TY - JOUR
T1 - Potential safety concerns of TLR4 antagonism with irinotecan
T2 - a preclinical observational report
AU - Coller, Janet K.
AU - Bowen, Joanne M.
AU - Ball, Imogen A.
AU - Wardill, Hannah R.
AU - van Sebille, Ysabella Z.A.
AU - Stansborough, Romany L.
AU - Lightwala, Zenab
AU - Wignall, Anthony
AU - Shirren, Joseph
AU - Secombe, Kate
AU - Gibson, Rachel J.
N1 - Publisher Copyright:
© 2016, Springer-Verlag Berlin Heidelberg.
Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2017/2/1
Y1 - 2017/2/1
N2 - 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.
AB - 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.
KW - Efficacy
KW - Gut toxicity
KW - Irinotecan
KW - TLR4 antagonist
UR - http://www.scopus.com/inward/record.url?scp=85007242119&partnerID=8YFLogxK
U2 - 10.1007/s00280-016-3223-3
DO - 10.1007/s00280-016-3223-3
M3 - Article
C2 - 28011980
AN - SCOPUS:85007242119
VL - 79
SP - 431
EP - 434
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
SN - 0344-5704
IS - 2
ER -