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

Abstract：

PURPOSE:Irinotecan-induced gut toxicity is mediated in part by Toll-Like receptor 4 (TLR4) signalling. The primary purpose of this preclinical study was to determine whether blocking TLR4 signalling by administering (-)-naloxone, a TLR4 antagonist, would improve irinotecan-induced gut toxicity. Our secondary aim was to determine the impact of (-)-naloxone on tumour growth. METHODS:Female Dark Agouti (DA) tumour-bearing rats were randomly assigned to four treatments (n = 6 in each); control, (-)-naloxone (100 mg/kg oral gavage at -2, 24, 48, and 72 h), irinotecan (175 mg/kg intraperitoneal at 0 h), and (-)-naloxone and irinotecan. Body weight and tumour growth were measured daily, and diarrhoea incidence and severity were recorded 4× per day up to 72 h post-treatment. RESULTS:At 72 h, all rats that received irinotecan lost weight compared to controls (p = 0.03). In addition, rats that received (-)-naloxone and irinotecan lost significantly more weight compared to controls (p < 0.005) than irinotecan only compared to controls (p = 0.001). (-)-Naloxone did not attenuate irinotecan-induced severe diarrhoea at 48 and 72 h. Finally, (-)-naloxone caused increased tumour growth compared to control at 72 h (p < 0.05) and significantly reduced the efficacy of irinotecan (p = 0.001). CONCLUSIONS:(-)-Naloxone in our preclinical model was unable to block irinotecan-induced gut toxicity and decreased the efficacy of irinotecan. As (-)-naloxone-oxycodone combination is used for cancer pain, this may present a potential safety concern for patients receiving (-)-naloxone-oxycodone and irinotecan concurrently and requires further investigation.

journal_name

Cancer Chemother Pharmacol

journal_title

Cancer chemotherapy and pharmacology

authors

Coller JK,Bowen JM,Ball IA,Wardill HR,van Sebille YZ,Stansborough RL,Lightwala Z,Wignall A,Shirren J,Secombe K,Gibson RJ

doi

10.1007/s00280-016-3223-3

subject

Has Abstract

pub_date

2017-02-01 00:00:00

pages

431-434

issue

2

eissn

0344-5704

issn

1432-0843

pii

10.1007/s00280-016-3223-3

journal_volume

79

pub_type

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