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- Title
Potential safety concerns of TLR4 antagonism with irinotecan: a preclinical observational report.
- Authors
Coller, Janet; Bowen, Joanne; Ball, Imogen; Wardill, Hannah; Sebille, Ysabella; Stansborough, Romany; Lightwala, Zenab; Wignall, Anthony; Shirren, Joseph; Secombe, Kate; Gibson, Rachel; Coller, Janet K; Bowen, Joanne M; Ball, Imogen A; Wardill, Hannah R; van Sebille, Ysabella Z A; Stansborough, Romany L; Gibson, Rachel J
- Abstract
<bold>Purpose: </bold>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.<bold>Methods: </bold>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.<bold>Results: </bold>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).<bold>Conclusions: </bold>(-)-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.
- Subjects
IRINOTECAN; TOLL-like receptors; NALOXONE; TUMOR growth; LABORATORY rats; DRUG toxicity; DIARRHEA prevention; ANIMAL experimentation; CAMPTOTHECIN; CELL receptors; DIARRHEA; RATS; PHARMACODYNAMICS; CELL physiology
- Publication
Cancer Chemotherapy & Pharmacology, 2017, Vol 79, Issue 2, p431
- ISSN
0344-5704
- Publication type
journal article
- DOI
10.1007/s00280-016-3223-3