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Potential safety concerns of TLR4 antagonism with irinotecan: a preclinical observational report

Janet K Coller1, Joanne M Bowen2, Imogen A Ball2

  • 1Discipline of Pharmacology, Adelaide Medical School, University of Adelaide, North Terrace, Adelaide, SA, 5005, Australia. janet.coller@adelaide.edu.au.

Cancer Chemotherapy and Pharmacology
|December 25, 2016
PubMed
Abstract

Insights

This study found that (-)-naloxone did not improve irinotecan-induced gut toxicity in rats and worsened weight loss. The TLR4 antagonist also reduced irinotecan

Area of Science:

  • Pharmacology and Toxicology
  • Gastroenterology
  • Oncology

Background:

  • Irinotecan is a chemotherapy agent with known gastrointestinal side effects.
  • Toll-Like receptor 4 (TLR4) signaling is implicated in irinotecan-induced gut toxicity.
  • (-)-Naloxone is a TLR4 antagonist with potential therapeutic applications.

Purpose of the Study:

  • To investigate if blocking TLR4 signaling with (-)-naloxone mitigates irinotecan-induced gut toxicity in a preclinical model.
  • To assess the impact of (-)-naloxone on tumor growth and irinotecan efficacy.

Main Methods:

  • Female Dark Agouti rats bearing tumors were randomized into four groups: control, (-)-naloxone, irinotecan, and (-)-naloxone + irinotecan.
  • Body weight and tumor growth were monitored daily.
  • Diarrhea incidence and severity were recorded up to 72 hours post-treatment.

Main Results:

  • Irinotecan administration led to significant weight loss in rats.
  • Co-administration of (-)-naloxone with irinotecan resulted in greater weight loss compared to irinotecan alone.
  • (-)-Naloxone did not reduce diarrhea severity and increased tumor growth, while decreasing irinotecan's anti-tumor efficacy.

Conclusions:

  • (-)-Naloxone failed to ameliorate irinotecan-induced gut toxicity in this preclinical study.
  • The TLR4 antagonist (-)-naloxone decreased irinotecan's efficacy and worsened weight loss.
  • Concurrent use of (-)-naloxone (as in some pain management regimens) with irinotecan may pose a safety concern requiring further investigation.
Keywords:
EfficacyGut toxicityIrinotecanTLR4 antagonist

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