Skip to main content
SpringerLink
Log in

Effect of Interleukin-11 on Ameliorating Intestinal Damage After Methotrexate Treatment of Breast Cancer in Rats

  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

Gastrointestinal mucositis after cancer chemotherapy is an increasing problem that is essentially untreatable once established, although it gradually remits. The aim of this study was to investigate the time-course and effect of interleukin-11 (IL-11) on apoptosis and intestinal morphometry as measures of mucositis. Female DA rats were implanted subcutaneously with syngeneic breast cancer and treated with methotrexate (MTX). Intestinal morphometry was used to assess villus area, crypt length, and mitotic count per crypt. Apoptosis was assessed by TUNEL assay in the tumor and jejunum. Tumor proliferation was assessed by mitotic count. The time-course study showed that MTX increased apoptosis by 28-fold in the crypts of the small intestine and by 3-fold in the tumor, and peaked at 6 hr after chemotherapy. IL-11 (100 μg/kg/ twice daily subcutaneously) maintained intestinal weight, and reduced the severity of mucositis, as measured by villus area, crypt length, and mitotic count per crypt. IL-11 at higher doses (200 μg and 400 μg/kg/twice daily subcutaneously), did not further improve villus area, crypt length, and mitotic count per crypt. IL-11 did not affect tumor apoptosis or proliferation. We conclude that IL-11 attenuated mucositis by maintaining intestinal weight and morphometry. IL-11 did not prevent apoptosis, but rather induced compensatory crypt cell proliferation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. Keefe DMK, Cummins AG, Kotasek D, Dale BM, Sage RE: Small intestinal side effects of chemotherapy: a study comparing symptoms, function and morphology. J Gastroenterol Hepatol 11:A121, 1996

    Google Scholar 

  2. Keefe DM, Cummins AG, Dale BM, Kotasek D, Robb TA, Sage RE: Effect of high-dose chemotherapy on intestinal permeability in humans. Clin Sci 92:385–389, 1997

    Google Scholar 

  3. Keefe DMK: The effect of cytotoxic chemotherapy on the mucosa of the small intestine. MD thesis. Adelaide; University of Adelaide, 1998

    Google Scholar 

  4. Pico J-L, Avila-Garavito A, Naccache P: Mucositis: its occurrence, consequences, and treatment in the oncology setting. Oncologist 3:446–451, 1998

    Google Scholar 

  5. Potten CS: The significance of spontaneous and induced apoptosis in the gastrointestinal tract of mice. Cancer Met Rev 11:179–195, 1992

    Google Scholar 

  6. Potten CS, Wilson JW, Booth C: Regulation and significance of apoptosis in the stem cells of the gastrointestinal epithelium. Stem Cells 15:82–93, 1997

    Google Scholar 

  7. Keefe DMK, Brealey J, Goland GJ, Cummins AG: Chemotherapy for cancer causes apoptosis that precedes hypoplasia in crypts of the small intestine in humans. Gut 47 (5):632–637, 2000

    Google Scholar 

  8. Ijiri K, Potten CS: Response of intestinal cells of differing topographical and hierarchical status to ten cytotoxic drugs and five sources of radiation. Br J Cancer 47:175–185, 1983

    Google Scholar 

  9. Ijiri K, Potten CS: Radiation-hypersensitive cells in small intestinal crypts; their relationships to clonogenic cells. Br J Cancer Suppl 7:20–22, 1986

    Google Scholar 

  10. Ijiri K, Potten CS: Further studies on the response of intestinal crypt cells of different hierarchical status to eighteen different cytotoxic agents. Br J Cancer 55:113–123, 1984

    Google Scholar 

  11. Du XX, Williams DA: Interleukin-11: A multifunctional growth factor derived from the hematopoietic microenvironment. Blood 83(8):2023–2030, 1994

    Google Scholar 

  12. Keith Jr JC, Albert A, Sonis ST, Pfeiffer CJ, Schaub RG: IL-11, a pleiotrophic cytokine: exciting new effects of IL-11 on gastrointestinal mucosal biology. Stem Cells 12(suppl 1):79–90, 1994

    Google Scholar 

  13. Orazi A, Cooper RJ, Tong J, Gordon MS, Battiato L, Sledge Jr GW, Kaye JA, Kahsai M, Hoffman R: Effects of recombinant human interleukin-11 (Numega™ rhIL-11 growth factor) on megakaryocytopoiesis in human bone marrow. Exp Hematol 24:1289–1297, 1996

    Google Scholar 

  14. Orazi A, Du X, Yang Z, Kashai M, Williams DA: Interleukin-11 prevents apoptosis and accelerates recovery of small intestinal mucosa in mice treated with combined chemotherapy and radiation. Lab Invest 75(1):33–42, 1996

    Google Scholar 

  15. Potten CS: Interleukin-11 protects the clonogenic stem cells in murine small-intestinal crypts from impairment of their reproductive capacity by radiation. Int J Cancer 62:356–361, 1995

    Google Scholar 

  16. Potten CS: Protection of the small intestinal clonogenic stem cells from radiation-induced damage by pretreatment with interleukin 11 also increases murine survival time. Stem Cells 14(4):452–459, 1996

    Google Scholar 

  17. Cummins AG, LaBrooy JT, Stanley DP, Rowland R, Shearman DJC: A quantitative histological study of enteropathy associated with HIV infection, Gut 31:317–321, 1990

    Google Scholar 

  18. Gavrieli Y, Sherman Y, Ben-Sasson SA: Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol 119(3):493–501, 1992

    Google Scholar 

  19. Harper JF: Peritz' F test: BASIC programme of a robust multiple comparison test for statistical analysis of all differences among group means. Comput Biol Med 14:437–445, 1994

    Google Scholar 

  20. Trier JS: Morphological alterations induced by methotrexate in the mucosa of human proximal intestine. Gastroenterology 42:295–305, 1962

    Google Scholar 

  21. Trier JS: Morphological alterations induced by methotrexate in the mucosa of the proximal small intestine: II. serial observations by electron microscopy, Gastroenterology 43:407–424, 1962

    Google Scholar 

  22. Booth C, Potten CS: Effects of IL-11 on the growth of intestinal epithelial cells in vitro. Cell Prolif 28:581–594, 1995

    Google Scholar 

  23. Pritchard DM, Potten CS, Hickman JA: The relationships between p53-dependent apoptosis, inhibition of proliferation, 5-fluorouracil-induced histopathology in murine intestinal epithelia. Cancer Res 58:5453–5465, 1998

    Google Scholar 

  24. Nandurkar HH, Hilton DJ, Nathan P, Willson T, Nicola N, Begley CG: The human IL-11 receptor requires gp130 for signalling: demonstration by molecular cloning of the receptor. Oncogene 12:585–593, 1996

    Google Scholar 

  25. Hilton DJ, Hilton AA, Raicevic A, Rakar S, Harrison-Smith M, Gough NM, Begley CG, Metcalf D, Nicola NA, Willson TA: Cloning of a murine IL-11 receptor α-chain; requirement for gp130 for high affinity binding and signal transduction. EMBO J 13(20):4765–4775, 1994

    Google Scholar 

  26. Perez Castro C, Carbia Nagashima A, Paez Pereda M, Goldberg V, Chervin A, Carrizo G, Molina H, Renner U, Stalla GK, Arzt E: Effects of the gp130 cytokines ciliary neurotropic factor (CNTF) and interleukin-11 on pituitary cells: CNTF receptors on human pituitary adenomas and stimulation of prolactin and GH secretion in normal rat anterior pituituary aggregate cultures. J Endocrinol 169:539–547, 2001

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medical Oncology, The Royal Adelaide Hospital, Adelaide, p, South Australia

    Rachel J. Gibson & Dorothy M.K. Keefe

  2. Department of Gastroenterology and Hepatology, The Queen Elizabeth Hospital, Adelaide, South Australia

    Fiona M. Thompson, Gary J. Goland & Adrian G. Cummins

  3. Child Health Research Institute, Women's and Children's Hospital, Adelaide, South Australia

    Julie M. Clarke

Authors
  1. Rachel J. Gibson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dorothy M.K. Keefe
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fiona M. Thompson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Julie M. Clarke
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gary J. Goland
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Adrian G. Cummins
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gibson, R.J., Keefe, D.M., Thompson, F.M. et al. Effect of Interleukin-11 on Ameliorating Intestinal Damage After Methotrexate Treatment of Breast Cancer in Rats. Dig Dis Sci 47, 2751–2757 (2002). https://doi.org/10.1023/A:1021061306913

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1021061306913

Search

Navigation