Cancer Chemotherapy and Pharmacology

, Volume 62, Issue 1, pp 33–41

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

  • Richard M. Logan
  • Rachel J. Gibson
  • Joanne M. Bowen
  • Andrea M. Stringer
  • Stephen T. Sonis
  • Dorothy M. K. Keefe
Original Article



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.


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.


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.


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.


Mucositis Nuclear factor-κB Pro-inflammatory cytokines Irinotecan Chemotherapy 


  1. 1.
    Alimonti A, Gelibter A, Pavese I et al (2004) New approaches to prevent intestinal toxicity of irinotecan-based regimens. Cancer Treat Rev 30:555–562CrossRefPubMedGoogle Scholar
  2. 2.
    Anthony L, Bowen J, Garden A et al (2006) New thoughts on the pathobiology of regimen-related mucosal injury. Support Care Cancer 14:516–518CrossRefPubMedGoogle Scholar
  3. 3.
    Bowen JM, Gibson RJ, Keefe DM et al (2005) Cytotoxic chemotherapy upregulates pro-apoptotic Bax and Bak in the small intestine of rats and humans. Pathology 37:56–62CrossRefPubMedGoogle Scholar
  4. 4.
    Cool JC, Dyer JL, Xian CJ et al (2005) Pre-treatment with insulin-like growth factor-I partially ameliorates 5-fluorouracil-induced intestinal mucositis in rats. Growth Hormone IGF Res 15:72–82CrossRefGoogle Scholar
  5. 5.
    Elting LS, Cooksley C, Chambers MS et al (2003) The burdens of cancer therapy: clinical and economic outcomes of chemotherapy-induced mucositis. Cancer 98:1531–1539CrossRefPubMedGoogle Scholar
  6. 6.
    Gibson R, Keefe D (2006) Cancer chemotherapy-induced diarrhoea and constipation: mechanisms of damage and prevention strategies. Supportive Care in Cancer 1–11Google Scholar
  7. 7.
    Gibson RJ, Bowen JM, Inglis MRB et al (2003) Irinotecan causes severe small intestinal damage, as well as colonic damage, in the rat with implanted breast cancer. J Gastroenterol Hepatol 18:1095–1100CrossRefPubMedGoogle Scholar
  8. 8.
    Gibson RJ, Cummins AG, Bowen JM et al (2006) Apoptosis occurs early in the basal layer of the oral mucosa following cancer chemotherapy. Asian Pacific J Clin Oncol 2:39–49CrossRefGoogle Scholar
  9. 9.
    Gibson RJ, Keefe DM, Thompson FM et al (2002) Effect of interleukin-11 on ameliorating intestinal damage after methotrexate treatment of breast cancer in rats. Dig Dis Sci 47:2751–2757CrossRefPubMedGoogle Scholar
  10. 10.
    Iyer L, King CD, Whitington PF et al (1998) Genetic predisposition to the metabolism of irinotecan (CPT-11). Role of uridine diphosphate glucuronosyltransferase isoform 1A1 in the glucuronidation of its active metabolite (SN-38) in human liver microsomes. J Clin Invest 101:847–854CrossRefPubMedGoogle Scholar
  11. 11.
    Junqueira L, Carneiro J, Long J (2005) Basic histology, 11th edn. McGraw-Hill, LangeGoogle Scholar
  12. 12.
    Kawahara M (2006) Irinotecan in the treatment of small cell lung cancer: a review of patient safety considerations. Expert Opin Drug Saf 5:303–312CrossRefPubMedGoogle Scholar
  13. 13.
    Keefe DM, Gibson RJ, Hauer-Jensen M (2004) Gastrointestinal mucositis. Semin Oncol Nurs 20:38–47CrossRefPubMedGoogle Scholar
  14. 14.
    Keefe DMK (2004) Gastrointestinal mucositis: a new biological model. Support Care Cancer 12:6–9CrossRefPubMedGoogle Scholar
  15. 15.
    Keefe DMK (2006) Mucositis guidelines: what have they acheived and where to from here? Support Care Cancer 14:489–491CrossRefPubMedGoogle Scholar
  16. 16.
    Keefe DMK, Brealey J, Goland GJ et al (2000) Chemotherapy for cancer causes apoptosis that precedes hypoplasia in crypts of the small intestine in humans. Gut 47:632–637CrossRefPubMedGoogle Scholar
  17. 17.
    Krajewska M, Wang HG, Krajewski S et al (1997) Immunohistochemical analysis of in vivo patterns of expression of CPP32 (Caspase-3), a cell death protease. Cancer Res 57:1605–13PubMedGoogle Scholar
  18. 18.
    Krajewska M, Zapata JM, Meinhold-Heerlein I et al (2002) Expression of Bcl-2 family member Bid in normal and malignant tissues. Neoplasia 4:129–40CrossRefPubMedGoogle Scholar
  19. 19.
    Krajewski S, Krajewska M, Reed JC (1996) Immunohistochemical analysis of in vivo patterns of Bak expression, a proapoptotic member of the Bcl-2 protein family. Cancer Res 56:2849–2855PubMedGoogle Scholar
  20. 20.
    Logan RM, Gibson RJ, Sonis ST et al (2007) Nuclear factor-kappaB (NF-kappaB) and cyclooxygenase-2 (COX-2) expression in the oral mucosa following cancer chemotherapy. Oral Oncol 43:395–401CrossRefPubMedGoogle Scholar
  21. 21.
    Logan RM, Stringer AM, Bowen JM et al. The role of pro-inflammatory cytokines in cancer treatment-induced alimentary tract mucositis: Pathobiology, animal models and cytotoxic drugs. Cancer Treat Rev. doi:10.1016/j.ctrv.2007.03.001
  22. 22.
    Melo M, Brito G, Soares R et al. Role of cytokines (TNF-α, IL-1β and KC) in the pathogenesis of CPT-11-induced intestinal mucositis in mice: effect of pentoxifylline and thalidomide. Cancer Chemotherapy and Pharmacology. doi:10.1007/s00280-007- 0534-4
  23. 23.
    Mocellin S, Rossi CR, Pilati P et al (2005) Tumor necrosis factor, cancer and anticancer therapy. Cytokine Growth Factor Rev 16:35–53CrossRefPubMedGoogle Scholar
  24. 24.
    Nakamura K, Honda K, Mizutani T et al (2006) Novel strategies for the treatment of inflammatory bowel disease: selective inhibition of cytokines and adhesion molecules. World J Gastroenterol 12:4628–4635PubMedGoogle Scholar
  25. 25.
    Pico J-L, Avila-Garavito A, Naccache P (1998) Mucositis: its occurrence, consequences, and treatment in the oncology setting. Oncologist 3:446–451PubMedGoogle Scholar
  26. 26.
    Podolsky DK (2002) Inflammatory Bowel Disease. N Engl J Med 347:417–429CrossRefPubMedGoogle Scholar
  27. 27.
    Scully C, Epstein J, Sonis S (2003) Oral mucositis: a challenging complication of radiotherapy, chemotherapy, and radiochemotherapy: part 1, pathogenesis and prophylaxis of mucositis. Head Neck 25:1057–70CrossRefPubMedGoogle Scholar
  28. 28.
    Sonis ST (1998) Mucositis as a biological process: a new hypothesis for the development of chemotherapy-induced stomatotoxicity. Oral Oncol 34:39–43CrossRefPubMedGoogle Scholar
  29. 29.
    Sonis ST (2002) The biologic role for nuclear factor-kappaB in disease and its potential involvement in mucosal injury associated with antineoplastic therapy. Crit Rev Oral Biol Med 13:380–390PubMedCrossRefGoogle Scholar
  30. 30.
    Sonis ST, Elting LS, Keefe D et al (2004) Perspectives on cancer therapy-induced mucosal injury: pathogenesis, measurement, epidemiology, and consequences for patients. Cancer 100:1995–2025CrossRefPubMedGoogle Scholar
  31. 31.
    Stringer AM, Gibson RJ, Logan RM et al (2007) Chemotherapy-Induced diarrhoea is associated with changes in the luminal environment in the DA rat. Exp Biol Med 232:96–106Google Scholar
  32. 32.
    Tallman MN, Miles KK, Kessler FK et al (2007) The contribution of intestinal UDP-glucuronosyltransferases in modulating 7-ethyl-10-hydroxy-camptothecin (SN-38)-induced gastrointestinal toxicity in rats. J Pharmacol Exp Ther 320:29–37CrossRefPubMedGoogle Scholar
  33. 33.
    Wang L, Walia B, Evans J et al (2003) IL-6 Induces NF-{kappa}B Activation in the intestinal epithelia. J Immunol 171:3194–3201PubMedGoogle Scholar
  34. 34.
    Yeoh ASJ, Bowen JM, Gibson RJ et al (2005) Nuclear factor- kappaB (NF-kappaB) and cyclooxygenase-2 (COX-2) expression in the irradiated colorectum is associated with subsequent histopathological changes. Int J Rad Oncol Biol Phys 63:1295–1303CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Richard M. Logan
    • 1
    • 2
  • Rachel J. Gibson
    • 3
  • Joanne M. Bowen
    • 3
    • 4
  • Andrea M. Stringer
    • 3
    • 4
  • Stephen T. Sonis
    • 5
  • Dorothy M. K. Keefe
    • 3
    • 4
  1. 1.Oral Pathology, School of Dentistry, Faculty of Health SciencesThe University of AdelaideNorth TerraceAustralia
  2. 2.Division of Tissue PathologyInstitute of Medical and Veterinary ScienceAdelaideAustralia
  3. 3.Department of Medical OncologyRoyal Adelaide HospitalAdelaideAustralia
  4. 4.Division of Medicine, Faculty of Health SciencesThe University of AdelaideAdelaideAustralia
  5. 5.Division of Oral Medicine, Oral and Maxillofacial Surgery and DentistryBrigham and Women’s HospitalBostonUSA

Personalised recommendations