE which could be transported outside of the cell; thereby, expanding the prodrug activation radius [146]. One safety concern with this system is that after systemic administration of irinotecan, it could get activated by CE that exist in normal tissues (e.g., liver) resulting in off-target toxicity [147, 148]. Currently there is one ongoing study in Phase I clinical trials with CE/Irinotecan using neural stem cells as delivery vehicle for the treatment of glioma (clinicaltrials.gov; NCT02192359).…”

Irinotecan-Induced Gastrointestinal Dysfunction Is Associated with Enteric Neuropathy, but Increased Numbers of Cholinergic Myenteric Neurons

“…Although neutropenia is manageable, IRI-induced diarrhea is typically severe, resulting in hospitalisations, dose-reductions and delays, and termination of treatment in many cases (Swami et al, 2013). Though the prevalence and severity of IRI-induced diarrhea vary greatly depending on regime specifics such as dosage and adjuvant therapies, rates as high as 80% have been reported (Rothenberg et al, 1996).…”

Effects of MTHFR Genetic Polymorphisms on Toxicity and Clinical Response of Irinotecan-Based Chemotherapy in Patients with Colorectal Cancer

“…However, the clinical use of irinotecan is often limited as a result of its frequent and severe side effects, such as neutropenia and late onset diarrhea, which can sometimes lead to severe dehydration and further hospitalization and treatments for alternate secondary health issues (Swami et al, 2013). According to a former study, almost 40% of patients treated with irinotecan-based chemotherapy suffer from severe late diarrhea (Chen et al, 2013).…”

“…If the toxicity of irinotecan can be reduced, then irinotecan-based clinical outcome of chemotherapy could be improved significantly (Wallace et al, 2010). Much attention has been focused on decreasing the side effects and improving the efficacy of irinotecan-based chemotherapy (Shulman et al, 2011;Swami et al, 2013).…”