Radioprotectors and Chemoprotectors in the Management of Lung Cancer

  • Ritsuko Komaki
  • Joe Chang
  • Zhongxing Liao
  • James D. Cox
  • K. A. Mason
  • Luka Milas
Part of the Medical Radiology Radiation Oncology book series (MEDRAD)


Angiotensin Converting Enzyme Inhibitor Radiat Oncol Biol Phys Radiation Pneumonitis Keratinocyte Growth Factor Radioprotective Agent 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Antonadou D, Coliarakis N, Synodinou M et al (2001) Randomized phase III trial of radiation treatment plus/minus amifostine in patients with advanced stage lung cancer. Int J Radiat Oncol Biol Phy 51:915–922CrossRefGoogle Scholar
  2. Antonadou D, Throuvalas N, Petridis A et al (2003) Effect of amifostine on toxicities associated with radiochemotherapy in patients with locally advanced non-small cell lung cancer. Int J Radiat Oncol Biol Phys 57:402–408CrossRefPubMedGoogle Scholar
  3. Bonner HS, Shaw LM (2002) New dosing regimens for amifostine: a pilot study to compare the relative bioavailability of oral and subcutaneous administration with intravenous infusion. J Clin Pharmacol 42:166–174CrossRefPubMedGoogle Scholar
  4. Breuer R, Tochner Z, Conner MW et al (2000) Superoxide dismutase inhibits radiation-induced lung injury in hamsters. Lung 170:19–29Google Scholar
  5. Brizel DM (2003) Does amifostine have a role in chemoradiation treatment? Lancet Oncol 4:378–380CrossRefPubMedGoogle Scholar
  6. Brizel DM, Wasserman TH, Henke M et al (2000) Phase III randomized trial of amifostine as a radioprotector in head and neck cancer. J Clin Oncol 18:3339–3345PubMedGoogle Scholar
  7. Calabro-Jones PM, Gahey RC, Smoluk GD et al (1985) Alkaline phosphatase promotes radioprotection and accumulation of WR-1065 in V79-171 cells incubated in medium containing WR-2721. Int J Radiat Biol 47:23–27Google Scholar
  8. Chopra M, Scott N, McMurray J et al (1989) A free radical scavenger. Br J Clin Pharmacol 27:396–399PubMedGoogle Scholar
  9. Choy H, Milas L (2003) Enhancing radiotherapy with cyclooxy-genase-2 enzyme inhibitors: a rational advance? J Natl Cancer Inst 95:1440–1452PubMedGoogle Scholar
  10. Curran WJ, Scott CB, Langer CJ et al (2003) Long-term benefit is observed in a phase III comparison of sequential vs concurrent chemo-radiation for patients with unresected stage III NSCLC: RTOG 9410. Proc Am Sco Clin Oncol 22:621 (abstract 2499)Google Scholar
  11. Delanian S, Baillet F, Huart J et al (1994) Successful treatment of radiation-induced fibrosis using liposomal Cu/Zn superoxide dismutase: clinical trial. Radiother Oncol 32:12–20CrossRefPubMedGoogle Scholar
  12. Dillman RO, Seagren SL, Propert KJ et al (1990) A randomized trial of induction chemotherapy plus high-dose radiation versus radiation alone in stage III non-small-cell lung cancer. N Engl J Med 323:940–945PubMedGoogle Scholar
  13. Dion MW, Hussey DH, Osborne JW (1989) The effect of pentoxifylline on early and late radiation injury following fractionated irradiation of C3H mice. Int J Radiat Oncol Biol Phys 17:101–107PubMedGoogle Scholar
  14. Durand RE (1983) Radioprotection by WR-2721 in vitro and low oxygen tensions: Implications for its mechanisms of action. Br J Cancer 47:387–392PubMedGoogle Scholar
  15. Durand RE, Olive PL (1989) Radiosensitization and radioprotection by BSO and WR-2721: the role of oxygenation. Br J Cancer 60:417–522Google Scholar
  16. Epperly MW, Bray JA, Krager S et al (1999) Intratracheal injectrion of adenovirus containing the human MnSOD transgene protects athymic nude mice from irradiation-induced organizing alveolitis. Int J Radiat Oncol Biol Phys 43:169–181CrossRefPubMedGoogle Scholar
  17. Epperly MW, Gretton JA, DeFilippi SJ et al (2001) Modulation of radiation-induced cytokine elevation associated with esophagitis and esophageal stricture by manganese superoxide dismutase-plasmid/liposome (SOD2-PL) gene therapy. Radiat Res 155:2–14PubMedGoogle Scholar
  18. Epperly MW, Guo HL, Jefferson M et al (2003) Cell phenotype specific kinetics of expression of intratracheally injected manganese superoxide dismutase plasmid/liposomes (MnSOD-PL) during lung radioprotective gene therapy. Gene Ther 2:163–171CrossRefGoogle Scholar
  19. Ferlay J, Bray F, Pisani P et al (2001) Cancer incidence, mortality and prevalence worldwide, Version 1.0 GLOBOCAN 2000. IARC cancer base no 5. IARC Press, LyonGoogle Scholar
  20. Fuks Z, Persaud RS, Alfieri A et al (1994) Basic Fibroblast growth factor protects endothelial cells against radiation-induced programmed cell death in vitro and in vivo. Cancer Res 54:2582–2590PubMedGoogle Scholar
  21. Giannopoulou E, Papadimitriou E (2003) Amifostine has antiangiogenic properties in vitro by changing the redox status of human endothelial cells. Free Radic Res 37:1191–1199CrossRefPubMedGoogle Scholar
  22. Gopal R, Cox JD, Liao Z et al (2002) Effects of amifostine on lung function in patients with non-small-cell lung cancer treated by radiation therapy and chemotherapy. In: Perez CA, Brady LW (eds) UPDATES: principles and practice of radiation oncology, vol 3(4), 3rd edn. Lippincott Williams and Wilkins, New YorkGoogle Scholar
  23. Graham NN, Evans ML, Dahlen DD et al (1988) Drug suppression of late radiation injury in the rat lung. 36th annual meeting of the Radiation Research Society, Philadelphia, 16–21 AprilGoogle Scholar
  24. Grdina DJ, Kataoka Y, Murley JS et al (2002) Inhibition of spontaneous metastases formation by amifostine. Int J Cancer 97:135–141CrossRefPubMedGoogle Scholar
  25. Greenberger JS, Epperly MW, Gretton J et al (2003) Radioprotective gene therapy. Curr Gene Ther 3:183–195CrossRefPubMedGoogle Scholar
  26. Guo H, Epperly MW, Bernarding M et al (2003) Manganese superoxide dismutase-plasmid/liposome (MnSOD-PL) intratracheal gene therapy reduction of irradiation induced inflammatory cytokines does not protect orthotopic Lewis lung carcinomas. In Vivo 17:13–21PubMedGoogle Scholar
  27. Haimovitz-Friedman A, Vlodavsky I, Chaudhuri A et al (1991) Autocrine effects of fibroblast growth factor in repair of radiation damage in endothelial cells. Cancer Res 51:2552PubMedGoogle Scholar
  28. Hanson W (1998) Eicosanoid-induced radioprotection and chemoprotection: laboratory studies and clinical applications. In: Bump E, Malaker K (eds) Radioprotectors: chemical, biological and clinical perspectives. CRC Press, Boca Raton, pp 197–221Google Scholar
  29. Hunter N, Milas L (1983) Protection byS-2-(3-Aminopropyl-amino)-ethylphosphorothioic acid against radiation-induced leg contractures in mice. Cancer Res 43:1630–1632PubMedGoogle Scholar
  30. Jemal A, Tiwari RC, Murray T et al (2004) Cancer statistics, 2004. CA Cancer J Clin 54:8–29PubMedGoogle Scholar
  31. Kemp G, Rose P, Lurain J et al (1996) Amifostine pretreatment for protection against cyclophosphamide-induced and cisplatin-induced toxicities: results of a randomized control trial in patients with advanced ovarian cancer. J Clin Oncol 14:2101–2112PubMedGoogle Scholar
  32. Kirk-Othmer (1996) Encyclopedia of chemical technology, vol 20, 4th edn. Wiley, New YorkGoogle Scholar
  33. Kligerman MM, Turrisi AT, Urtasan RC et al (1988) Final report on Phase I trial of WR-2721 before protracted fractionated radiation therapy. Int J Radiat Oncol Biol Phys 14:1119–1122PubMedGoogle Scholar
  34. Koh W-J, Stelzer KJ, Peterson LM, et al (1995) Effect of pentoxifyl-line on radiation-induced lung and skin toxicity in rats. Int J Radiat Oncol Biol Phys 31:71–77PubMedGoogle Scholar
  35. Komaki R, Lee JS, Kaplan B, et al (2002a) Randomized phase III study of chemoradiation with or without amifostine for patients with favorable performance status inoperable stage II-III non-small cell lung cancer: preliminary results. Semin Radiat Oncol 12:46–49CrossRefPubMedGoogle Scholar
  36. Komaki R, Seiferheld W, Ettinger D, et al (2002b) Randomized phase II chemotherapy and radiotherapy trial for patients with locally advanced inoperable non-small-cell lung cancer: Long-term follow-up of RTOG 92-04. Int J Radiat Oncol 53:548–557CrossRefGoogle Scholar
  37. Komaki R, Lee JS, Milas L, et al (2004) Effects of amifostine on acute toxicity from concurrent chemotherapy and radiotherapy for inoperable non-small cell lung cancer: report of a randomized comparative trial. Int J Radiat Oncol Biol Phy 58:1369–1377CrossRefGoogle Scholar
  38. Koukourakis MI, Kyrias G, Kakolyris S, et al (2000) Subcutaneous administration of amifostine during fractionated radiotherapy: A randomized Phase 11 Study. J Clin Oncol 18:2226–2233PubMedGoogle Scholar
  39. Kwon HC, Kim SK, Chung WK et al (2000) Effect of pentoxifyl-line on radiation response of non-small cell lung cancer: a phase III randomized multicenter trial. Radiother Oncol 56:175–179CrossRefPubMedGoogle Scholar
  40. LeChevalier T, Arriagada R, Quoix E, et al (1991) Radiotherapy alone versus combined chemotherapy and radiotherapy in nonresectable non-small-cell lung cancer: First analysis of a randomized trial in 353 patients. J Natl Cancer Inst 83:417–423PubMedGoogle Scholar
  41. Lee I, Biaglow JE, Lee J et al (2000) Physiological mechanisms of radiation sensitization by pentoxifylline. Anticancer Res (6B):4605–4609Google Scholar
  42. Lefaix JL, Delanian S, Jean Jacques, et al (1999) Striking regression of subcutaneous fibrosis induced by high doses of gamma rays using a combination of pentoxifylline and a-tocopherol: an experimental study. Int J Radiat Oncol Biol Phys 43:839–847CrossRefPubMedGoogle Scholar
  43. Leong SS, Tan EH, Fong KW, et al (2003) Randomized double-blind trial of combined modality treatment with or without amifostine in unresectable stage III non-small cell lung cancer. J Clin Oncol 21:1767–1774CrossRefPubMedGoogle Scholar
  44. Lockhart SP (1990) Inhaled thiol and phosphothiol radioprotectors fail to protect the mouse lung. Radiother. Oncol. 19:187–191CrossRefPubMedGoogle Scholar
  45. Michalowski AS (1994) On radiation damage to normal tissues and its treatment: II. Anti-inflammatory drugs. Acta Oncol. 33:139–157PubMedGoogle Scholar
  46. Miki T, Bottaro DP, Fleming TP, et al (1992) Determination of ligand-binding specificity by alternative splicing: two distinct growth factor receptors encoded by a single gene. Proc Natl Acad Sci USA 89:246–250PubMedGoogle Scholar
  47. Milas L (2001) Cyclooxygenase-2 (COX-2) enzyme inhibitors as potential enhancers of tumor radioresponse. Semin Radiat Oncol 11:290–299CrossRefPubMedGoogle Scholar
  48. Milas L, Hanson WR (1995) Eicosanoids and radiation. Eur J Cancer 31A:1580–1585CrossRefPubMedGoogle Scholar
  49. Milas L, Hunter N, Reid BO, et al (1982) Protective effects of S-2-(3-Aminopropylamino)-ethylphosphorothioic acid against radiation damage of normal tissues and a fibrosarcoma in mice. Cancer Res 42:1888–1897PubMedGoogle Scholar
  50. Milas L, Murray D, Brock, VA, et al (1988) Radioprotectors in tumor radiotherapy: Factors and settings determining therapeutic ratio. Pharmacol Ther 30:179–187CrossRefGoogle Scholar
  51. Milas L, Nishiguchi I, Hunter N, et al (1992) Radiation protection against early and late effects of ionizing irradiation by the prostaglandin inhibitor indomethacin. Adv. Space Res. 12:265–271CrossRefGoogle Scholar
  52. Milas L, Mason KA, Liao Z, et al (2003a) Chemoradiotherapy: emerging treatment improvement strategies. Head and Neck 25:152–167CrossRefPubMedGoogle Scholar
  53. Milas L, Mason K, Liao Z, et al (2003b) Role of Cyclooxygenase-2 (COX-2) and its inhibition in tumor biology and radiotherapy. In: Nieder C, Milas L, Ang KK (eds) Biological modification of radiation response: cytokines, growth factors and other biological targets. Springer-Verlag, Berlin Heidelberg New York, pp 241–258Google Scholar
  54. Moulder JE, Fish BL, Cohen EP (1993) Treatment of radiation nephropathy with ACE inhibitors. Int J Radat Oncol Biol Phys 27:93–99Google Scholar
  55. Movsas B, Scott C, Langer C, et al (2003) Phase III study of amifostine in patients with locally advanced NSCLC receiving chemotherapy and hyperfractionated radiation: RTOG 98-01. Proc Am Soc Clin Oncol 22:636Google Scholar
  56. Murray D, McBride WH (1996) Radioprotective agents. In: Kirk-Othmer Encyclopedia of Chemical Technology, 4th ed, vol. 20, pp 963–1006Google Scholar
  57. National Cancer Institute. Cancer. Gov. Non-small celllung cancer (PGQ): treatment. Health professional version, June 2002Google Scholar
  58. Nieder C, Jermic B, Astner S, et al (2003) Radiotherapy-induced lung toxicity: Risk factors and prevention strategies. Anticancer Res 23:4991–4998PubMedGoogle Scholar
  59. Ohnishi ST, Ohnishi T, Glick JH, et al (1992) In vitro study on the antioxidant activities of Amifostine (WR-2721). Proc Amer Assoc Cancer Res 33:419 (2503A)Google Scholar
  60. Ozturk B, Egehan I, Atavci S et al (2004) Pentoxifylline in prevention of radiation-induced lung toxicity in patients with breast and lung cancer: a double-blind randomized trial. Int I Radiat Oncol Biol Phys 58:213–219Google Scholar
  61. Panos RJ, Rubin JS, Aaronson SA, et al (1993) Keratinocyte growth factor and hepatocyte growth factor/scatter factor are heparin-binding growth factors for alveolar type II cells in fibroblast-conditioned medium. J Clin Invest 92:969–977PubMedGoogle Scholar
  62. Petkau A (1987) Role of superoxide dismutase in modification of radiation injury. Brit J Cancer 55(Suppl VIII):87–95Google Scholar
  63. Rasey JS, Krohn KA, Menard TW, et al (1986) Comparative biodistribution and radioprotection studies with three radioprotective drugs in mouse tumors. Intl J Radiat Oncol Biol Phys 12:1487–1490Google Scholar
  64. Rasey JS, Grunbaum Z, Krohn KA, et al (1985) Biodistribution of the radioprotective drug 35S-labeled 3-amino-2-hydroxypropyl phosphorothioate (WR77913). Radiat Res 102:130–137PubMedGoogle Scholar
  65. Redlich CA, Gao X, Rockwell S et al (1996) IL-11 enhances survival and decreases TNF production after radiation-induced thoracic injury. J Immunol 157:1705–1710PubMedGoogle Scholar
  66. Roberts NA and Robinson PA (1995) Copper chelates of anti-rheumatic and anti-inflammatory agents and their super-oxide dismutase-like activity and stability. Br J Rheumatol 24:128–136Google Scholar
  67. Rube CE, Wilfert F, Uthe D et al (2002) Modulation of radiation-induced tumour necrosis factor alpha (TNF-alpha) expression in the lung tissue by pentoxifylline. Radiother Oncol 64:177–187CrossRefPubMedGoogle Scholar
  68. Rubin JS, Osada H, Finch PW, et al (1989) Purification and characterization of a newly identified growth factor specific for epithelial cells. Proc Natl Acad Sci USAGoogle Scholar
  69. Savoye C, Swenberg C, Hugot S (1997) Thiol WR-1065 and disulphide WR-33278, two metabolities of the drug ethyol (WR-2721), protect DNA against fast neutron-induced strand breakage. Int J Radiat Biol 71:193–202CrossRefPubMedGoogle Scholar
  70. Schaake-Koning C, van den Bogaert W, Dalesio O, et al (1992) Effects of concomitant cisplatin and radiotherapy on inoperable non-small-cell lung cancer. N Engl I Med 326:524–530Google Scholar
  71. Schuchter LM and Glick J (1993) The current status of WR-2721 (Amifostine): A chemotherapy and radiation therapy protector. J. Clin. Oncol 14: 3112–3120Google Scholar
  72. Senzer N (2002) A phase III randomized evaluation of amifostine in stage IIIA/IIIB non-small cell lung cancer patients receiving concurrent carboplatin, paclitaxel, and radiation therapy followed by gemcitabine and cisplatin intensification: preliminary findings. Semin Oncol 29:38–41CrossRefGoogle Scholar
  73. Shaw LM, Bonner H, Lieberman R (1999a) Pharmacokinetic profile of amifostine. Sem Oncol 23:18–22Google Scholar
  74. Shaw LM, Bonner HS, Schuchter L, et al (1999b) Pharmacokinetcs of Amifostine: Effects of doses and method of administration. Semin Oncol 26(2 Suppl 7):34–36Google Scholar
  75. Tee PG and Travis EL (1995) Basic fibroblast growth factor does not protect against classical radiation pneumonitis in two strains of mice. Cancer Res 55:298–302PubMedGoogle Scholar
  76. Terry NHA, Brinkely J, Doig AJ, et al (2004) Cellular kinetics of murine lung: model system to determine basis for radioprotection with keratinocyte growth factor. Int J Radiat Oncol Biol Phys 58:435–444CrossRefPubMedGoogle Scholar
  77. Travis E (1984) The oxygen dependence of protection by aminothiols: implications for normal tissues and solid tumors. Int J Radiat Oncol Biol Phys 10:1495–1501PubMedGoogle Scholar
  78. Travis EL, Thames HD, Jr, Tucker SL, et al (1985) Late functional and biochemical changes in mouse lung after irradiation: Differential effects of WR-2721. Rad Res 103:219–231Google Scholar
  79. Ulich TR, Yi ES, Longmuir K, et al (1994) Keratinocyte growth factor is a growth factor for type II pneumocytes in vivo J Clin Invest 93:1298–1306PubMedGoogle Scholar
  80. Utley JF, Seaver N, Newton GL, et al (1984) Pharmacokinetics of WR-1065 in mouse tissue following treatment with WR-2721. Int J Radiat Oncol Biol Phys 10:1525–1528PubMedGoogle Scholar
  81. Vujaskovic Z, Feng Q, Rabbani ZN, et al (2002a) Assessment of the protective effect of amifostine on radiation-induced pulmonary toxicity. Exp Lung Res 28:577–590CrossRefPubMedGoogle Scholar
  82. Vujaskovic Z, Feng Q, Rabbani ZN, et al (2002b) Radioprotection of lungs by amifostine is associated with reduction in profibrogenic cytokine activity. Radiat Res 157:656–660PubMedGoogle Scholar
  83. Wang LW, Fu XL, Clough R, et al (2000) Can angiotensin-converting enzyme inhibitors protect against symptomatic radiation pneumonitis? Radiat Res 153:405–410PubMedGoogle Scholar
  84. Ward HE, Kemsley L, Davies L, et al (1992a) The effect of steroids on radiation-induced lung disease in the rat. Radiat Res 136:22–28Google Scholar
  85. Ward WF, Kim YT, Molteni A, et al (1988) Radiation-induced pulmonary endothelial dysfunction in rats: Modification by an inhibitor of angiotensin converting enzyme. Int J Radiat Oncol Biol Phys 15:135–140PubMedGoogle Scholar
  86. Ward WF, Molteni A, Ts'ao C, et al (1990a) Captopril reduces collagen and mast cell accumulation in irradiated rat lung. Int J Radiat Oncol Biol Phys 19:1405–1409PubMedGoogle Scholar
  87. Ward WF, Molteni A, Ts'ao C, et al (1990b) The effect of captopril on benign and malignant reactions in irradiated rat skin. Br J Radiol 63:349–354PubMedGoogle Scholar
  88. Ward WF, Molteni A, Ts'ao C, et al (1992c) Radiation pneumotoxicity in rats: Modification by inhibitors of angiotensin converting enzyme. Int J Radiat Oncol Biol Phys 22:623–625PubMedGoogle Scholar
  89. Ward WF, Kim YT, Molteni A, et al. (1992b) Pentoxifylline does not spare acute radiation reactions in rat lung and skin. Radiat Res 129:107–111PubMedGoogle Scholar
  90. Ward WF, Lin PP, Wong PS, et al (1993) Radiation pneumonitis in rats and its modification by the angiotensin-converting enzyme inhibitor captopril evaluated by high resolution computer tomography. Radiat Res 135:81–87PubMedGoogle Scholar
  91. Wasserman TH, Phillips TL, Ross G, et al (1981) Differential protection against cytotoxic chemotherapeutic effects on bone marrow CFUs by WR-2721. Cancer Clin Trials 4:3–6PubMedGoogle Scholar
  92. Yarom R, Harper IS, Wynchangk, et al. (1993) Effect of captopril on changes in rat's hearts induced by long-term irradiation. Radat Res 133:187–197Google Scholar
  93. Yi ES, Williams ST, Lee H, et al (1996) Keratinocyte growth factor ameliorates radiation-and bleomycin-induced lung injury and mortality. Am J Pathol 149:1963–1970PubMedGoogle Scholar
  94. Yoon S, Park J, Jang H, Bahk Y and Shinn K. (1994) Radioprotective effect of captopril on the mouse jejunal mucosa. Int J Radiat Oncol Biol Phys 30:873–878PubMedGoogle Scholar
  95. Yuhas JM (1980) Active versus passive absorption kinetics as the basis for selective protection of normal tissues by S-2-(3-Aminopropylamino)-ethylphosphorothioic acid. Cancer Res 40:1519–1524PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2005

Authors and Affiliations

  • Ritsuko Komaki
    • 1
  • Joe Chang
    • 1
  • Zhongxing Liao
    • 1
  • James D. Cox
    • 1
  • K. A. Mason
    • 1
  • Luka Milas
    • 1
  1. 1.Department of Radiation OncologyThe University of Texas, M. D. Anderson Cancer CenterHoustonUSA

Personalised recommendations