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Apoptotic and inflammation markers in oral mucositis in head and neck cancer patients receiving radiotherapy: preliminary report

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Abstract

Goal of work

The aim of this study was to investigate the expression of pro-apoptotic protein p53 and anti-apoptotic proteins BCl-2 and MCl-1, as well as the expression of pro-inflammatory cytokines tumor necrosis factor (TNF) and interleukin-1beta (IL-1β) in patients developing mucositis during radiotherapy for head and neck cancer.

Materials and methods

Thirty-five patients receiving radiotherapy for head/neck cancer were included in this study. Patients were examined before radiotherapy. Oral mucositis was recorded weekly during radiotherapy. Cytologic smears from the oral cavity were taken with a brush. Immunocytochemical staining was performed by the use of p53, BCl-2, MCl-1 TNF and IL-1β monoclonal antibodies.

Main results

P53 was expressed in 1 of 15 smears before the initiation of radiotherapy (6.5%) compared to 3 of 7 smears from patients with grade III mucositis (43%) during radiotherapy. BCl-2 was expressed in 15 of 15 smears before radiotherapy (100%) and in three of seven patients with grade III mucositis (43%) during radiotherapy. MCl-1 was expressed in 10 of 14 samples before radiotherapy (71.5%) and in two of seven patients with grade III (28.5%) mucositis during radiotherapy. TNF was expressed in 9 of 14 patients before radiotherapy (64%) and in six of seven patients with grade III mucositis during radiotherapy (86%). IL-1β was detected in 7 of 14 patients before radiotherapy (50%) compared to 6 of 7 patients with grade III mucositis during radiotherapy (86%).

Conclusion

Our preliminary results indicate an induction of apoptosis and inflammation in the oral mucosa in patients developing mucositis during radiotherapy for head/neck cancer.

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References

  1. Adams J, Cory S (1998) The Bcl-2 protein family: arbiters of cell survival. Science 281:1322–1326

    Article  PubMed  CAS  Google Scholar 

  2. Aggarwal B, Kohr W, Hass P (1985) Human tumor necrosis factor. Production, puri®cation and characterization. J Biol Chem 260:2345–2354

    PubMed  CAS  Google Scholar 

  3. Anilkumar T, Sarraf C, Hunt T, Alison M (1992) The nature of cytotoxic drug-induced cell death in murine intestinal crypts. Br J Cancer 65:552–558

    PubMed  CAS  Google Scholar 

  4. Anthony L, Bowen J, Garden A, Hewson I, Sonis S (2006) New thoughts on the pathobiology of regimen-related mucosal injury. Support Care Cancer 14:516–518

    Article  PubMed  Google Scholar 

  5. Baker S, Markowitz S, Fearon E, Willson J, Vogelstein B (1990) Suppression of human colorectal carcinoma cell growth by wild-type p53. Science 249:912–915

    Article  PubMed  CAS  Google Scholar 

  6. Bellm L, Epstein J, Rose-Ped A (2000) Patient reports of complications of bone marrow transplantation. Support Care Cancer 8:33–39

    PubMed  CAS  Google Scholar 

  7. Bianco J, Appelbaum F, Nemunaitis J (1991) Phase I–II trial of pentoxifylline for the prevention of transplant-related toxicities following bone marrow transplantation. Blood 78:1205–1211

    PubMed  CAS  Google Scholar 

  8. Bowen J, Gibson R, Keefe D, Cummins A (2005) Cytotoxic chemotherapy upregulates pro-apoptotic Bax and Bak in the small intestine of rats and humans. Pathology 37:56–62

    Article  PubMed  CAS  Google Scholar 

  9. Bowen J, Gibson R, Cummins A, Keefe D (2006) Intestinal mucositis: the role of the Bcl-2 family, p53 and caspases in chemotherapy-induced damage. Support Care Cancer 14:713–731

    Article  PubMed  Google Scholar 

  10. Bowen J, Gibson R, Cummins A, Tyskin A, Keefe D (2007) Irinotecan changes gene expression in the small intestine of the rat with breast cancer. Cancer Chemother Pharmacol 59:337–348

    Article  PubMed  CAS  Google Scholar 

  11. Carswell E, Old L, Kassel R (1975) An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci U S A 72:3666–3670

    Article  PubMed  CAS  Google Scholar 

  12. Cox J, Stetz J, Pajak T (1995) Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys 31:1341–1346

    PubMed  CAS  Google Scholar 

  13. Dinarello C (1996) Biologic basis for interleukin-1 in disease. Blood 87:2095–2147

    PubMed  CAS  Google Scholar 

  14. Dinarello C (2000) Proinflammatory cytokines. Chest 118:503–508

    Article  PubMed  CAS  Google Scholar 

  15. Elting L, Cooksley C, Chambers M (2003) The burdens of cancer therapy: clinical and economic outcomes of chemotherapy-induced mucositis. Cancer Nurs 98:153–159

    Google Scholar 

  16. Ferra C, de Sanjose S, Lastra C (1997) Pentoxifylline, ciprofloxacin and prednisone failed to prevent transplantrelated toxicities in bone marrow transplant recipients and were associated with an increased incidence of infectious complications. Bone Marrow Transplant 20:1075–1080

    Article  PubMed  CAS  Google Scholar 

  17. Ferra C, de Sanjose S, Gallardo D (1998) IL-6 and IL-8 levels in plasma during hematopoietic progenitor transplantation. Haematologica 83:1082–1087

    PubMed  CAS  Google Scholar 

  18. Ferra C, de Sanjose S, Gallardo D, Berlanga JJ, Rueda F, Marin D, de la Banda E, Ancin I, Peris J, Garcia J, Granena A (1998) IL-6 and IL-8 levels in plasma during hematopoietic progenitor transplantation. Haematologica 83:1082–1087

    PubMed  CAS  Google Scholar 

  19. Ferrara J, Abhyankar S, Gilliland D (1993) Cytokine stem of graft-versus-host disease: a critical e€ector role for interleukin-1. Transplant Proc 25:1216–1217

    PubMed  CAS  Google Scholar 

  20. Gibson L, Fortney J, Magro G, Ericson S, Lynch J, Landreth K (1999) Regulation of BAX and BCL-2 expression in breast cancer cells by chemotherapy. Breast Cancer Res Treat 55:107–117

    Article  PubMed  CAS  Google Scholar 

  21. Gross A, McDonnell J, Korsmeyer S (1999) BCL-2 family members and the mitochondria in apoptosis. Genes Dev 13:1899–1911

    Article  PubMed  CAS  Google Scholar 

  22. Hall P, Benko H, Hogan K (1995) The influence of serum tumor necrosis factor-alpha and interleukin-6 concentrations or nonhematologic toxicities and hematologic recovery in patients with acute myelogenous leukemia. Exp Hematol 23:1256–1260

    PubMed  CAS  Google Scholar 

  23. Hehlgans T, Pfeffer K (2005) The intriguing biology of the tumour necrosis factor/tumour necrosis factor receptor superfamily: players, rules and the games. Immunology 115:1–20

    Article  PubMed  CAS  Google Scholar 

  24. Herr I, Debatin K (2001) Cellular stress response and apoptosis in cancer therapy. Blood 98:2603–2614

    Article  PubMed  CAS  Google Scholar 

  25. Hsu S, Raine L, Fanger H (1981) Use of avidin–biotin peroxidase complex (ABC) in immunoperoxidase techniques: a comparison between ABC and unlabeled antibody (PAP) procedures. J Histochem Cytochem 29:577–580

    PubMed  CAS  Google Scholar 

  26. Inomata A, Horii I, Suzuki K (2002) 5-Fluorouracil-induced intestinal toxicity: what determines the severity of damage to murine intestinal crypt epithelia. Toxicol Lett 133:231–240

    Article  PubMed  CAS  Google Scholar 

  27. Keefe D, Brealey J, Goland G, Cummins A (2000) Chemotherapy for cancer causes apoptosis that precedes hypoplasia in crypts of the small intestine in humans. Gut 47:632–637

    Article  PubMed  CAS  Google Scholar 

  28. Khan S, Wingard J (2001) Infection and mucosal injury in cancer treatment. J Natl Cancer Inst Monogr:31–36

  29. Kitada S, Krajewski S, Miyashita T, Krajewska M, Reed J (1996) Gamma-radiation induces upregulation of Bax protein and apoptosis in radiosensitive cells in vivo. Oncogene 12:187–192

    PubMed  CAS  Google Scholar 

  30. Krenger W, Ferrara J (1996) Graft-vs-host disease and the Th1/Th2 paradigm. Immunol Res 15:50–73

    Article  PubMed  CAS  Google Scholar 

  31. Leung L, Wang T (1999) Differential effects of chemotherapeutic agents on the Bcl-2/Bax apoptosis pathway in human breast cancer cell line MCF-7. Breast Cancer Res Treat 55:73–83

    Article  PubMed  CAS  Google Scholar 

  32. Lima V, Brito G, Cunha F (2005) Effects of the tumour necrosis factor-a inhibitors pentoxifylline and thalidomide in short-term experimental oral mucositis in hamsters. Eur J Oral Sci 113:210–217

    Article  PubMed  CAS  Google Scholar 

  33. Logan R, Stringer A, Bowen J, Yeoh A, Gibson R, Sonis S, Keefe D (2007) The role of pro-inflammatory cytokines in cancer treatment-induced alimentary tract mucositis: Pathobiology, animal models and cytotoxic drugs. Cancer Treat Rev 33(5):448–460 (May 14)

    Article  PubMed  CAS  Google Scholar 

  34. Lorenz H-M, Kalden J (2002) Perspectives for TNF-a-targeting therapies. Arthritis Res 4:S17–S24

    Article  PubMed  Google Scholar 

  35. Nicolatou-Galitis O, Dardoufas K, Markoulatos P (2001) Oral pseudomembranous candidiasis, herpes simplex virus-1 infection, and oral mucositis in head and neck cancer patients receiving radiotherapy and granulocyte-macrophage colony-stimulating factor (GM-CSF) mouthwash. J Oral Pathol Med 30:471–480

    Article  PubMed  CAS  Google Scholar 

  36. Nicolatou-Galitis O, Athanassiadou P, Kouloulias V, Sotiropoulou-Lontou A, Dardoufas K, Polychronopoulou A, Gonidi M, Kyprianou K, Kolitsi G, Skarleas C, Pissakas G, Papanikolaou I, Kouvaris J (2006) Herpes simplex virus-1 (HSV-1) infection in radiation-induced oral mucositis. Support Care Cancer 14:753–762

    Article  PubMed  Google Scholar 

  37. Nicolatou-Galitis O, Velegraki A, Sotiropoulou-Lontou A (2006) Effect of fluconazole antifungal prophylaxis on oral mucositis in head and neck cancer patients receiving radiotherapy. Support Care Cancer 14(1):44–51

    Article  PubMed  Google Scholar 

  38. Nita M, Nagawa H, Tominaga O, Tsuno N, Fujii S, Sasaki S, Fu C, Takenoue T, Tsuruo T, Muto T (1998) 5-Fluorouracil induces apoptosis in human colon cancer cell lines with modulation of Bcl-2 family proteins. Br J Cancer 78:986–992

    PubMed  CAS  Google Scholar 

  39. Peterson DE, Schubert MM (2001) Oral toxicity. In: Perry MC (ed) The chemotherapy source book. 3rd edn. Lippincott, Williams and Wilkins, Philadelphia, pp 404–424

    Google Scholar 

  40. Potten C, Wilson J, Booth C (1997) Regulation and significance of apoptosis in the stem cells of the gastrointestinal epithelium. Stem Cells 15:82–93

    Article  PubMed  CAS  Google Scholar 

  41. Rabinowitz J, Petros W, Stuart A, Peters W (1993) Characterization of endogenous cytokine concentrations after high-dose chemotherapy with autologous bone marrow support. Blood 81:2452–2459

    PubMed  CAS  Google Scholar 

  42. Remberger M, Ringdem O, Markling L (1995) TNF alpha levels are increased during bone marrow transplantation conditioning regimens in patients who develop acute GVHD. Bone Marrow Transplant 15:99–104

    PubMed  CAS  Google Scholar 

  43. Rose-Ped A, Bellm L, Epstein J (2002) Complications of radiation therapy for head and neck cancers: the patient’s perspective. Cancer Nurs 25:461–467

    Article  PubMed  Google Scholar 

  44. Sleijfer S, Vujaskovic Z, Limburg P, Koops H, Mulder N (1998) Induction of tumor necrosis factor-a as a cause of bleomycinrelated toxicity. Cancer Chemother Pharmacol 82:970–974

    CAS  Google Scholar 

  45. Smith N, Rubenstein J, Eggener S, Kozlowski J (2003) The p53 tumor suppressor gene and nuclear protein: basic science review and relevance in the management of bladder cancer. J Urol 169:1219–1228

    Article  PubMed  CAS  Google Scholar 

  46. Sonis S (1998) Mucositis as a biological process: a new hypothesis for the development of chemotherapy-induced stomatotoxicity. Oral Oncol 34:39–43

    Article  PubMed  CAS  Google Scholar 

  47. Sonis S (2004) A biological approach to mucositis. J Support Oncol 2:21–32

    PubMed  Google Scholar 

  48. Sonis S, Peterson R, Edwards L (2000) Defining mechanisms of action of interleukin-11 on the progression of radiation-induced mucositis in hamsters. Oral Oncol 36:393–381

    Article  Google Scholar 

  49. Sonis S, Oster G, Fuchs H (2001) Oral mucositis and the clinical and economic outcomes of hematopoietic stem cell transplantation. J Clin Oncol 19:2201–2205

    PubMed  CAS  Google Scholar 

  50. Stiff P (2001) Mucositis associated with stem cell transplantation: current status and innovative approaches to management. Bone Marrow Transplant 17:S3–S11

    Article  Google Scholar 

  51. Sutherland S, Browman G (2001) Prophylaxis of oral mucositis in irradiated head-and-neck cancer patients: a proposed classification scheme of interventions and metaanalysis of randomized controlled trials. Int J Radiat Oncol Biol Phys 49:917–930

    Article  PubMed  CAS  Google Scholar 

  52. Vousden K, Lu X (2002) Live or let die: the cell’s response to p53. Nat Rev Cancer 2:594–604

    Article  PubMed  CAS  Google Scholar 

  53. Xun C, Thompson J, Jennings C, Brown S, Widmerru B (1994) E€ect of total body irradiation, busulfan-cyclophosphamide or cyclophasphamide conditioning on in¯ammatory cytokine release and development of acute and chronic graft-vs-host disease in H-2-incompatible transplanted ScID mice. Blood 83:2360–2367

    PubMed  CAS  Google Scholar 

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Acknowledgements

We wish to thank Ms Antonia Sipsa and Ms Amalia Moumouri for their valuable technical assistance.

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Correspondence to Arsinoi Xanthinaki.

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Xanthinaki, A., Nicolatou-Galitis, O., Athanassiadou, P. et al. Apoptotic and inflammation markers in oral mucositis in head and neck cancer patients receiving radiotherapy: preliminary report. Support Care Cancer 16, 1025–1033 (2008). https://doi.org/10.1007/s00520-007-0379-8

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