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23.12.2016 | Short Communication | Ausgabe 2/2017

Cancer Chemotherapy and Pharmacology 2/2017

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

Zeitschrift:
Cancer Chemotherapy and Pharmacology > Ausgabe 2/2017
Autoren:
Janet K. Coller, Joanne M. Bowen, Imogen A. Ball, Hannah R. Wardill, Ysabella Z. A. van Sebille, Romany L. Stansborough, Zenab Lightwala, Anthony Wignall, Joseph Shirren, Kate Secombe, Rachel J. Gibson

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.

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