title: Potential safety concerns of TLR4 antagonism with irinotecan: a preclinical observational report.
abstract: 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.
  
  
  
  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.
  
  
  
  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).
  
  
  
  (-)-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.
authors.affiliation: Discipline of Pharmacology, Adelaide Medical School, University of Adelaide, North Terrace, Adelaide, SA, 5005, Australia. janet.coller@adelaide.edu.au.
authors.forename: Janet K
authors.initials: JK
authors.lastname: Coller
authors.affiliation: Discipline of Physiology, Adelaide Medical School, University of Adelaide, Adelaide, Australia.
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Bowen
authors.affiliation: Discipline of Physiology, Adelaide Medical School, University of Adelaide, Adelaide, Australia.
authors.forename: Imogen A
authors.initials: IA
authors.lastname: Ball
authors.affiliation: Discipline of Anatomy and Pathology, Adelaide Medical School, University of Adelaide, Adelaide, Australia.
authors.forename: Hannah R
authors.initials: HR
authors.lastname: Wardill
authors.affiliation: Discipline of Physiology, Adelaide Medical School, University of Adelaide, Adelaide, Australia.
authors.forename: Ysabella Z A
authors.initials: YZ
authors.lastname: van Sebille
authors.affiliation: Discipline of Anatomy and Pathology, Adelaide Medical School, University of Adelaide, Adelaide, Australia.
authors.forename: Romany L
authors.initials: RL
authors.lastname: Stansborough
authors.affiliation: Discipline of Anatomy and Pathology, Adelaide Medical School, University of Adelaide, Adelaide, Australia.
authors.forename: Zenab
authors.initials: Z
authors.lastname: Lightwala
authors.affiliation: Discipline of Physiology, Adelaide Medical School, University of Adelaide, Adelaide, Australia.
authors.forename: Anthony
authors.initials: A
authors.lastname: Wignall
authors.affiliation: Discipline of Physiology, Adelaide Medical School, University of Adelaide, Adelaide, Australia.
authors.forename: Joseph
authors.initials: J
authors.lastname: Shirren
authors.affiliation: Discipline of Physiology, Adelaide Medical School, University of Adelaide, Adelaide, Australia.
authors.forename: Kate
authors.initials: K
authors.lastname: Secombe
authors.affiliation: Discipline of Anatomy and Pathology, Adelaide Medical School, University of Adelaide, Adelaide, Australia.|Division of Health Sciences, University of South Australia, Adelaide, Australia.
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Gibson
mesh_terms: D000818:Animals; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000633:toxicity; D000072716:Cancer Pain / Q000188:drug therapy; D003967:Diarrhea / Q000139:chemically induced / Q000517:prevention & control; D005260:Female; D000077146:Irinotecan; D009270:Naloxone / Q000494:pharmacology / Q000633:toxicity*; D051381:Rats; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D009270:Naloxone; D000077146:Irinotecan; D002166:Camptothecin
keywords: Efficacy; Gut toxicity; Irinotecan; TLR4 antagonist