Skip to main content
SpringerLink
Log in

Pentoxifylline, Vitamin E, and Modification of Radiation-Induced Fibrosis

  • Chapter
  • First Online:
Oxidative Stress in Cancer Biology and Therapy

  • 1292 Accesses

Abstract

Radiation-induced fibrosis (RIF) in the breast, skin, and head and neck sites can result in pain, poor cosmesis, and functional limitations. In addition, RIF in the lung, kidney, and bowel, can result in functional loss that can be extremely morbid or life threatening. Studies with pentoxifylline (PTX) have demonstrated the ability of PTX to prevent or improve chronic RIF. Endogenous tocopherol (vitamin E) protects cell membranes against lipid peroxidation. The majority of clinical studies involving PTX and/or vitamin E have investigated their potential role in reversing late radiation changes while only a few studies have focused on their possible role in prevention of delayed radiation effects. The extensive clinical trial experience from 1989 to the present suggests that PTX with or without vitamin E is effective at both preventing and reversing some manifestations of RIF. Mechanisms may include reversal of local hypoxia, inhibition of fibroblast proliferation, and reduction of oxidative stress via multiple pathways. The change in perception of RIF as fixed and irreversible to the realization that it represents a dynamic and continuous process invites us to continue to explore the mechanisms involved and to develop appropriate treatments.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 139.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 179.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Delanian S, Lefaix JL (2007) Current management for late normal tissue injury: radiation-induced fibrosis and necrosis. Semin Radiat Oncol 17:99–107

    Article  PubMed  Google Scholar 

  2. Cerutti PA, Trump BF (1991) Inflammation and oxidative stress in carcinogenesis. Cancer Cells 3:1–7

    PubMed  CAS  Google Scholar 

  3. Finkel T (1998) Oxygen radicals and signaling. Curr Opin Cell Biol 10:248–253

    Article  PubMed  CAS  Google Scholar 

  4. Mikkelsen RB, Wardman P (2003) Biological chemistry of reactive oxygen and nitrogen and radiation-induced signal transduction mechanisms. Oncogene 22:5734–5754

    Article  PubMed  CAS  Google Scholar 

  5. Riley PA (1994) Free radicals in biology: oxidative stress and the effects of ionizing radiation. Int J Radiat Biol 65:27–33

    Article  PubMed  CAS  Google Scholar 

  6. Pena LA, Fuks Z, Kolesnick R (1997) Stress-induced apoptosis and the sphingomyelin pathway. Biochem Pharmacol 53:615–621

    Article  PubMed  CAS  Google Scholar 

  7. Pena LA, Fuks Z, Kolesnick RN (2000) Radiation-induced apoptosis of endothelial cells in the murine central nervous system: protection by fibroblast growth factor and sphingomyelinase deficiency. Cancer Res 60:321–327

    PubMed  CAS  Google Scholar 

  8. Barcellos-Hoff MH, Park C, Wright EG (2005) Radiation and the microenvironment – tumorigenesis and therapy. Nat Rev Cancer 5:867–875

    Article  PubMed  CAS  Google Scholar 

  9. Denham JW, Hauer-Jensen M (2002) The radiotherapeutic injury–a complex ‘wound’. Radiother Oncol 63:129–145

    Article  PubMed  Google Scholar 

  10. Robbins ME, Zhao W (2004) Chronic oxidative stress and radiation-induced late normal tissue injury: a review. Int J Radiat Biol 80:251–259

    Article  PubMed  CAS  Google Scholar 

  11. Clemens MR, Ladner C, Schmidt H, Ehninger G, Einsele H, Buhler E, Waller HD, Gey KF (1989) Decreased essential antioxidants and increased lipid hydroperoxides following high-dose radiochemotherapy. Free Radic Res Commun 7:227–232

    Article  PubMed  CAS  Google Scholar 

  12. Robbins ME, Zhao W, Davis CS, Toyokuni S, Bonsib SM (2002) Radiation-induced kidney injury: a role for chronic oxidative stress? Micron 33:133–141

    Article  PubMed  CAS  Google Scholar 

  13. Jack CI, Cottier B, Jackson MJ, Cassapi L, Fraser WD, Hind CR (1996) Indicators of free radical activity in patients developing radiation pneumonitis. Int J Radiat Oncol Biol Phys 34:149–154

    Article  PubMed  CAS  Google Scholar 

  14. Tofilon PJ, Fike JR (2000) The radioresponse of the central nervous system: a dynamic process. Radiat Res 153:357–370

    Article  PubMed  CAS  Google Scholar 

  15. Haroon ZA, Raleigh JA, Greenberg CS, Dewhirst MW (2000) Early wound healing exhibits cytokine surge without evidence of hypoxia. Ann Surg 231:137–147

    Article  PubMed  CAS  Google Scholar 

  16. Shweiki D, Itin A, Soffer D, Keshet E (1992) Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 359:843–845

    Article  PubMed  CAS  Google Scholar 

  17. Poli G, Parola M (1997) Oxidative damage and fibrogenesis. Free Radic Biol Med 22:287–305

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  19. Magnusson M, Gunnarsson M, Berntorp E, Bjorkman S, Hoglund P (2008) Effects of pentoxifylline and its metabolites on platelet aggregation in whole blood from healthy humans. Eur J Pharmacol 581:290–295

    Article  PubMed  CAS  Google Scholar 

  20. Stefanovich V (1973) Effect of 3,7-dimethyl-1-(5-oxo-hexyl)xanthine and 1-hexyl-3,7-­dimethyl xanthine on cyclic AMP phosphodiesterase of the human umbilical cord vessels. Res Commun Chem Pathol Pharmacol 5:655–662

    PubMed  CAS  Google Scholar 

  21. Berman B, Duncan MR (1990) Pentoxifylline inhibits the proliferation of human fibroblasts derived from keloid, scleroderma and morphoea skin and their production of collagen, glycosaminoglycans and fibronectin. Br J Dermatol 123:339–346

    Article  PubMed  CAS  Google Scholar 

  22. Fang CC, Yen CJ, Chen YM, Shyu RS, Tsai TJ, Lee PH, Hsieh BS (2000) Pentoxifylline inhibits human peritoneal mesothelial cell growth and collagen synthesis: effects on TGF-beta. Kidney Int 57:2626–2633

    Article  PubMed  CAS  Google Scholar 

  23. Hung KY, Huang JW, Chen CT, Lee PH, Tsai TJ (2003) Pentoxifylline modulates intracellular signalling of TGF-beta in cultured human peritoneal mesothelial cells: implications for prevention of encapsulating peritoneal sclerosis. Nephrol Dial Transplant 18:670–676

    Article  PubMed  CAS  Google Scholar 

  24. Lin SL, Chen RH, Chen YM, Chiang WC, Lai CF, Wu KD, Tsai TJ (2005) Pentoxifylline attenuates tubulointerstitial fibrosis by blocking Smad3/4-activated transcription and profibrogenic effects of connective tissue growth factor. J Am Soc Nephrol 16:2702–2713

    Article  PubMed  CAS  Google Scholar 

  25. Rajendran R, Rani V, Shaikh S (2006) Pentoxifylline therapy: a new adjunct in the treatment of oral submucous fibrosis. Indian J Dent Res 17:190–198

    Article  PubMed  CAS  Google Scholar 

  26. Seigneur M, Dufourcq P, Belloc F, Lenoble M, Renard M, Boisseau MR (1995) Influence of pentoxifylline on membrane thrombomodulin levels in endothelial cells submitted to hypoxic conditions. J Cardiovasc Pharmacol 25(Suppl 2):S85–87

    Article  PubMed  CAS  Google Scholar 

  27. Neuner P, Klosner G, Schauer E, Pourmojib M, Macheiner W, Grunwald C, Knobler R, Schwarz A, Luger TA, Schwarz T (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 83:262–267

    PubMed  CAS  Google Scholar 

  28. Rube CE, Wilfert F, Uthe D, Schmid KW, Knoop R, Willich N, Schuck A, Rube C (2002) Modulation of radiation-induced tumour necrosis factor alpha (TNF-alpha) expression in the lung tissue by pentoxifylline. Radiother Oncol 64:177–187

    Article  PubMed  CAS  Google Scholar 

  29. Boerma M, Roberto KA, Hauer-Jensen M (2008) Prevention and treatment of functional and structural radiation injury in the rat heart by pentoxifylline and alpha-tocopherol. Int J Radiat Oncol Biol Phys 72:170–177

    Article  PubMed  CAS  Google Scholar 

  30. Lefaix JL, Delanian S, Vozenin MC, Leplat JJ, Tricaud Y, Martin M (1999) Striking regression of subcutaneous fibrosis induced by high doses of gamma rays using a combination of pentoxifylline and alpha-tocopherol: an experimental study. Int J Radiat Oncol Biol Phys 43:839–847

    Article  PubMed  CAS  Google Scholar 

  31. Packer L, Weber SU, Rimbach G (2001) Molecular aspects of alpha-tocotrienol antioxidant action and cell signalling. J Nutr 131:369S–373S

    PubMed  CAS  Google Scholar 

  32. Empey LR, Papp JD, Jewell LD, Fedorak RN (1992) Mucosal protective effects of vitamin E and misoprostol during acute radiation-induced enteritis in rats. Dig Dis Sci 37:205–214

    Article  PubMed  CAS  Google Scholar 

  33. Bese NS, Munzuroglu F, Uslu B, Arbak S, Yesiladali G, Sut N, Altug T, Ober A (2007) Vitamin E protects against the development of radiation-induced pulmonary fibrosis in rats. Clin Oncol (R Coll Radiol) 19:260–264

    Article  CAS  Google Scholar 

  34. Baillet F (1997) Alpha-tocopherol treatment of radiofibrosis post-brachytherapy for breast cancer. Radiother Oncol 43:S3

    Google Scholar 

  35. Delanian S, Porcher R, Balla-Mekias S, Lefaix JL (2003) Randomized, placebo-controlled trial of combined pentoxifylline and tocopherol for regression of superficial radiation-induced fibrosis. J Clin Oncol 21:2545–2550

    Article  PubMed  CAS  Google Scholar 

  36. Ferreira PR, Fleck JF, Diehl A, Barletta D, Braga-Filho A, Barletta A, Ilha L (2004) Protective effect of alpha-tocopherol in head and neck cancer radiation-induced mucositis: a double-blind randomized trial. Head Neck 26:313–321

    Article  PubMed  Google Scholar 

  37. Lonn E, Bosch J, Yusuf S, Sheridan P, Pogue J, Arnold JM, Ross C, Arnold A, Sleight P, Probstfield J, Dagenais GR (2005) Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial. JAMA 293:1338–1347

    Article  PubMed  Google Scholar 

  38. Miller ER 3rd, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E (2005) Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med 142:37–46

    PubMed  CAS  Google Scholar 

  39. Berry D, Wathen JK, Newell M (2009) Bayesian model averaging in meta-analysis: vitamin E supplementation and mortality. Clin Trials 6:28–41

    Article  PubMed  Google Scholar 

  40. Dion MW, Hussey DH, Doornbos JF, Vigliotti AP, Wen BC, Anderson B (1990) Preliminary results of a pilot study of pentoxifylline in the treatment of late radiation soft tissue necrosis. Int J Radiat Oncol Biol Phys 19:401–407

    Article  PubMed  CAS  Google Scholar 

  41. Dion MW, Hussey DH, Osborne JW (1989) The effect of pentoxifylline on early and late radiation injury following fractionated irradiation in C3H mice. Int J Radiat Oncol Biol Phys 17:101–107

    Article  PubMed  CAS  Google Scholar 

  42. Withers HR, Peters LJ, Kolenik LJ (1980) The pathobiology of late effects of irradiation. In: Meyn RE, Withers HR (eds) Radiation biology in cancer research. Raven, New York

    Google Scholar 

  43. Fajardo LF, Stewart JR (1971) Capillary injury preceding radiation-induced myocardial fibrosis. Radiology 101:429–433

    PubMed  CAS  Google Scholar 

  44. Reinhold HS, Buisman GH (1975) Repair of radiation damage to capillary endothelium. Br J Radiol 48:727–731

    Article  PubMed  CAS  Google Scholar 

  45. Delanian S, Balla-Mekias S, Lefaix JL (1999) Striking regression of chronic radiotherapy damage in a clinical trial of combined pentoxifylline and tocopherol. J Clin Oncol 17:3283–3290

    PubMed  CAS  Google Scholar 

  46. Delanian S, Porcher R, Rudant J, Lefaix JL (2005) Kinetics of response to long-term treatment combining pentoxifylline and tocopherol in patients with superficial radiation-induced fibrosis. J Clin Oncol 23:8570–8579

    Article  PubMed  Google Scholar 

  47. Delanian S, Lefaix JL (2002) Complete healing of severe osteoradionecrosis with treatment combining pentoxifylline, tocopherol and clodronate. Br J Radiol 75:467–469

    PubMed  CAS  Google Scholar 

  48. Delanian S, Lefaix JL, Maisonobe T, Salachas F, Pradat PF (2008) Significant clinical improvement in radiation-induced lumbosacral polyradiculopathy by a treatment combining pentoxifylline, tocopherol, and clodronate (Pentoclo). J Neurol Sci 275:164–166

    Article  PubMed  CAS  Google Scholar 

  49. Ledee-Bataille N, Olivennes F, Lefaix JL, Chaouat G, Frydman R, Delanian S (2002) Combined treatment by pentoxifylline and tocopherol for recipient women with a thin endometrium enrolled in an oocyte donation programme. Hum Reprod 17:1249–1253

    Article  PubMed  CAS  Google Scholar 

  50. Letur-Konirsch H, Guis F, Delanian S (2002) Uterine restoration by radiation sequelae regression with combined pentoxifylline-tocopherol: a phase II study. Fertil Steril 77:1219–1226

    Article  PubMed  Google Scholar 

  51. Okunieff P, Augustine E, Hicks JE, Cornelison TL, Altemus RM, Naydich BG, Ding I, Huser AK, Abraham EH, Smith JJ, Coleman N, Gerber LH (2004) Pentoxifylline in the treatment of radiation-induced fibrosis. J Clin Oncol 22:2207–2213

    Article  PubMed  CAS  Google Scholar 

  52. Haddad P, Kalaghchi B, Amouzegar-Hashemi F (2005) Pentoxifylline and vitamin E combination for superficial radiation-induced fibrosis: a phase II clinical trial. Radiother Oncol 77:324–326

    Article  PubMed  CAS  Google Scholar 

  53. Hille A, Christiansen H, Pradier O, Hermann RM, Siekmeyer B, Weiss E, Hilgers R, Hess CF, Schmidberger H (2005) Effect of pentoxifylline and tocopherol on radiation proctitis/enteritis. Strahlenther Onkol 181:606–614

    Article  PubMed  Google Scholar 

  54. Gothard L, Cornes P, Earl J, Hall E, MacLaren J, Mortimer P, Peacock J, Peckitt C, Woods M, Yarnold J (2004) Double-blind placebo-controlled randomised trial of vitamin E and pentoxifylline in patients with chronic arm lymphoedema and fibrosis after surgery and radiotherapy for breast cancer. Radiother Oncol 73:133–139

    Article  PubMed  CAS  Google Scholar 

  55. Gothard L, Cornes P, Brooker S, Earl J, Glees J, Hall E, Peckitt C, Tait D, Yarnold J (2005) Phase II study of vitamin E and pentoxifylline in patients with late side effects of pelvic radiotherapy. Radiother Oncol 75:334–341

    Article  PubMed  CAS  Google Scholar 

  56. Ozturk B, Egehan I, Atavci S, Kitapci M (2004) Pentoxifylline in prevention of radiation-induced lung toxicity in patients with breast and lung cancer: a double-blind randomized trial. Int J Radiat Oncol Biol Phys 58:213–219

    Article  PubMed  CAS  Google Scholar 

  57. (1995) LENT SOMA scales for all anatomic sites. Int J Radiat Oncol Biol Phys 31:1049–1091

    Google Scholar 

  58. CTC (1998) Cancer therapy evaluation program. In: NCI (ed) Common toxicity criteria version 2. DCDT, DHHS, Bethesda

    Google Scholar 

  59. Aygenc E, Celikkanat S, Kaymakci M, Aksaray F, Ozdem C (2004) Prophylactic effect of pentoxifylline on radiotherapy complications: a clinical study. Otolaryngol Head Neck Surg 130:351–356

    Article  PubMed  Google Scholar 

  60. Magnusson M, Hoglund P, Johansson K, Jonsson C, Killander F, Malmstrom P, Weddig A, Kjellen E (2009) Pentoxifylline and vitamin E treatment for prevention of radiation-induced side-effects in women with breast cancer: a phase two, double-blind, placebo-controlled randomised clinical trial (Ptx-5). Eur J Cancer 45:2488–2495

    Article  PubMed  CAS  Google Scholar 

  61. Scott J, Huskisson EC (1976) Graphic representation of pain. Pain 2:175–184

    Article  PubMed  CAS  Google Scholar 

  62. Jacobson G, Smith BJ, Bodeker K (2008) A randomized trial of pentoxifylline and vitamin E versus standard follow-up after breast irradiation to prevent breast fibrosis, evaluated by tissue compliance meter (TCM). J Clin Oncol 26

    Google Scholar 

  63. Kwon HC, Kim SK, Chung WK, Cho MJ, Kim JS, Moon SR, Park WY, Ahn SJ, Oh YK, Yun HG, Na BS (2000) Effect of pentoxifylline on radiation response of non-small cell lung cancer: a phase III randomized multicenter trial. Radiother Oncol 56:175–179

    Article  PubMed  CAS  Google Scholar 

  64. Theron T, Binder A, Verheye-Dua F, Bohm L (2000) The role of G2-block abrogation, DNA double-strand break repair and apoptosis in the radiosensitization of melanoma and squamous cell carcinoma cell lines by pentoxifylline. Int J Radiat Biol 76:1197–1208

    Article  PubMed  CAS  Google Scholar 

  65. Vernimmen F, Verheye-Dua F, du Toit H, Bohm L (1994) Effect of pentoxifylline on radiation damage and tumor growth. Strahlenther Onkol 170:595–601

    PubMed  CAS  Google Scholar 

  66. Friedman N (1988) The effects of irradiation on breast cancer and the breast. CA Cancer J Clin 38:368–371

    Article  PubMed  CAS  Google Scholar 

  67. Leith JT, Michelson S (1990) Tumor radiocurability: relationship to intrinsic tumor heterogeneity and to the tumor bed effect. Invasion Metastasis 10:329–351

    PubMed  CAS  Google Scholar 

  68. Hartsell WF, Scott CB, Dundas GS, Mohiuddin M, Meredith RF, Rubin P, Weigensberg IJ (2007) Can serum markers be used to predict acute and late toxicity in patients with lung cancer? Analysis of RTOG 91–03. Am J Clin Oncol 30:368–376

    Article  PubMed  CAS  Google Scholar 

  69. Zhao L, Sheldon K, Chen M, Yin MS, Hayman JA, Kalemkerian GP, Arenberg D, Lyons SE, Curtis JL, Davis M, Cease KB, Brenner D, Anscher MS, Lawrence TS, Kong FM (2008) The predictive role of plasma TGF-beta1 during radiation therapy for radiation-induced lung toxicity deserves further study in patients with non-small cell lung cancer. Lung Cancer 59:232–239

    Article  PubMed  Google Scholar 

  70. Fernet M, Hall J (2008) Predictive markers for normal tissue reactions: fantasy or reality? Cancer Radiother 12:614–618

    Article  PubMed  CAS  Google Scholar 

  71. Canney PA, Dean S (1990) Transforming growth factor beta: a promotor of late connective tissue injury following radiotherapy? Br J Radiol 63:620–623

    Article  PubMed  CAS  Google Scholar 

  72. Martin M, Lefaix JL, Pinton P, Crechet F, Daburon F (1993) Temporal modulation of TGF-beta 1 and beta-actin gene expression in pig skin and muscular fibrosis after ionizing radiation. Radiat Res 134:63–70

    Article  PubMed  CAS  Google Scholar 

  73. Rodemann HP, Binder A, Bamberg M (1995) Radiation induced fibrosis: experimental studies. In: Sauer R, Dunst J (eds) Late sequelae in oncology. Springer, Berlin

    Google Scholar 

  74. Sivan V, Vozenin-Brotons MC, Tricaud Y, Lefaix JL, Cosset JM, Dubray B, Martin MT (2002) Altered proliferation and differentiation of human epidermis in cases of skin fibrosis after radiotherapy. Int J Radiat Oncol Biol Phys 53:385–393

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Radiation Oncology, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA, 52242, USA

    Geraldine Jacobson MD, MPH, MBA

Authors
  1. Geraldine Jacobson MD, MPH, MBA
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Geraldine Jacobson MD, MPH, MBA .

Editor information

Editors and Affiliations

  1. Free Radical & Radiation Biology, Graduate Program, University of Iowa, Iowa City, 52242, Iowa, USA

    Douglas R. Spitz

  2. Duluth Clinic, Radiation Oncology, University of Minnesota, East 3rd Street 400, Duluth, 55805, Minnesota, USA

    Kenneth J. Dornfeld

  3. James H. Quillen College of Medicine, Internal Medicine, East Tennessee State University, Johnson City, 37614, Tennessee, USA

    Koyamangalath Krishnan

  4. Radiation Oncology, Cancer Biology and Pediatrics, Vanderbilt Medical School, 21st Ave. 1161, Nashville, 37232, Tennessee, USA

    David Gius

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Jacobson, G. (2012). Pentoxifylline, Vitamin E, and Modification of Radiation-Induced Fibrosis. In: Spitz, D., Dornfeld, K., Krishnan, K., Gius, D. (eds) Oxidative Stress in Cancer Biology and Therapy. Oxidative Stress in Applied Basic Research and Clinical Practice. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-61779-397-4_17

Download citation

Publish with us

Policies and ethics

Search

Navigation