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

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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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Funding

This study was supported by the Ray and Shirl Norman Cancer Trust. Hannah R Wardill and Ysabella Z A van Sebille are recipients of Australian Postgraduate Awards and Doctor Chun Chung Wong and Madam So Sau Lam are recipients of Memorial Postgraduate Cancer Research Top Up Scholarships, and Romany Stansborough is a recipient of an Australian Postgraduate Award.

Author information

Authors and Affiliations

  1. Discipline of Pharmacology, Adelaide Medical School, University of Adelaide, North Terrace, Adelaide, SA, 5005, Australia

    Janet K. Coller

  2. Discipline of Physiology, Adelaide Medical School, University of Adelaide, Adelaide, Australia

    Joanne M. Bowen, Imogen A. Ball, Ysabella Z. A. van Sebille, Anthony Wignall, Joseph Shirren & Kate Secombe

  3. Discipline of Anatomy and Pathology, Adelaide Medical School, University of Adelaide, Adelaide, Australia

    Hannah R. Wardill, Romany L. Stansborough, Zenab Lightwala & Rachel J. Gibson

  4. Division of Health Sciences, University of South Australia, Adelaide, Australia

    Rachel J. Gibson

Authors
  1. Janet K. Coller
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  2. Joanne M. Bowen
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  3. Imogen A. Ball
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  4. Hannah R. Wardill
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  5. Ysabella Z. A. van Sebille
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  6. Romany L. Stansborough
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  7. Zenab Lightwala
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  8. Anthony Wignall
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  9. Joseph Shirren
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  10. Kate Secombe
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  11. Rachel J. Gibson
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Corresponding author

Correspondence to Janet K. Coller.

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Conflict of interest

Professor Rachel Gibson is a current consultant/advisory board member to Mundipharma (Singapore).

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

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Coller, J.K., Bowen, J.M., Ball, I.A. et al. Potential safety concerns of TLR4 antagonism with irinotecan: a preclinical observational report. Cancer Chemother Pharmacol 79, 431–434 (2017). https://doi.org/10.1007/s00280-016-3223-3

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  • DOI: https://doi.org/10.1007/s00280-016-3223-3

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