Skip to main content

Advertisement

SpringerLink
Log in

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

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Introduction

Irinotecan (CPT-11) is an inhibitor of DNA topoisomerase I and is clinically effective against several cancers. A major toxic effect of CPT-11 is delayed diarrhea; however, the exact mechanism by which the drug induces diarrhea has not been established.

Purpose

Elucidate the mechanisms of induction of delayed diarrhea and determine the effects of the cytokine production inhibitor pentoxifylline (PTX) and thalidomide (TLD) in the experimental model of intestinal mucositis, induced by CPT-11.

Materials and methods

Intestinal mucositis was induced in male Swiss mice by intraperitoneal administration of CPT-11 (75 mg/kg) daily for 4 days. Animals received subcutaneous PTX (1.7, 5 and 15 mg/kg) or TLD (15, 30, 60 mg/kg) or 0.5 ml of saline daily for 5 and 7 days, starting 1 day before the first CPT-11 injection. The incidence of delayed diarrhea was monitored by scores and the animals were sacrificed on the 5th and 7th experimental day for histological analysis, immunohistochemistry for TNF-α and assay of myeloperoxidase (MPO) activity, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and KC ELISA.

Results

CPT-11 caused significant diarrhea, histopathological alterations (inflammatory cell infiltration, loss of crypt architecture and villus shortening) and increased intestinal tissue MPO activity, TNF-α, IL-1β and KC level and TNF-α immuno-staining. PTX inhibited delayed diarrhea of mice submitted to intestinal mucositis and reduced histopathological damage, intestinal MPO activity, tissue level of TNF-α, IL-1β and KC and TNF-α immuno-staining. TLD significantly reduced the lesions induced by CPT-11 in intestinal mucosa, decreased MPO activity, TNF-α tissue level and TNF-α immuno-staining, but did not reduce the severity of diarrhea.

Conclusion

These results suggest an important role of TNF-α, IL-1β and KC in the pathogenesis of intestinal mucositis induced by CPT-11.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Abdel-Salam OME, Baiuomy AR, El-Shenawy SM, Arbid MS (2003) The anti-inflammatory effects of the phosphodiesterase inhibitor pentoxifylline in the rat. Pharmacol Res 47:331–340

    Article  PubMed  CAS  Google Scholar 

  2. Allegrini G, Di Paolo A, Cerri E, Cupini S, Amatori F, Masi G, Danesi R, Marcucci L, Bocci G, Tacca MD, Falcone A (2006) Irinotecan in combination with thalidomide in patients with advanced solid tumors: a clinical study with pharmacodynamic and pharmacokinetic evaluation. Cancer Chemother Pharmacol 58:585–593

    Article  PubMed  CAS  Google Scholar 

  3. Bianco JA, Appelbaum FR, Nemunaitis J, Almgren J, Andrews F, Kettner P, Shields A, Singer JW (1991) Phase I–II trial of pentoxifylline for the prevention of transplant-related toxicities following bone marrow transplantion. Blood 78(5):1205–1211

    PubMed  CAS  Google Scholar 

  4. Bombini G, Canetti C, Rocha FAC, Cunha FQ (2004) Tumour necrosis factor-α mediates neutrophil migration to the knee synovial cavity during immune inflammation. Eur J Pharmacol 496:197–204

    Article  PubMed  CAS  Google Scholar 

  5. Bradley PP, Christensen RD, Rothstein G (1982) Cellular and extracellular myeloperoxidase in pyogenic inflammation. Blood 60:618–22

    PubMed  CAS  Google Scholar 

  6. Carneiro-Filho BA, Sousa MLP, Lima AAM, Ribeiro RA (2001) The effect of tumour necrosis factor (TNF) inhibitors in Clostridium difficile toxin-induced paw oedeme and neutrophil migration. Pharmacol Toxicol 88:313–318

    Article  PubMed  CAS  Google Scholar 

  7. Chester JD, Joel SP, Cheeseman SL, Hall GD, Braun MS, Perry J, Davis T, Button CJ, Seymour MT (2003) Phase I and pharmacokinetic study of intravenous irinotecan plus oral ciclosporin in patients with fluorouracil-refractory metastatic colon cancer. J Clin Oncol 21(6):1125–1132

    Article  PubMed  CAS  Google Scholar 

  8. Cunha FQ, Boukili MA, Motta JIB, Vargaftig BB, Ferreira SH (1993) Blockade by fenspiride of endotoxin-induced neutrophil migration in the rat. Eur J Pharmacol 238:47–52

    Article  PubMed  CAS  Google Scholar 

  9. De Koning BAE, van Dieren JM, Lindenbergh-Kortleve DJ, van der Sluis M, Matsumoto T, Yamaguchi K, Einerthand AW, Samsom JN, Pieters R, Nieuwenhuis EES (2006) Contributions of mucosal immune cells to methotrexate-induced mucositis. Int Immunol 24:1–9

    Google Scholar 

  10. Ferrà C, de Sanjosé S, Lastra CF, Martí F, Mariño EL, Sureda A, Brunet S, Gallardo D, Berlanga JJ, García J, Grañena A (1997) Pentoxifylline, ciprofloxacin and prednisone failed to prevent transplant-related toxicities in bone marrow transplant recipients and were associated with an increased incidence of infectious complications. Bone Marrow Transplant 20:1075–1080

    Article  PubMed  Google Scholar 

  11. Gibson RJ, Bowen JM, Inglis MRB, Cummins AG, Keefe DMK (2003) Irinotecan causes severe small intestinal damage, as well as colonic damage, in the rat with implanted breast cancer. J Gastroenterol Hepatol 18:1095–1100

    Article  PubMed  CAS  Google Scholar 

  12. Gibson RJ Keefe DMK (2006) Cancer chemotherapy-induced diarrhea and constipation: mechanism of damage and prevention strategies. Support Care Cancer 14(9):890–900

    Article  Google Scholar 

  13. Gómez-Cambronero L, Camps B, de la Asunción JG, Cerdá M, Pellín A, Pallardo FV, Calvete J, Sweiry JH, Mann GE, Viña J, Sastre J (2000) Pentoxifylline ameliorates cerulein-induced pancreatitis in rats: role of glutathione and nitric oxide. J Pharmacol Exp Ther 293(2):670–676

    PubMed  Google Scholar 

  14. Govindarajan R, Heaton KM, Broadwater R, Zeltlin A, Lang NP, Hauer-Jensen M (2000) Effect of thalidomide on gastrointestinal toxic effects of irinotecan. Lancet 356:566–567

    Article  PubMed  CAS  Google Scholar 

  15. Gupta E, Wang X, Ramirez J, Ratain MJ (1997) Modulation of glucuronidation of SN-38, the active metabolite of irinotecan, by valproic acid and phenobarbital. Cancer Chemother Pharmacol 39:440–444

    Article  PubMed  CAS  Google Scholar 

  16. Gutierrez-Reyes G, Lopez-Ortal P, Sixtos S, Cruz S, Ramirez-Iglesias MT, Gutierrez-Ruiz MC, Sanchez-Avila F, Roldan E, Vargas-Vorackova F, Kershenobich D (2006) Effect of pentoxifylline on levels of pro-inflammatory cytokines during chronic hepatitis C. Scand J Immunol 63(6):461–467

    Article  PubMed  CAS  Google Scholar 

  17. Hsu SM, Raine L (1981) Protein A, avidin, and biotin in immunohistochemistry. J Histochem Cytochem 29(11):1349–1353

    PubMed  CAS  Google Scholar 

  18. Ikuno N, Soda H, Watanabe M, Oka M (1995) Irinotecan (CPT-11) and characteristic mucosal changes in the mouse ileum and cecum (reports). J Natl Cancer Inst 87(24):1876–1883

    Article  PubMed  CAS  Google Scholar 

  19. Kim YS, Kim JS, Jung HC, Song IS (2004) The effects of thalidomide on the stimulation of NF-кB activity and TNF-α production by lipopolysaccharide in a human colonic epithelial cell line. Mol Cells 17(2):210–216

    PubMed  CAS  Google Scholar 

  20. Kurita A, Kado S, Kaneda N, Onoue M, Hashimoto S, Yokokura T (2000) Modified irinotecan hydrochloloride (CPT-11) administration schedule improves induction of delayed-onset diarrhea in rats. Cancer Chemother Pharmacol 46:211–220

    Article  PubMed  CAS  Google Scholar 

  21. Langer CJ (2004) Irinotecan in advanced lung cancer: focus on North American trials. Oncology 18(7):17–28

    PubMed  Google Scholar 

  22. Lima V, Brito GAC, Cunha FQ, Rebouças CG, Falcão BAA, Augusto RF, Souza MLP, Leitão BT, Ribeiro RA (2005) Effects of the tumour necrosis factor-α inhibitors pentoxifylline and thalidomide in short-term experimental oral mucositis in hamsters. Eur J Oral Sci 113(3):210–217

    Article  PubMed  CAS  Google Scholar 

  23. Marcinkiewicz J, Grabowska A, Lauterbach R, Bobek M (2000) Differential effects of pentoxifylline, a non-specific phosphodiesterase inhibitor, on the production of IL-10, IL-12 p40 and p35 subunits by murine peritoneal macrophages. Immunopharmacology 49:335–343

    Article  PubMed  CAS  Google Scholar 

  24. Moreira AL, Sampaio EP, Zmuidzinas A, Frindt P, Smith KA, Kaplan G (1993) Thalidomide exerts its inhibitory action on tumor necrosis factor α by enhancing mRNA degradation. J Exp Med 177:1675–1680

    Article  PubMed  CAS  Google Scholar 

  25. National Research Council (1986) Guide for the care and use of laboratory animals. Institute of Laboratory Animal Resources, Commission on Life Sciences, National Research Council. National Academy Press, Washington, DC

    Google Scholar 

  26. Neuner P, Klosner E, Schauer E, Pourmojib M, Macheiner W, Grünwald C, Knobler R, Schwarz A, Luger TA, Schwarz T (1994) Pentoxifylline in vivo down-regulates the release of IL-1β, IL-6, IL-8 and tumour necrosis factor-α by human peripheral blood mononuclear cells. Immunology 83:262–267

    PubMed  CAS  Google Scholar 

  27. Perez EA, Hillman DW, Mailliard JA, Ingle JN, Ryan JM, Fitch TR, Rowland KM, Kardinal CG, Krook JE, Kugler JW, Dakhil SR (2004) Randomized phase II study of two irinotecan schedules for patients with metastatic breast cancer refractory to an anthracycline, a taxane, or both. J Clin Oncol 22(14):2849–2855

    Article  PubMed  CAS  Google Scholar 

  28. Pohanka E, Sinzinger H (1986) Effect of a single pentoxifylline administration on platelet sensitivity, plasma factor activity, plasma-6-oxo-PGF1 alpha and thromboxane B2 in health volunteers. Prostaglandins Leukot Med 22:191–200

    Article  PubMed  CAS  Google Scholar 

  29. Reaves TA, Chin AC, Parkos CA (2005) Neutrophil transepithelial migration: role of toll-like receptors in mucosal inflammation. Mem Inst Oswaldo Cruz 100(suppl 1):191–198

    PubMed  CAS  Google Scholar 

  30. Rocha-Lima CM, Green MR, Rotche R, Miller WH Jr, Jeffrey GM, Cisar LA, Morganti A, Orlando N, Gruia G, Miller LL (2004) Irinotecan plus gemcitabine results in no survival advantage compared with gemcitabine monotherapy in patients with locally advanced or metastatic pancreatic cancer despite increased tumor response rate. J Clin Oncol 22:18–21

    Article  Google Scholar 

  31. Rubenstein EB, Peterson DE, Schubert M, Keefe D, McGuire D, Epstein J, Elting LS, Fox PC, Cooksley C, Sonis ST (2004) Clinical practice guidelines for the prevention and treatment of cancer therapy-induced oral and gastrointestinal mucositis. Cancer 100(suppl 9):2026–46

    Article  PubMed  Google Scholar 

  32. Safieh-Garabedian B, Poole S, Allchorne A, Winter J, Woolf CJ (1995) Contribution of interleukin-1 beta to the inflammation-induced increase in nerve growth factor levels and inflammatory hyperalgesia. Br J Pharmacol 115:1265–1275

    PubMed  CAS  Google Scholar 

  33. Sampaio EP, Sarno EN, Galilly R, Cohn ZA, Kaplan G (1991) Thalidomide selectively inhibits tumor necrosis factor α production by stimulated human monocytes. J Exp Med 173:699–703

    Article  PubMed  CAS  Google Scholar 

  34. Sartor RB (1994) Cytokines in intestinal inflammation: pathophysiological and clinical considerations. Gastroenterology 106:533–539

    PubMed  CAS  Google Scholar 

  35. Sonis ST (2004) The pathobiology of mucositis. Nat Rev Cancer 4(4):277–284

    Article  PubMed  CAS  Google Scholar 

  36. Takasuna K, Hagiwara T, Watanabe K, Onose S, Yoshida S, Kumazawa E, Nagai E, Kamataki T (2006) Optimal antidiarrhea treatment for antitumor agent irinotecan hydrochloride (CPT-11)-induced delayed diarrhea. Cancer Chemother Pharmacol 25:1–10

    Google Scholar 

  37. Van Furth AM, Verhard-Seijmonbergen EM, Van Furth R, Langermans JAM (1997) Effect of lisofylline and pentoxifylline on the bacterial-stimulated production of TNF-α, IL-1β and IL-10 by human leucocytes. Immunology 91:193–196

    Article  PubMed  Google Scholar 

  38. Williams DA (2001) inflammatory cytokines and mucosal injury. J Natl Cancer Inst Monogr 29:26–30

    PubMed  CAS  Google Scholar 

  39. Woo PCY, Ng WF, Leung HCH, Tsoi HW, Yuen KY (2000) Clarithromycin attenuates cyclophosphamide-induced mucositis in mice. Pharmacol Res 41(5):526–32

    Article  Google Scholar 

  40. Xie R, Mathijssen RHJ, Sparreboom A, Verweij J, Karlsson MO (2002) Clinical pharmacokinetics of irinotecan and its metabolites in relation with diarrhea. Clin Pharmacol Ther 72(3):265–275

    Article  PubMed  CAS  Google Scholar 

  41. Yang XX, Hu ZP, Xu AL, Duan W, Zhu YZ, Huang M, Sheu FS, Zhang Q, Bian JS, Chan E, Li X, Wang JC, Zhou SF (2006) A mechanistic study on reduced toxicity of irinotecan by coadministered thalidomide, a tumor necrosis factor-alpha inhibitor. J Pharmacol Exp Ther 319(1):82–104

    Article  PubMed  CAS  Google Scholar 

  42. Yang XX, Hu ZP, Chan SY, Duan W, Ho PC, Boelsterli UA, Ng KY, Chan E, Bian JS, Chen YZ, Huang M, Zhou SF (2006) Pharmacokinetic mechanisms for reduced toxicity of irinotecan by coadministered thalidomide. Curr Drug Metab 7(4):431–455

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors thank Maria Silvandira França Pinheiro, Department of Physiology and Pharmacology, and José Ivan Rodrigues de Sousa, Department of Morphology, Faculty of Medicine, Federal University of Ceará, Brazil. This work was supported by the Brazilian Agency for Scientific and Technological Development (CNPq).

Author information

Authors and Affiliations

  1. Departments of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Rua Cel. Nunes de Melo, 1127, CEP 60.430-270, Fortaleza, CE, Brazil

    Maria Luisa P. Melo, Rudy C. Soares, Sarah B. L. M. Carvalho, Johan V. Silva, Pedro M. G. Soares, Mariana L. Vale, Marcellus H. L. P. Souza & Ronaldo A. Ribeiro

  2. Departments of Morphology, Faculty of Medicine, Federal University of Ceará, Fortaleza, Brazil

    Gerly A. C. Brito

  3. Department of Nutrition, Health Sciences Centre, Statue University of Ceará, Fortaleza, Brazil

    Maria Luisa P. Melo

  4. Department of Pharmacology, Faculty of Medicine, University of São Paulo, Ribeirão Preto, Brazil

    Fernando Q. Cunha

Authors
  1. Maria Luisa P. Melo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gerly A. C. Brito
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rudy C. Soares
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sarah B. L. M. Carvalho
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Johan V. Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Pedro M. G. Soares
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mariana L. Vale
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Marcellus H. L. P. Souza
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Fernando Q. Cunha
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ronaldo A. Ribeiro
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ronaldo A. Ribeiro.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Melo, M.L.P., Brito, G.A.C., Soares, R.C. 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 Chemother Pharmacol 61, 775–784 (2008). https://doi.org/10.1007/s00280-007-0534-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-007-0534-4

Keywords

Search

Navigation