Clinical Oncology
Volume 19, Issue 6 , Pages 397-417 , August 2007

Chemical Radiosensitizers for Use in Radiotherapy

  • P. Wardman

      Affiliations

    • Corresponding Author InformationAuthor for correspondence: P. Wardman, University of Oxford, Gray Cancer Institute, PO Box 100, Mount Vernon Hospital, Northwood, Middlesex HA6 2JR, UK.

Received 27 February 2007 ,Accepted 13 March 2007.

References 

  1. Steel GG. Terminology in the description of drug-radiation interactions. Int J Radiat Oncol Biol Phys. 1979;5:1145–1150
  2. Steel GG. Basic clinical radiobiology. London: Arnold; 1997;
  3. Wilson GD, Bentzen SM, Harari PM. Biologic basis for combining drugs with radiation. Semin Radiat Oncol. 2006;16:2–9
  4. Seiwert TY, Salama JK, Vokes EE. The concurrent chemoradiation paradigm — general principles. Nat Clin Pract Oncol. 2007;4:86–100
  5. Tannock IF. Treatment of cancer with radiation and drugs. J Clin Oncol. 1996;14:3156–3174
  6. Poggi MM, Coleman CN, Mitchell JB. Sensitizers and protectors of radiation and chemotherapy. Curr Probl Cancer. 2001;25:331–411
  7. Spalding AC, Lawrence TS. New and emerging radiosensitizers and protectors. Cancer Invest. 2006;24:444–456
  8. Horsman MR, Bohm L, Margison GP, et al. Tumor radiosensitizers — current status of development of various approaches: report of an International Atomic Energy Agency meeting. Int J Radiat Oncol Biol Phys. 2006;64:551–561
  9. Coleman CN, Turrisi AT. Radiation and chemotherapy sensitizers and protectors. Crit Rev Oncol Hematol. 1990;10:225–252
  10. Grdina DJ, Murley JS, Kataoka Y. Radioprotectants: current status and new directions. Oncology. 2002;63(Suppl. 2):2–10
  11. Weiss JF, Landauer MR. Radioprotection by antioxidants. Ann NY Acad Sci. 2000;899:44–60
  12. Thomas CT, Ammar A, Farrell JJ, Elsaleh H. Radiation modifiers: treatment overview and future investigations. Hematol Oncol Clin North Am. 2006;20:119–139
  13. Shenoy MA, Asquith JC, Adams GE, Michael BD, Watts ME. Time-resolved oxygen effects in irradiated bacteria and mammalian cells: a rapid-mix study. Radiat Res. 1975;62:498–512
  14. Michael BD, Harrop HA, Maughan RL. Fast response methods in the radiation chemistry of lethal damage in intact cells. In:  Okada S,  Imamura M,  Terashima T,  Yamaguchi H editor. Radiation research (Proceedings of the Sixth International Congress), Tokyo, Japanese Association of Radiation Research. 1979;p. 288–296
  15. Adams GE. Chemical radiosensitization of hypoxic cells. Br Med Bull. 1973;29:48–53
  16. Fowler JF, Adams GE, Denekamp J. Radiosensitization of hypoxic cells in solid tumours. Cancer Treat Rev. 1976;3:227–256
  17. Hall EJ. Radiobiology for the radiologist. Philadelphia: Lippincott Williams & Wilkins; 2000;
  18. Denny WA, Wilson WR, Hay MP. Recent developments in the design of bioreductive drugs. Br J Cancer. 1996;74(Suppl. XXVII):S32–S38
  19. Naylor MA, Thomson P. Recent advances in bioreductive drug targeting. Mini Rev Med Chem. 2001;1:17–29
  20. Jaffar M, Abou-Zeid N, Bai L, et al. Quinone bioreductive prodrugs as delivery agents. Curr Drug Deliv. 2004;1:345–350
  21. Wardman P. Electron transfer and oxidative stress as key factors in the design of drugs selectively active in hypoxia. Curr Med Chem. 2001;8:739–761
  22. Thomson P, Naylor MA, Everett SA, et al. Synthesis and biological properties of bioreductively targeted nitrothienyl prodrugs of combretastatin A-4. Mol Cancer Ther. 2006;5:2886–2894
  23. Cohen-Jonathon E, Bernhard EJ, McKenna WG. How does radiation kill cells?. Curr Opin Chem Biol. 1999;3:77–83
  24. Brown JM, Wilson WR. Exploiting tumour hypoxia in cancer treatment. Nat Rev Cancer. 2004;4:437–447
  25. Janssen HL, Haustermans KM, Balm AJ, Begg AC. Hypoxia in head and neck cancer: how much, how important?. Head Neck. 2005;27:622–638
  26. Isa AY, Ward TH, West CML, Slevin NJ, Homer JJ. Hypoxia in head and neck cancer. Br J Radiol. 2006;79:791–798
  27. Dendy PP, Wardman P. Hypoxia in biology and medicine — the legacy of L H Gray. Br J Radiol. 2006;79:545–549
  28. Whillans DW, Rauth AM. An experimental and analytical study of oxygen depletion in stirred cell suspensions. Radiat Res. 1980;84:97–114
  29. Koch CJ. A thin-film culturing technique allowing rapid gas–liquid equilibration (6 sec) with no toxicity to mammalian cells. Radiat Res. 1984;97:434–442
  30. Joiner MC, Marples B, Lambin P, Short SC, Turesson I. Low-dose hypersensitivity: current status and possible mechanisms. Int J Radiat Oncol Biol Phys. 2001;49:379–389
  31. Krause M, Wohlfarth J, Georgi B, et al. Low-dose hyperradiosensitivity of human glioblastoma cell lines in vitro does not translate into improved outcome of ultrafractionated radiotherapy in vivo. Int J Radiat Biol. 2005;81:751–758
  32. Palcic B, Brosing JW, Skarsgard LD. Survival measurements at low doses: oxygen enhancement ratio. Br J Cancer. 1982;46:980–984
  33. Watts ME, Hodgkiss RJ, Jones NR, Fowler JF. Radiosensitization of Chinese hamster cells by oxygen and misonidazole at low X-ray doses. Int J Radiat Biol. 1986;50:1009–1021
  34. Marples B, Joiner MC, Skov KA. The effect of oxygen on low-dose hypersensitivity and increased radioresistance in Chinese hamster V79-379A cells. Radiat Res. 1994;138:S17–S20
  35. Wardman P, Rothkamm K, Folkes LK, Woodcock M, Johnston PJ. Radiosensitization by nitric oxide at low radiation doses. Radiat Res. 2007;167:475–484
  36. Saunders M, Dische S. Clinical results of hypoxic cell radiosensitization from hyperbaric oxygen to accelerated radiotherapy, carbogen and nicotinamide. Br J Cancer. 1996;74(Suppl. XXVII):S271–S278
  37. Overgaard J, Horsman MR. Modification of hypoxia-induced radioresistance in tumors by the use of oxygen and sensitizers. Semin Radiat Oncol. 1996;6:10–21
  38. Feldmeier JJ. Hyperbaric oxygen for delayed radiation injuries. Undersea Hyperb Med. 2004;31:133–145
  39. Koch CJ, Oprysko PR, Shuman AL, Jenkins WT, Brandt G, Evans SM. Radiosensitization of hypoxic tumor cells by dodecafluoropentane: a gas-phase perfluorochemical emulsion. Cancer Res. 2002;62:3626–3629
  40. Chang TMS. Evolution of artificial cells using nanobiotechnology of hemoglobin based RBC blood substitute as an example. Artif Cells Blood Substit Immobil Biotechnol. 2006;34:551–556
  41. Harrison L, Blackwell K. Hypoxia and anemia: factors in decreased sensitivity to radiation therapy and chemotherapy?. Oncologist. 2004;9(Suppl. 5):31–40
  42. Varlotto J, Stevenson MA. Anemia, tumor hypoxia, and the cancer patient. Int J Radiat Oncol Biol Phys. 2005;63:25–36
  43. Harrison LB, Chadha M, Hill RJ, Hu K, Shasha D. Impact of tumor hypoxia and anemia on radiation therapy outcomes. Oncologist. 2007;7:492–508
  44. Hirst DG. What is the importance of anaemia in radiotherapy? The value of animal studies. Radiother Oncol. 1991;20(Suppl. 1):29–33
  45. Thomas GM. Raising hemoglobin: an opportunity for increasing survival?. Oncology. 2002;63(Suppl. 2):19–28
  46. Rowinsky EK. Novel radiation sensitizers targeting tissue hypoxia. Oncology. 1999;13(Suppl. 5):61–70
  47. Kaanders JHAM, Bussink J, van der Kogel AJ. Clinical studies of hypoxia modification in radiotherapy. Semin Radiat Oncol. 2004;14:233–240
  48. Aapro M, Vaupel P. Erythropoietin: effects on life expectancy in patients with cancer-related anaemia. Curr Med Res Opin. 2006;22(Suppl. 4):5–13
  49. Calais G, Hirst DG. In situ tumour radiosensitization induced by clofibrate administration: single dose and fractionated studies. Radiother Oncol. 1991;22:99–103
  50. Abraham DJ, Wireko FC, Randad RS, et al. Allosteric modifiers of hemoglobin: 2-[4-[[(3,5-disubstituted anilino)carbonyl]methyl]phenoxy]-2-methylpropionic acid derivatives that lower the oxygen affinity of hemoglobin in red cell suspensions, in whole blood, and in vivo in rats. Biochemistry. 1992;31:9141–9149
  51. Khandelwal SR, Kavanagh BD, Lin P-S, et al. RSR13, an allosteric effector of haemoglobin, and carbogen radiosensitize FSAII and SCCVII tumours in C3H mice. Br J Cancer. 1999;79:814–820
  52. Wahr JA, Gerber M, Venitz J, Baliga N. Allosteric modification of oxygen delivery by hemoglobin. Anesth Analg. 2001;92:615–620
  53. Mehta MP, Suh JH. Novel radiosensitizers for tumors of the central nervous system. Curr Opin Investig Drugs. 2004;5:1284–1291
  54. Rosenberg A, Knox S. Radiation sensitization with redox modulators: a promising approach. Int J Radiat Oncol Biol Phys. 2006;64:343–354
  55. Stea B, Suh JH, Boyd AP, Cagnoni PJ, Shaw E, Group RS. Whole-brain radiotherapy with or without efaproxiral for the treatment of brain metastases: determinants of response and its prognostic value for subsequent survival. Int J Radiat Oncol Biol Phys. 2006;64:1023–1030
  56. Collingridge DR, Rockwell S. Pentoxifylline improves the oxygenation and radiation response of BA1112 rat rhabdomyosarcomas and EMT6 mouse mammary carcinomas. Int J Cancer. 2000;90:256–264
  57. Nieder C, Zimmermann FB, Adam M, Molls M. The role of pentoxifylline as a modifier of radiation therapy. Cancer Treat Rev. 2005;31:448–455
  58. Kjellen E, Joiner MC, Collier JM, Johns H, Rojas A. A therapeutic benefit from combining normobaric carbogen or oxygen with nicotinamide in fractionated X-ray treatments. Radiother Oncol. 1991;22:81–91
  59. Horsman MR. Nicotinamide and the hypoxia problem. Radiother Oncol. 1991;22:79–80
  60. Rojas A, Denekamp J, Johns H, et al. Nicotinamide as a repair inhibitor in vivo: studies using single and fractionated X-ray doses in mouse skin and kidneys. Radiat Res. 1996;145:419–431
  61. Rojas A, Vojnovic B, Johns H, et al. Radiosensitization in normal tissues with oxygen, carbogen or nicotinamide: therapeutic gain comparisons for fractionated X-ray schedules. Radiother Oncol. 1996;39:53–64
  62. Hoskin PJ, Saunders MI. ARCON. Clin Oncol (R Coll Radiol). 1994;6:281–282
  63. Saunders MI, Hoskin PJ, Pigott K, et al. Accelerated radiotherapy, carbogen and nicotinamide (ARCON) in locally advanced head and neck cancer: a feasibility study. Radiother Oncol. 1997;45:159–166
  64. Hoskin PJ, Saunders MI, Phillips H, et al. Carbogen and nicotinamide in the treatment of bladder cancer with radical radiotherapy. Br J Cancer. 1997;76:260–263
  65. Kaanders JHAM, Stratford MRL, Liefers J, et al. Administration of nicotinamide during a five to seven week course of radiotherapy: pharmcokinetics, tolerance, and compliance. Radiother Oncol. 1997;43:67–73
  66. Hoskin PJ, Rojas AM, Phillips H, Saunders MI. Acute and late morbidity in the treatment of advanced bladder carcinoma with accelerated radiotherapy, carbogen, and nicotinamide. Cancer. 2005;103:2287–2297
  67. Kaanders JHAM, Bussink J, van der Kogel AJ. ARCON: a novel biology-based approach in radiotherapy. Lancet Oncol. 2002;3:728–737
  68. Bernier J, Denekamp J, Rojas A, et al. ARCON: accelerated radiotherapy with carbogen and nicotinamide in head and neck squamous cell carcinomas. The experience of the Cooperative Group of Radiotherapy of the European Organization for Research and Treatment of Cancer (EORTC). Radiother Oncol. 2000;55:111–119
  69. Hoogsteen IJ, Pop LAM, Marres HAM, et al. Oxygen-modifying treatment with ARCON reduces the prognostic significance of hemoglobin in squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys. 2006;64:83–89
  70. Adams GE, Cooke MS. Electron-affinic sensitization. I. A structural basis for chemical radiosensitizers in bacteria. Int J Radiat Biol. 1969;15:457–471
  71. Adams GE, Asquith JC, Dewey DL, Foster JL, Michael BD, Willson RL. Electron affinic sensitization. Part II: para-nitroacetophenone: a radiosensitizer for anoxic bacterial and mammalian cells. Int J Radiat Biol. 1971;19:575–585
  72. Chapman JD, Webb RG, Borsa J. Radiosensitization of mammalian cells by p-nitroacetophenone. I. Characterization in asynchronous and synchronous populations. Int J Radiat Biol. 1971;19:561–573
  73. Asquith JC, Foster JL, Willson RL, Ings R, McFadzean JA. Metronidazole (‘Flagyl’). A radiosensitizer of hypoxic cells. Br J Radiol. 1974;47:474–481
  74. Adams GE. Hypoxia-mediated drugs for radiation and chemotherapy. Cancer. 1981;48:696–707
  75. Stewart FA, Denekamp J, Randhawa VS. Skin sensitization by misonidazole: a demonstration of uniform mild hypoxia. Br J Cancer. 1982;45:869–877
  76. Hendry JH. Sensitization of hypoxic normal tissue. Br J Cancer. 1978;37(Suppl. III):232–234
  77. Fowler JF. Chemical modifiers of radiosensitivity — theory and reality: a review. Int J Radiat Oncol Biol Phys. 1985;11:665–674
  78. Wouters BG, Brown JM. Cells at intermediate oxygen levels can be more important than the “hypoxic fraction” in determining tumor response to fractionated radiotherapy. Radiat Res. 1997;147:541–550
  79. Overgaard J. Clinical evaluation of nitroimidazoles as modifiers of hypoxia in solid tumors. Oncol Res. 1994;6:509–518
  80. Adams GE, Clarke ED, Flockhart IR, et al. Structure–activity relationships in the development of hypoxic cell radiosensitizers: I. Sensitization efficiency. Int J Radiat Biol. 1979;35:133–150
  81. Adams GE, Clarke ED, Gray P, et al. Structure–activity relationships in the development of hypoxic cell radiosensitizers: II. Cytotoxicity and therapeutic ratio. Int J Radiat Biol. 1979;35:151–160
  82. Coleman CN, Wasserman TH, Urtasun RC, et al. Final report of the phase I trial of the hypoxic cell radiosensitizer SR 2508 (etanidazole) Radiation Therapy Oncology Group 83-03. Int J Radiat Oncol Biol Phys. 1990;18:389–393
  83. Smithen CE, Clarke ED, Dale JA, et al. Novel (nitro-1-imidazolyl) alkanolamines as potential radiosensitizers with improved therapeutic properties. In:  Brady LW editors. Radiation sensitizers: their use in the clinical management of cancer. New York: Masson; 1980;p. 22–32
  84. Dennis MF, Stratford MRL, Wardman P, Watts ME. Cellular uptake of misonidazole and analogues with acidic or basic functions. Int J Radiat Biol. 1985;47:629–643
  85. Watts ME, Dennis MF, Roberts IJ. Radiosensitization by misonidazole, pimonidazole and azomycin and intracellular uptake in human tumour cell lines. Int J Radiat Biol. 1990;57:361–372
  86. Dische S, Bennett MH, Orchard R, Stratford MRL, Wardman P. The uptake of the radiosensitizing compound Ro 03-8799 (pimonidazole) in human tumors. Int J Radiat Oncol Biol Phys. 1989;16:1089–1092
  87. Raleigh JA, Dewhirst MW, Thrall DE. Measuring tumor hypoxia. Semin Radiat Oncol. 1996;6:37–45
  88. Overgaard J, Eriksen JG, Nordsmark M, Alsner J, Horsman MR, Group DHaNCS . Plasma osteopontin, hypoxia, and response to the hypoxia sensitiser nimorazole in radiotherapy of head and neck cancer: results from the DAHANCA 5 randomised double-blind placebo-controlled trial. Lancet Oncol. 2005;6:757–764
  89. Nagasawa H, Uto Y, Kirk KL, Hori H. Design of hypoxia-targeting drugs as new cancer chemotherapeutics. Biol Pharm Bull. 2006;29:2335–2342
  90. Sugie C, Shibamoto Y, Ito M, et al. Reevaluation of the radiosensitizing effects of sanazole and nimorazole in vitro and in vivo. J Radiat Res (Tokyo). 2005;46:453
  91. Dobrowsky W, Huigol NG, Jayatilake RS, et al. AK-2123 (Sanazol) as a radiation sensitizer in the treatment of stage III cervical cancer: results of an IAEA multicentre randomised trial. Radiother Oncol. 2007;82:24–29
  92. Das T, Chakraborty S, Banerjee S, et al. Preparation and preliminary biological evaluation of a 177Lu labeled sanazole derivative for possible use in targeting tumor hypoxia. Bioorg Med Chem. 2004;12:6077–6084
  93. Jonathan RA, Wijffels KIEM, Peeters W, et al. The prognostic value of endogenous hypoxia-related markers for head and neck squamous cell carcinomas treated with ARCON. Radiother Oncol. 2006;79:288–297
  94. Koch CJ, Evans SM, Lord EM. Oxygen dependence of cellular uptake of EF5 [2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl) acetamide]: analysis of drug adducts by fluorescent antibodies vs. bound radioactivity. Br J Cancer. 1995;72:869–874
  95. Chapman JD, Schneider RF, Urbain JL, Hanks GE. Single-photon emission computed tomography and positron-emission tomography assays for tissue oxygenation. Semin Radiat Oncol. 2001;11:47–57
  96. Sunamura M, Karasawa K, Okamoto A, et al. Phase III trial of radiosensitizer PR-350 combined with intraoperative radiotherapy for the treatment of locally advanced pancreatic cancer. Pancreas. 2004;28:330–334
  97. von Sonntag C. The chemical basis of radiation biology. London: Taylor & Francis; 1987;
  98. von Sonntag C. Free-radical-induced DNA damage and its repair. A chemical perspective. Berlin: Springer; 2006;
  99. Wardman P. Sensitization and protection of oxidative damage caused by high energy radiation. In:  Scott G editors. Atmospheric oxidation and antioxidants. Vol. III:Amsterdam: Elsevier; 1993;p. 101–127
  100. Bamatraf MMM, O'Neill P, Rao BSM. Redox dependence of the rate of interaction of hydroxyl radical adducts of DNA nucleobases with oxidants: consequences for DNA strand breakage. J Am Chem Soc. 1998;120:11852–11857
  101. Skov KA. Workshop report. DNA targeted hypoxic cytotoxins and radiosensitizers. Int J Radiat Biol. 1989;56:387–393
  102. Cowan DSM, Matejovic JF, McClelland RA, Rauth AM. DNA-targeted 2-nitroimidazoles: in vitro and in vivo studies. Br J Cancer. 1994;70:1067–1074
  103. Cowan DSM, Matejovic JF, Wardman P, McClelland RA, Rauth AM. Radiosensitizing and cytotoxic properties of DNA-targeted phenanthridine-linked nitroheterocycles of varying electron affinities. Int J Radiat Biol. 1994;66:729–738
  104. Wilson WR, Siim BG, Denny WA, et al. 5-Nitro-4-(N,N-dimethylaminopropylamino)quinoline (5-nitraquine), a new DNA-affinic hypoxic cell radiosensitizer and bioreductive agent: comparison with nitracrine. Radiat Res. 1992;131:257–265
  105. Parrick J, Porssa M, Davies LK, et al. Targeting radiosensitizers to DNA by minor groove binding: nitroarenes based on netropsin and distamycin. Bioorg Med Chem Lett. 1993;3:1697–1702
  106. Holley J, Mather A, Cullis P, et al. Uptake and cytotoxicity of novel nitroimidazole–polyamine conjugates in Ehrlich ascites tumour cells. Biochem Pharmacol. 1992;43:763–769
  107. Wardman P, Dennis MF, White J. A probe for intracellular concentrations of drugs: delayed fluorescence from acridine orange. Int J Radiat Oncol Biol Phys. 1989;16:935–938
  108. Stratford MRL, Dennis MF, Watts ME, Watfa RR, Woodcock M. Radiosensitizer-DNA interactions in relation to intracellular uptake. Int J Radiat Oncol Biol Phys. 1989;16:1007–1010
  109. Wilson WR, Hicks KO. Measurement of extravascular drug diffusion in muticellular layers. Br J Cancer. 1999;79:1620–1628
  110. Kyle AH, Minchinton AI. Measurement of delivery and metabolism of tirapazamine to tumour tissue using the mutilayered cell culture model. Cancer Chemother Pharmacol. 1999;43:213–220
  111. Hicks KO, Pruijn FB, Secomb TW, et al. Use of three-dimensional tissue cultures to model extravascular transport and predict in vivo activity of hypoxia-targeted anticancer drugs. J Natl Cancer Inst. 2006;98:1118–1128
  112. Minchinton AI, Tannock IF. Drug penetration in solid tumours. Nat Rev Cancer. 2006;6:583–592
  113. Brown JM. Therapeutic targets in radiotherapy. Int J Radiat Oncol Biol Phys. 2001;49:319–326
  114. Peters KB, Brown JM. Tirapazamine: a hypoxia-activated topoisomerase II poison. Cancer Res. 2002;62:5248–5253
  115. Foster JL, Conroy PJ, Searle AJ, Willson RL. Metronidazole (Flagyl): characterization as a cytotoxic drug specific for hypoxic tumour cells. Br J Cancer. 1976;33:485–490
  116. Wardman P, Clarke ED. Oxygen inhibition of nitroreductase: electron transfer from nitro radical-anions to oxygen. Biochem Biophys Res Commun. 1976;69:942–949
  117. Laderoute K, Wardman P, Rauth AM. Molecular mechanisms for the hypoxia-dependent activation of 3-amino-1,2,4-benzo-triazine-1,4-dioxide (SR 4233). Biochem Pharmacol. 1988;37:1487–1495
  118. Brown JM, Lemmon MJ. Potentiation of the hypoxic cytotoxin SR 4233 of cell killing produced by fractionated irradiation of mouse tumors. Cancer Res. 1990;50:7745–7749
  119. Priyadarsini KI, Tracy M, Wardman P. The one-electron reduction potential of 3-amino-1,2,4-benzotriazine 1,4-dioxide (tirapazamine): a hypoxia-selective bioreductive drug. Free Radic Res. 1996;25:393–399
  120. Wardman P. Chemistry of nitroarene and aromatic N-oxide radicals. In:  Alfassi ZB editors. The chemistry of N-centered radicals. New York: Wiley; 1998;p. 615–661
  121. Zeman EM, Brown JM. Pre- and post-irradiation radiosensitization by SR 4233. Int J Radiat Oncol Biol Phys. 1989;16:967–971
  122. Zeman EM, Lemmon MJ, Brown JM. Aerobic radiosensitization by SR 4233 in vitro and in vivo. Int J Radiat Oncol Biol Phys. 1990;18:125–132
  123. Itani W, Geara F, Haykal J, Haddadin M, Gali-Muhtasib H. Radiosensitization by 2-benzoyl-3-phenyl-6,7-dichloroquinoxaline 1,4-dioxide under oxia and hypoxia in human colon cancer cells. Radiat Oncol. 2007;2:1–13
  124. Jenkins TC, Naylor MA, O'Neill P, et al. Synthesis and evaluation of a-[[(2-haloethyl)amino]methyl]-2-nitro-1H-imidazole-1-ethanols as prodrugs of a-[(1-aziridinyl)methyl]2-nitro-1H-imidazole-1-ethanol (RSU-1069) and its analogues which are radiosensitizers and bioreductively activated cytotoxins. J Med Chem. 1990;33:2603–2610
  125. Suto MJ, Stier MA, Werbel LM, et al. A new class of analogues of the bifunctional radiosensitizer a-(1-aziridinylmethyl)2-nitro-1H-imidazole-1-ethanol (RSU 1069): the cycloalkylaziridines. J Med Chem. 1991;34:2484–2488
  126. Bremner JCM. Assessing the bioreductive effectiveness of the nitroimidazole RSU1069 and its prodrug RB6145: with particular reference to in vivo methods of evaluation. Cancer Metastasis Rev. 1993;12:177–193
  127. Wood PJ, Horsman MR, Khalil AA, et al. A comparison of the physiological effects of RSU1069 and RB6145 in the SCCVII murine tumour. Acta Oncol. 1996;35:989–994
  128. Lunt SJ, Telfer BA, Fitzmaurice RJ, Stratford IJ, Williams KJ. Tirapazamine administered as a neoadjuvant to radiotherapy reduces metastatic dissemination. Clin Cancer Res. 2005;11:4212–4216
  129. Ross AB, Mallard WG, Helman WP, Buxton GV, Huie RE, Neta P. NDRL-NIST Solution Kinetics Database: Version 3. Notre Dame, Indiana and Gaithersburg, Maryland: Notre Dame Radiation Laboratory and National Institute of Standards and Technology, 1998.
  130. Shafirovich V, Lymar SV. Nitroxyl and its anion in aqueous solutions: spin states, protic equilibria, and reactivities toward oxygen and nitric oxide. Proc Natl Acad Sci USA. 2002;99:7340–7345
  131. Whitaker SJ, McMillan TJ. Oxygen effect for DNA double-strand break induction determined by pulsed-field gel electrophoresis. Int J Radiat Biol. 1992;61:29–41
  132. Olive PL, Bánath JP, MacPhail HS. Lack of correlation between radiosensitivity and DNA double-strand breaks: induction or rejoining in six human tumor cell lines. Cancer Res. 1994;54:3939–3946
  133. Howard-Flanders P. Effect of nitric oxide on the radiosensitivity of bacteria. Nature. 1957;180:1191–1192
  134. Gray LH, Green FO, Hawes CA. Effect of nitric oxide on the radiosensitivity of tumour cells. Nature. 1958;182:952–953
  135. Mitchell JB, Wink DA, DeGraff W, Gamson J, Keefer LK, Krishna MC. Hypoxic mammalian cell radiosensitization by nitric oxide. Cancer Res. 1993;53:5845–5848
  136. Mitchell JB, Cook JA, Krishna MC, et al. Radiation sensitization by nitric oxide releasing agents. Br J Cancer. 1996;74(Suppl. XXVII):S181–S184
  137. Mitchell JB, DeGraff W, Kim S, et al. Redox generation of nitric oxide to radiosensitize hypoxic cells. Int J Radiat Oncol Biol Phys. 1998;42:795–798
  138. In:  Ignarro LJ editors. Nitric oxide. Biology and pathobiology. San Diego: Academic Press; 2000;
  139. Worthington J, McCarthy HO, Barrett E, Adams C, Robson T, Hirst DG. Use of the radiation-inducible WAF1 promoter to drive iNOS gene therapy as a novel anti-cancer treatment. J Gene Med. 2004;6:673–680
  140. Wang Z, Cook T, Alber S, et al. Adenoviral gene transfer of the human inducible nitric oxide synthase gene enhances the radiation response of human colorectal cancer associated with alterations in tumor vascularity. Cancer Res. 2004;64:1386–1395
  141. Cook T, Wang Z, Alber S, et al. Nitric oxide and ionizing radiation synergistically promote apoptosis and growth inhibition of cancer by activating p53. Cancer Res. 2004;64:8015–8021
  142. Worthington J, Robson T, Scott S, Hirst D. Evaluation of a synthetic CArG promoter for nitric oxide synthase gene therapy of cancer. Gene Ther. 2005;12:1417–1423
  143. McCarthy HO, Worthington J, Barrett E, et al. p21(WAF1)-mediated transcriptional targeting of inducible nitric oxide synthase gene therapy sensitizes tumours to fractionated radiotherapy. Gene Ther. 2007;14:246–255
  144. Jordan BF, Beghein N, Aubry M, Grégoire V, Gallez B. Potentiation of radiation-induced regrowth delay by isosorbide dinitrate in FSAII murine tumors. Int J Cancer. 2003;103:138–141
  145. Jordan BF, Sonveaux P, Feron O, Grégoire V, Beghein N, Gallez B. Nitric oxide-mediated increase in tumor blood flow and oxygenation of tumors implanted in muscles stimulated by electric pulses. Int J Radiat Oncol Biol Phys. 2003;55:1066–1073
  146. Kashiwagi S, Izumi Y, Gohongi T, et al. NO mediates mural cell recruitment and vessel morphogenesis in murine melanomas and tissue-engineered blood vessels. J Clin Invest. 2005;115:1816–1827
  147. Shan SQ, Rosner GL, Braun RD, Hahn J, Pearce C, Dewhirst MW. Effects of diethylamine/nitric oxide on blood perfusion and oxygenation in the R3230Ac mammary carcinoma. Br J Cancer. 1997;76:429–437
  148. Sonveaux P, Feron O. Nitric oxide and tumor biology. In:  Lamas S,  Cadenas E editor. Nitric oxide, cell signaling, and gene expression. Boca Raton: CRC Press; 2006;p. 395–420
  149. Ichinose F, Roberts JD, Zapol WM. Inhaled nitric oxide. A selective pulmonary vasodilator. Current uses and therapeutic potential. Circulation. 2004;109:3106–3111
  150. Hataishi R, Zapol WM, Bloch KD, Ichinose F. Inhaled nitric oxide does not reduce systemic vascular resistance in mice. Am J Physiol Heart Circ Physiol. 2006;209:H1826–H1829
  151. Ng Q-S, Goh V, Milner J, et al. Effect of nitric-oxide synthesis on tumour blood volume and vascular activity: a phase I study. Lancet Oncol. 2007;8:111–118
  152. Siemann DW, Chaplin DJ, Horsman MR. Vascular-targeting therapies for treatment of malignant disease. Cancer. 2004;100:2491–2499
  153. Tozer GM, Kanthou C, Baguley BC. Disrupting tumour blood vessels. Nat Rev Cancer. 2005;5:423–435
  154. Denekamp J. Limited role of vasculature-mediated injury in tumor response to radiotherapy. J Natl Cancer Inst. 1994;85:935–937
  155. Tozer GM, Everett SA. Nitric oxide in tumour biology and cancer therapy. Part 2: therapeutic implications. Clin Oncol (R Coll Radiol). 1997;9:357–364
  156. Tozer GM, Everett SA. Nitric oxide in tumour biology and cancer therapy. Part 1: physiological aspects. Clin Oncol (R Coll Radiol). 1997;9:282–293
  157. Jordan BF, Grégoire V, Demeure RJ, et al. Insulin increases the sensitivity of tumors to irradiation: involvement of an increase in tumor oxygenation mediated by a nitric oxide-dependent decrease of the tumor cells oxygen consumption. Cancer Res. 2002;62:3555–3561
  158. De Ridder M, Verovski VN, Chiavaroli C, et al. The radiosensitizing effect of immunoadjuvant OM-174 requires cooperation between immune and tumor cells through interferon-gamma and inducible nitric oxide synthase. Int J Radiat Oncol Biol Phys. 2006;66:1473–1480
  159. Behar D, Neta P. Intramolecular electron transfer and dehalogenation of anion radicals. 2. Halonitroaromatic compounds. J Phys Chem. 1981;85:690–693
  160. Wilson WR, Ferry DM, Tercel M, Anderson RF, Denny WA. Reduction of nitroarylmethyl quaternary ammonium prodrugs of mechloramine by radiation. Radiat Res. 1998;149:237–245
  161. Kriste AG, Tercel M, Anderson RF, Ferry DM, Wilson WR. Pathways of reductive fragmentation of heterocyclic nitroarylmethyl quaternary ammonium prodrugs of mechlorethamine. Radiat Res. 2002;158:753–762
  162. Ahn G-O, Ware DC, Denny WA, Wilson WR. Optimization of the auxiliary ligand shell of cobalt(III)(8-hydroxyquinoline) complexes as model hypoxia-selective radiation-activated prodrugs. Radiat Res. 2004;162:315–325
  163. Ahn G-O, Botting KJ, Patterson AV, Ware DC, Tercel M, Wilson WR. Radiolytic and cellular reduction of a novel hypoxia-activated cobalt(III) prodrug of a chloromethylbenzindoline DNA minor groove alkylator. Biochem Pharmacol. 2006;71:1683–1694
  164. Tanabe K, Makimura Y, Tachi Y, Imagawa-Sato A, Nishimoto S. Hypoxia-selective activation of 5-fluorodeoxyuridine prodrug possessing indolequinone structure: radiolytic reduction and cytotoxicity characteristics. Bioorg Med Chem Lett. 2005;15:2321–2324
  165. Shibamoto Y, Tachi T, Tanabe K, Hatta H, Nishimoto S-I. In vitro and in vivo evaluation of novel antitumor prodrugs of 5-fluoro-2-deoxyuridine activated by hypoxic irradiation. Int J Radiat Oncol Biol Phys. 2004;58:397–402
  166. Cramp WA. Radiosensitization by copper ions, and consequent reversal of the oxygen effect. Nature. 1965;206:636–637
  167. Hesslewood IP, Cramp WA, McBrien DCH, Williamson P, Lott KAK. Copper as a hypoxic cell sensitizer of mammalian cells. Br J Cancer. 1978;37(Suppl. III):95–97
  168. Selvaraj S, Chabita (Saha) K, Chakraborty A, Bhattacharyya SN, Saha A. Influence of copper (II) ions and its derivatives on radiosensitivity of Escherichia coli. Radiat Phys Chem (in press).
  169. Buettner GR, Jurkiewicz BA. Catalytic metals, ascorbate and free radicals: combinations to avoid. Radiat Res. 1996;145:532–541
  170. Burkitt MJ. A critical overview of the chemistry of copper-dependent low density lipoprotein oxidation: roles of lipid hydroperoxides, alpha-tocopherol, thiols, and ceruloplasmin. Arch Biochem Biophys. 2001;394:117–135
  171. Antholine WE, Byrnes R, Petering DH. Copper complexes as drugs. In:  Berthon G editors. Handbook of metal–ligand interactions in biological fluids. Vol. 2:New York: Marcel Dekker; 1995;p. 1024–1038
  172. Wardman P. The kinetics of the reaction of ‘anomalous’ 4-nitroimidazole radiosensitizers with thiols. Int J Radiat Biol. 1982;41:231–235
  173. Wardman P, Clarke ED. Redox properties and rate constants in free-radical mediated damage. Br J Cancer. 1987;55(Suppl. VIII):172–177
  174. Young SW, Qing F, Harriman A, et al. Gadolinium(III) texaphyrin: a tumor selective radiation sensitizer that is detectable by MRI. Proc Natl Acad Sci USA. 1996;93:6610–6615
  175. Bernhard EJ, Mitchell JB, Deen D, Cardell M, Rosenthal DI, Brown JM. Re-evaluating gadolinium(III) texaphyrin as a radiosensitizing agent. Cancer Res. 2000;60:86–91
  176. Sessler JL, Tvermoes NA, Guldi DM, Mody TD, Allen WE. One-electron reduction and oxidation studies of the radiation sensitizer gadolinium(III) texaphyrin (PCI-0120) and other water soluble metallotexaphyrins. J Phys Chem A. 1999;103:787–794
  177. Magda D, Lepp C, Gerasimchuk N, et al. Redox cycling by motexafin gadolinium enhances cellular response to ionizing radiation by forming reactive oxygen species. Int J Radiat Oncol Biol Phys. 2001;51:1025–1036
  178. Wood PM. The redox potential of the system oxygen-superoxide. FEBS Lett. 1974;44:21–24
  179. Wardman P. The reduction potential of benzyl viologen: an important reference compound for oxidant/radical redox couples. Free Radic Res Commun. 1991;14:57–67
  180. Renschler MF. The emerging role of reactive oxygen species in cancer therapy. Eur J Cancer. 2004;40:1934–1940
  181. Mikkelsen RB, Wardman P. Biological chemistry of reactive oxygen and nitrogen and ionizing radiation-induced signal transduction mechanisms. Oncogene. 2003;22:5734–5754
  182. Rockwell S, Donnelly ET, Liu Y, Tang LQ. Preliminary studies of the effects of gadolinium texaphyrin on the growth and radiosensitivity of EMT6 cells in vitro. Int J Radiat Oncol Biol Phys. 2002;54:536–541
  183. Donnelly ET, Liu Y, Paul TK, Rockwell S. Effects of motexafin gadolinium on DNA damage and X-ray-induced DNA damage repair, as assessed by the Comet assay. Int J Radiat Oncol Biol Phys. 2004;62:1176–1186
  184. Xu S, Zakian K, Thaler H, et al. Effects of motexafin gadolinium on tumor metabolism and radiation sensitivity. Int J Radiat Oncol Biol Phys. 2001;49:1381
  185. Donnelly ET, Liu Y, Fatunmbi YO, Lee I, Magda D, Rockwell S. Effects of texaphyrins on the oxygenation of EMT6 mouse mammary tumors. Int J Radiat Oncol Biol Phys. 2004;58:1570–1576
  186. Magda D, Miller RA. Motexafin gadolinium: a novel redox active drug for cancer therapy. Semin Cancer Biol. 2006;16:466–476
  187. Khuntia D, Mehta M. Motexafin gadolinium: a clinical review of a novel radioenhancer for brain tumors. Expert Rev Anticancer Ther. 2004;4:981–989
  188. Richards GM, Mehta MP. Motexafin gadolinium in the treatment of brain metastases. Expert Opin Pharmacother. 2007;8:351–359
  189. Gomer CJ, Rucker N, Ferrario A, Wong S. Properties and applications of photodynamic therapy. Radiat Res. 1989;120:1–18
  190. Schaffer M, Schaffer PM, Hofstetter A, Dühmke E, Jori G. On the double role of Photofrin as a photo- and a radio-sensitising agent: a possible new combination therapy for tumours. Photochem Photobiol. 2002;1:438–439
  191. Schaffer M, Ertl-Wagner B, Schaffer PM, et al. The application of Photofrin II as a sensitizing agent for ionizing radiation — a new approach in tumor therapy?. Curr Med Chem. 2005;12:1209–1215
  192. Schaffer M, Ertl-Wagner B, Schaffer PM, et al. Feasibility of photofrin II as a radiosensitizing agent in solid tumors — preliminary results. Onkologie. 2006;29:514–519
  193. Kinsella TJ, Dobson PP, Mitchell JB, Fornace AJ. Enhancement of X-ray induced DNA damage by prep-treatment with halogenated pyrimidine analogs. Int J Radiat Oncol Biol Phys. 1987;13:1–7
  194. Seo Y, Yan T, Schupp JE, Colussi V, Taylor KL, Kinsella TJ. Differential radiosensitization in DNA mismatch repair-proficient and -deficient human colon cancer xenografts with 5-iodo-2-pyrimidinone-2-deoxyribose. Clin Cancer Res. 2004;10:7520–7528
  195. Berry SE, Kinsella TJ. Targeting DNA mismatch repair for radiosensitization. Semin Radiat Oncol. 2001;11:300–315
  196. McGinn CJ, Shewach DS, Lawrence TS. Radiosensitizing nucleosides. J Natl Cancer Inst. 1996;88:1193–1203
  197. McGinn CJ, Lawrence TS. Recent advances in the use of radiosensitizing nucleosides. Semin Radiat Oncol. 2001;11:270–280
  198. Glynne-Jones R, Debus J. Improving chemoradiotherapy in rectal cancer. Oncologist. 2001;6(Suppl. 4):29–34
  199. Zhu AX, Willett CG. Chemotherapeutic and biologic agents as radiosensitizers in rectal cancer. Semin Radiat Oncol. 2003;13:454–468
  200. Vallerga AK, Zarling DA, Kinsella TJ. New radiosensitizing regimens, drugs, prodrugs, and candidates. Clin Adv Hematol Oncol. 2004;2:793–805
  201. Pauwels B, Korst AEC, Lardon F, Vermorken JB. Combined modality therapy of gemcitabine and radiation. Oncologist. 2005;10:34–51
  202. Douple EB, Richmond RC, O'Hara JA, Coughlin CT. Carboplatin as a potentiator of radiation therapy. Cancer Treat Rev. 1985;12(Suppl. A):111–124
  203. Yang L, Douple EB, O'Hara JA, Crabtree RA, Eastman A. Enhanced radiation-induced cell killing by carboplatin in cells of repair-proficient and repair-deficient cell lines. Radiat Res. 1995;144:230–236
  204. Yang LX, Douple EB, O'Hara JA, Wang HJ. Production of DNA double-strand breaks by interactions between carboplatin and radiation: a potential mechanism for radiopotentiation. Radiat Res. 1995;143:309–315
  205. Skov KA, Farrell NP, Adomat H. Platinum complexes with one radiosensitizing ligand [PtCl2(NH3)(Sensitizer)]: radiosensitization and toxicity studies in vitro. Radiat Res. 1987;112:273–282
  206. Skov KA. Modification of radiation response by metal complexes: a review with emphasis on nonplatinum studies. Radiat Res. 1987;112:217–242
  207. Chan PKL, Skov KA, James BR. Further studies on toxic and radiosensitizing properties of ruthenium complexes of 4-nitroimidazoles. Int J Radiat Biol. 1987;52:49–55
  208. Eberhardt W, Pöttgen C, Stuschke M. Chemoradiation paradigm for the treatment of lung cancer. Nat Clin Pract Oncol. 2006;3:188–199
  209. Hao D, Ritter MA, Oliver T, Browman GP. Platinum-based concurrent chemoradiotherapy for tumors of the head and neck and the esophagus. Semin Radiat Oncol. 2006;18:10–19
  210. Miyamoto S, Huang TT, Würzberger-Davis S, et al. Cellular and molecular responses to topoisomerase I poisons. Exploiting synergy for improved radiotherapy. Ann N Y Acad Sci. 2000;922:274–292
  211. Chen AY, Chou R, Shih S-J, Laub D, Gandara D. Enhancement of radiotherapy with DNA topoisomerase I-targeted drugs. Crit Rev Oncol Hematol. 2004;50:111–119
  212. Shih SJ, Erbele T, Chen AY. Ku86 modulates DNA topoisomerase I-mediated radiosensitization, but not cytotoxicity, in mammalian cells. Cancer Res. 2005;65:9194–9199
  213. Wong ET, Berkenblit A. The role of topotecan in the treatment of brain metastases. Oncologist. 2004;9:68–79
  214. Patterson LH, McKeown SR, Ruparelia K, et al. Enhancement of chemotherapy and radiotherapy of murine tumours by AQ4N, a bioreductively activated anti-tumour agent. Br J Cancer. 2000;82:1984–1990
  215. McErlane V, Yakkundi A, McCarthy HO, et al. A cytochrome P450 2B6 meditated gene therapy strategy to enhance the effects of radiation or cyclophosphamide when combined with the bioreductive drug AQ4N. J Gene Med. 2005;7:851–859
  216. Zhang M, Chakravarti A. Novel radiation-enhancing agents in malignant gliomas. Semin Radiat Oncol. 2006;16:29–37
  217. Virág L, Szabó C. The therapeutic potential of poly(ADP-ribose) polymerase inhibitors. Pharmacol Rev. 2002;54:375–429
  218. Calabrese CR, Almassy R, Barton S, et al. Anticancer chemosensitization and radiosensitization by the novel poly(ADP-ribose) polymerase-1 inhibitor AG14361. J Natl Cancer Inst. 2004;96:56–67
  219. Sarkaria JN, Eshleman JS. ATM as a target for novel radiosensitizers. Semin Radiat Oncol. 2001;11:316–327
  220. Wong JS, Ara G, Keyes SR, Herbst R, Coleman CN, Teicher BA. Lisofylline as a modifier of radiation therapy. Oncol Res. 1996;8:513–518
  221. Choudhury A, Cuddihy A, Bristow RG. Radiation and new molecular agents. Part I: Targeting ATM-ATR checkpoints, DNA repair, and the proteasome. Semin Radiat Oncol. 2006;16:51–58
  222. Chinnaiyan P, Allen GW, Harari PM. Radiation and new molecular agents. Part II: Targeting HDAC, HSP90, IGF-1R, PI3K, and Ras. Semin Radiat Oncol. 2006;16:59–64
  223. Downward J. Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer. 2003;3:11–22
  224. Gupta AK, Bakanauskas VJ, Cerniglia GJ, et al. The Ras radiation resistance pathway. Cancer Res. 2001;61:4278–4282
  225. Cengel KA, McKenna WG. Molecular targets for altering radiosensitivity: lessons from Ras as a pre-clinical and clinical model. Crit Rev Oncol Hematol. 2005;55:103–116
  226. Sartor CI. Mechanisms of disease: radiosensitization by epidermal growth factor receptor inhibitors. Nat Clin Pract Oncol. 2004;1:80–87
  227. Williams KJ, Telfer BA, Brave S, et al. ZD6474, a potent inhibitor of vascular endothelial growth factor signaling, combined with radiotherapy: schedule-dependent enhancement of antitumor activity. Clin Cancer Res. 2004;10:8587–8593
  228. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006;354:567–578
  229. Posner MR, Wirth LJ. Cetuximab and radiotherapy for head and neck cancer. N Engl J Med. 2006;354:634–636
  230. Harari PM, Huang S. Radiation combined with EGFR signal inhibitors: head and neck cancer focus. Semin Radiat Oncol. 2006;16:38–44
  231. Liao Z, Komaki R, Milas L, et al. A phase I clinical trial of thoracic radiotherapy and concurrent celecoxib for patients with unfavorable performance status inoperable/unresectable non-small cell lung cancer. Clin Cancer Res. 2005;11:3342–3348
  232. Raju U, Ariga H, Dittmann K, Nakata E, Ang KK, Milas L. Inhibition of DNA repair as a mechanism of enhanced radioresponse of head and neck carcinoma cells by a selective cyclooxygenase-2 inhibitor, celecoxib. Int J Radiat Oncol Biol Phys. 2005;63:520–528
  233. Nieder C, Wiedenmann N, Andratschke N, Molls M. Current status of angiogenesis inhibitors combined with radiation therapy. Cancer Treat Rev. 2006;32:348–364
  234. Miura M, Sakimoto I, Ohta K, Sugawara F, Sakaguchi K. Sulfoglycolipids as candidate antiangiogenic radiosensitizers. Anti-Cancer Drugs. 2007;18:1–5
  235. Jendrossek V, Handrick R. Membrane targeted anticancer drugs: potent inducers of apoptosis and putative radiosensitizers. Curr Med Chem Anti-Cancer Agents. 2003;3:343–353
  236. Bridges BA. Sensitization of Escherichia coli to gamma-radiation by N-ethylmaleimide. Nature. 1960;4748:415
  237. Bridges BA. Sensitization of organisms to radiation by sulfhydryl-binding agents. Adv Radiat Biol. 1969;3:123–176
  238. Watts ME, Whillans DW, Adams GE. Studies of the mechanisms of radiosensitization of bacterial and mammalian cells by diamide. Int J Radiat Biol. 1975;27:259–270
  239. Harris JW. Mammalian cell studies with diamide. Pharmacol Ther. 1979;7:375–391
  240. Wardman P. Thiol reactivity towards drugs and radicals: some implications in the radiotherapy and chemotherapy of cancer. In:  Chatgilialoglu C,  Asmus K-D editor. Sulfur-centered reactive intermediates in chemistry and biology. New York: Plenum Press; 1990;p. 415–427
  241. Griffith OW, Meister A. Potent and specific inhibition of glutathione synthesis by buthionine sulfoximine (S-n-butyl homocysteine sulfoximine). J Biol Chem. 1979;254:7558–7560
  242. Hodgkiss RJ, Middleton RW. Enhancement of misonidazole radiosensitization by an inhibitor of glutathione biosynthesis. Int J Radiat Biol. 1983;43:179–183
  243. Minchinton AI, Rojas A, Smith KA, et al. Glutathione depletion in tissues after administration of buthionine sulphoximine. Int J Radiat Oncol Biol Phys. 1984;10:1261–1264
  244. Rojas A, Smith KA, Soranson JA, Minchinton AI, Middleton RW, Denekamp J. Enhancement of misonidazole radiosensitization by buthionine sulphoximine. Radiother Oncol. 1984;2:325–332
  245. Lespinasse F, Biscay P, Malaise EP, Guichard M. SR-2508 plus buthionine sulfoximine or SR-2508 alone: effect on the radiation response and the glutathione content of a human tumor xenograft. Radiat Res. 1987;110:149–154
  246. Ono K, Komuro C, Nishidai T, et al. Radiosensitizing effect of misonidazole in combination with an inhibitor of glutathione synthesis in murine tumors. Int J Radiat Oncol Biol Phys. 1986;12:1661–1666
  247. Minchinton AI, Chaplin DJ. Spatial characterization of glutathione depletion in the KHT sarcoma using flow cytometry. Int J Radiat Biol. 1991;59:1425–1433
  248. Vukovic V, Nicklee T, Hedley DW. Microregional heterogeneity of non-protein thiols in cervical carcinomas assessed by combined use of HPLC and fluorescence image analysis. Clin Cancer Res. 2000;6:1826–1832
  249. Vukovic V, Nicklee T, Hedley DW. Differential effects of buthionine sulphoximine in hypoxic and non-hypoxic regions of human cervical carcinoma xenografts. Radiother Oncol. 2001;60:69–73
  250. Bailey HH, Ripple G, Tutsch KD, et al. Phase I study of continuous-infusion L-S,R-buthionine sulfoximine with intravenous melphalan. J Natl Cancer Inst. 1997;89:1789–1796
  251. Bailey HH. L-S,R-buthionine sulfoximine: historical development and clinical issues. Chem Biol Interact. 1998;111–112:239–254
  252. Hamilton D, Wu J, Batist G. Structure-based identification of novel classes of human γ-glutamylcysteine synthetase inhibitors. Mol Pharmacol. 2007;71:1140–1147
  253. Koch CJ, Evans SM. Cysteine concentrations in rodent tumors: unexpectedly high values may cause therapy resistance. Br J Cancer. 1996;67:661–667
  254. Kinnaert E, Duez P, Morandini R, Dubois J, Van Houtte P, Ghanem G. Cysteine but not glutathione modulates the radiosensitivity of human melanoma cells by affecting both survival and DNA damage. Pigment Cell Res. 2004;17:275–280
  255. Biaglow JE, Ayene IS, Koch CJ, et al. Radiation response of cells during altered protein thiol redox. Radiat Res. 2003;159:484–494
  256. O'Neill P. Pulse radiolytic study of the interaction of thiols and ascorbate with OH adducts of dGMP and dG: implications for DNA repair processes. Radiat Res. 1983;96:198–210
  257. Hodgkiss RJ, Stratford MRL. Competitive dose-modification between ascorbate and misonidazole in human and hamster cells: effects of glutathione depletion. Int J Radiat Biol. 1988;54:601–610
  258. Coleman CN, Mitchell JB. Clinical radiosensitization: why it does and does not work. J Clin Oncol. 1999;17:1–3
  259. Hornig D. Distribution of ascorbic acid, metabolites and analogues in man and animals. Ann NY Acad Sci. 1975;258:103–117
  260. Wardman P. Evaluation of the ‘radical sink’ hypothesis from a chemical-kinetic viewpoint. J Radioanal Nucl Chem. 1998;232:23–27

☆ The chemical structures of many of the drugs referred to in this overview are shown in Fig. 1; these are asterisked on first mention.

PII: S0936-6555(07)00580-8

doi: 10.1016/j.clon.2007.03.010

Clinical Oncology
Volume 19, Issue 6 , Pages 397-417 , August 2007

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