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01.03.2015 | Original article

Modulation of radiation-induced oral mucositis by pentoxifylline: Preclinical studies

verfasst von: Sylvia Gruber, Margret Schmidt, Eva Bozsaky, Kathrin Wolfram, Julia Haagen, Bettina Habelt, Martin Puttrich, Prof. Dr. Wolfgang Dörr, DVM, PhD

Erschienen in: Strahlentherapie und Onkologie | Ausgabe 3/2015

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Abstract

Background and purpose

Oral mucositis is a frequent early side effect of radio(chemo)therapy of head-and-neck malignancies. The epithelial radiation response is accompanied by inflammatory reactions; their interaction with epithelial processes remains unclear. The aim of the present study was to investigate the effect of pentoxifylline (PTX) on the oral mucosal radiation response in the mouse tongue model.

Materials and methods

Irradiation comprised fractionation (5 fractions of 3 Gy/week) over 1 (days 0–4) or 2 weeks (days 0–4, 7–11), followed by graded local top-up doses (day 7/14), in order to generate complete dose–effect curves. PTX (15 mg/kg subcutaneously) was applied once daily over varying time intervals. Ulceration of mouse tongue epithelium, corresponding to confluent mucositis, was analyzed as the clinically relevant endpoint.

Results

With fractionated irradiation over 1 week, PTX administration significantly reduced the incidence of mucosal reactions when initiated before (day − 5) the onset of fractionation; a trend was observed for start of PTX treatment on day 0. Similarly, PTX treatment combined with 2 weeks of fractionation had a significant effect on ulcer incidence in all but one experiment. This clearly illustrates the potential of PTX to ameliorate oral mucositis during daily fractionated irradiation.

Conclusion

PTX resulted in a significant reduction of oral mucositis during fractionated irradiation, which may be attributed to stimulation of mucosal repopulation processes. The biological basis of this effect, however, needs to be clarified in further, detailed mechanistic studies.

Budach V, Becker ET, Boehmer D et al (2014) Concurrent hyperfractionated accelerated radiotherapy with 5-FU and once weekly cisplatin in locally advanced head and neck cancer. The 10-year results of a prospective phase II trial. Strahlenther Onkol 190:250–255CrossRefPubMed

Elting LS, Keefe DM, Sonis ST et al (2008) Patient-reported measurements of oral mucositis in head and neck cancer patients treated with radiotherapy with or without chemotherapy: demonstration of increased frequency, severity, resistance to palliation, and impact on quality of life. Cancer 113:2704–2713CrossRefPubMed

Murphy BA (2007) Clinical and economic consequences of mucositis induced by chemotherapy and/or radiation therapy. J Support Oncol 5:13–21PubMed

Wygoda A, Rutkowski T, Hutnik M et al (2013) Acute mucosal reactions in patients with head and neck cancer. Three patterns of mucositis observed during radiotherapy. Strahlenther Onkol 189:547–551CrossRefPubMed

Lalla RV, Sonis ST, Peterson DE (2008) Management of oral mucositis in patients who have cancer. Dent Clin North Am 52:61–77, viiiCrossRefPubMedCentralPubMed

Butof R, Baumann M (2013) Time in radiation oncology—keep it short! Radiother Oncol 106:271–275CrossRefPubMed

Fowler JF, Lindstrom MJ (1992) Loss of local control with prolongation in radiotherapy. Int J Radiat Oncol Biol Phys 23:457–467CrossRefPubMed

Herrmann T, Baumann M (2005) Prolongation of latency or overall treatment time by unplanned radiation pauses. The clinical importance of compensation. Strahlenther Onkol 181:65–76CrossRefPubMed

Dorr W, Hendry JH (2001) Consequential late effects in normal tissues. Radiother Oncol 61:223–231CrossRefPubMed

10.

Viet CT, Corby PM, Akinwande A et al (2014) Review of preclinical studies on treatment of mucositis and associated pain. J Dent Res 93:868–875CrossRefPubMed

11.

Elting LS, Cooksley CD, Chambers MS et al (2007) Risk, outcomes, and costs of radiation-induced oral mucositis among patients with head-and-neck malignancies. Int J Radiat Oncol Biol Phys 68:1110–1120CrossRefPubMed

12.

Keefe DM, Schubert MM, Elting LS et al (2007) Updated clinical practice guidelines for the prevention and treatment of mucositis. Cancer 109:820–831CrossRefPubMed

13.

Rosenthal DI, Trotti A (2009) Strategies for managing radiation-induced mucositis in head and neck cancer. Semin Radiat Oncol 19:29–34CrossRefPubMed

14.

Treister N, Sonis S (2007) Mucositis: biology and management. Curr Opin Otolaryngol Head Neck Surg 15:123–129CrossRefPubMed

15.

Maier P, Wenz F, Herskind C (2014) Radioprotection of normal tissue cells. Strahlenther Onkol 190:745–752CrossRefPubMed

16.

Logan RM, Stringer AM, Bowen JM et al (2007) The role of pro-inflammatory cytokines in cancer treatment-induced alimentary tract mucositis: pathobiology, animal models and cytotoxic drugs. Cancer Treat Rev 33:448–460CrossRefPubMed

17.

Sonis ST (2007) Pathobiology of oral mucositis: novel insights and opportunities. J Support Oncol 5:3–11PubMed

18.

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

19.

Saito N, Truong MT, Qureshi MM et al (2013) Correlation of mucositis during head and neck radiotherapy with computed tomography perfusion imaging of the oropharyngeal mucosa. J Comput Assist Tomogr 37:499–504CrossRefPubMed

20.

Jensen SB, Jarvis V, Zadik Y et al (2013) Systematic review of miscellaneous agents for the management of oral mucositis in cancer patients. Support Care Cancer 21:3223–3232CrossRefPubMed

21.

Worthington HV, Clarkson JE, Eden OB (2007) Interventions for preventing oral mucositis for patients with cancer receiving treatment. Cochrane Database Syst Rev 3:CD000978

22.

Ward A, Clissold SP (1987) Pentoxifylline. A review of its pharmacodynamic and pharmacokinetic properties, and its therapeutic efficacy. Drugs 34:50–97CrossRefPubMed

23.

Green LA, Kim C, Gupta SK et al (2012) Pentoxifylline reduces tumor necrosis factor-alpha and HIV-induced vascular endothelial activation. AIDS Res Hum Retroviruses 28:1207–1215CrossRefPubMedCentralPubMed

24.

Peterson TC, Peterson MR, Raoul JM (2011) The effect of pentoxifylline and its metabolite-1 on inflammation and fibrosis in the TNBS model of colitis. Eur J Pharmacol 662:47–54CrossRefPubMed

25.

Ji Q, Zhang L, Jia H et al (2004) Pentoxifylline inhibits endotoxin-induced NF-kappa B activation and associated production of proinflammatory cytokines. Ann Clin Lab Sci 34:427–436PubMed

26.

Samardzic T, Jankovic V, Stosic-Grujicic S et al (2001) Pentoxifylline inhibits the synthesis and IFN-gamma-inducing activity of IL-18. Clin Exp Immunol 124:274–281CrossRefPubMedCentralPubMed

27.

Dorr W, Brankovic K, Hartmann B (2000) Repopulation in mouse oral mucosa: changes in the effect of dose fractionation. Int J Radiat Biol 76:383–390CrossRefPubMed

28.

Schmidt M, Haagen J, Noack R et al (2014) Effects of bone marrow or mesenchymal stem cell transplantation on oral mucositis (mouse) induced by fractionated irradiation. Strahlenther Onkol 190:399–404CrossRefPubMed

29.

Dorr W, Heider K, Spekl K (2005) Reduction of oral mucositis by palifermin (rHuKGF): dose-effect of rHuKGF. Int J Radiat Biol 81:557–565CrossRefPubMed

30.

Dorr W, Reichel S, Spekl K (2005) Effects of keratinocyte growth factor (palifermin) administration protocols on oral mucositis (mouse) induced by fractionated irradiation. Radiother Oncol 75:99–105CrossRefPubMed

31.

Al-Dasooqi N, Sonis ST, Bowen JM et al (2013) Emerging evidence on the pathobiology of mucositis. Support Care Cancer 21:2075–2083CrossRefPubMed

32.

Neuner P, Klosner G, Schauer E et al (1994) Pentoxifylline in vivo down-regulates the release of IL-1 beta, IL-6, IL-8 and tumour necrosis factor-alpha by human peripheral blood mononuclear cells. Immunology 83:262–267PubMedCentralPubMed

33.

Gutierrez-Reyes G, Lopez-Ortal P, Sixtos S et al (2006) Effect of pentoxifylline on levels of pro-inflammatory cytokines during chronic hepatitis C. Scand J Immunol 63:461–467CrossRefPubMed

34.

Melo ML, Brito GA, Soares RC et al (2008) Role of cytokines (TNF-alpha, IL-1beta and KC) in the pathogenesis of CPT-11-induced intestinal mucositis in mice: effect of pentoxifylline and thalidomide. Cancer Chemother Pharmacol 61:775–784CrossRefPubMed

35.

Lima V, Brito GA, Cunha FQ et al (2005) Effects of the tumour necrosis factor-alpha inhibitors pentoxifylline and thalidomide in short-term experimental oral mucositis in hamsters. Eur J Oral Sci 113:210–217CrossRefPubMed

36.

Dorr W (1997) Three A's of repopulation during fractionated irradiation of squamous epithelia: asymmetry loss, Acceleration of stem-cell divisions and Abortive divisions. Int J Radiat Biol 72:635–643CrossRefPubMed

37.

Dorr W (2003) Modulation of repopulation processes in oral mucosa: experimental results. Int J Radiat Biol 79:531–537CrossRefPubMed

38.

Dörr W (2009) Pathogenesis of normal tissue side effects. In: Joiner M Van der Kogel A (ed) Basic Clinical Radiobiology. Hodder Arnold, London, pp 169–190

Titel: Modulation of radiation-induced oral mucositis by pentoxifylline: Preclinical studies
verfasst von: Sylvia Gruber
Margret Schmidt
Eva Bozsaky
Kathrin Wolfram
Julia Haagen
Bettina Habelt
Martin Puttrich
Prof. Dr. Wolfgang Dörr, DVM, PhD
Publikationsdatum: 01.03.2015
Verlag: Springer Berlin Heidelberg
Erschienen in: Strahlentherapie und Onkologie / Ausgabe 3/2015
Print ISSN: 0179-7158
Elektronische ISSN: 1439-099X
DOI: https://doi.org/10.1007/s00066-014-0775-1

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Modulation of radiation-induced oral mucositis by pentoxifylline: Preclinical studies