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Characterisation of mucosal changes in the alimentary tract following administration of irinotecan: implications for the pathobiology of mucositis

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Abstract

Purpose

The pathobiology of alimentary tract (AT) mucositis is complex and there is limited information about the events which lead to the mucosal damage that occurs during cancer treatment. Various transcription factors and proinflammatory cytokines are thought to play important roles in pathogenesis of mucositis. The aim of this study was to determine the expression of nuclear factor-κB (NF-κB), tumor necrosis factor (TNF) and interleukins-1β (IL-1β) and -6 (IL-6) in the AT following the administration of the chemotherapeutic agent irinotecan.

Methods

Eighty-one female dark Agouti rats were assigned to either control or experimental groups according to a specific time point. Following administration of irinotecan, rats were monitored for the development of diarrhoea. The rats were killed at times ranging from 30 min to 72 h after administration of irinotecan. Oral mucosa, jejunum and colon were collected and standard immunohistochemical techniques were used to identify NF-κB, TNF, IL-1β and IL-6 within the tissues. Sections were also stained with haematoxylin and eosin for histological examination.

Results

Irinotecan caused mild to moderate diarrhoea in a proportion of the rats that received the drug. Altered histological features of all tissues from rats administered irinotecan were observed which included epithelial atrophy in the oral mucosa, reduction of villus height and crypt length in the jejunum and a reduction in crypt length in the colon. Tissue staining for NF-κB, TNF and IL-1β and IL-6 peaked at between 2 and 12 h in the tissues examined.

Conclusions

This is the first study to demonstrate histological and immunohistochemical evidence of changes occurring concurrently in different sites of the AT following chemotherapy. The results of the study provide further evidence for the role of NF-κB and associated pro-inflammatory cytokines in the pathobiology of AT mucositis. The presence of these factors in tissues from different sites of the AT also suggests that there may be a common pathway along the entire AT causing mucositis following irinotecan administration.

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Acknowledgments

This project was supported by a research grant awarded by the Royal Adelaide Hospital Research Committee and the Australian Dental Research Foundation Incorporated. Dr. Rachel Gibson was supported by a Cancer Council South Australia Research Fellowship; Dr. Joanne Bowen and Ms. Andrea Stringer were supported by a Dawes Research Scholarship. Assistance with the statistical analysis for this study was provided by Mr. Thomas Sullivan from the Department of Public Health, The University of Adelaide. The authors also acknowledge Ms Marjorie Quinn, Oral Pathology, School of Dentistry, The University of Adelaide for her assistance in cutting sections.

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Authors and Affiliations

  1. Oral Pathology, School of Dentistry, Faculty of Health Sciences, The University of Adelaide, North Terrace, SA, 5005, Australia

    Richard M. Logan

  2. Division of Tissue Pathology, Institute of Medical and Veterinary Science, Frome Rd, Adelaide, SA, 5000, Australia

    Richard M. Logan

  3. Department of Medical Oncology, Royal Adelaide Hospital, North Tce, Adelaide, SA, 5000, Australia

    Rachel J. Gibson, Joanne M. Bowen, Andrea M. Stringer & Dorothy M. K. Keefe

  4. Division of Medicine, Faculty of Health Sciences, The University of Adelaide, Adelaide, SA, 5005, Australia

    Joanne M. Bowen, Andrea M. Stringer & Dorothy M. K. Keefe

  5. Division of Oral Medicine, Oral and Maxillofacial Surgery and Dentistry, Brigham and Women’s Hospital, Boston, MA, USA

    Stephen T. Sonis

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  1. Richard M. Logan
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  2. Rachel J. Gibson
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  3. Joanne M. Bowen
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  4. Andrea M. Stringer
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  5. Stephen T. Sonis
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  6. Dorothy M. K. Keefe
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Correspondence to Richard M. Logan.

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Conflict of interest statement: None of the authors are aware of any potential conflicts of interest that may have inappropriately influenced or biased this work.

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Logan, R.M., Gibson, R.J., Bowen, J.M. et al. Characterisation of mucosal changes in the alimentary tract following administration of irinotecan: implications for the pathobiology of mucositis. Cancer Chemother Pharmacol 62, 33–41 (2008). https://doi.org/10.1007/s00280-007-0570-0

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  • DOI: https://doi.org/10.1007/s00280-007-0570-0

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