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Combinations of Hypoxia-Targeting Compounds and Radiation-Activated Prodrugs with Ionizing Radiation

  • G-One Ahn
  • J. Martin Brown
Chapter
Part of the Medical Radiology book series (MEDRAD)

5.7 Conclusion

The potential clinical benefit of exploiting tumor hypoxia by combining a hypoxia activated drug with conventional cancer therapy has yet to be realized in routine clinical practice. Despite this, the positive clinical results with the combination of the hypoxic cytotoxin tirapazamine with cisplatin in advanced non-small cell lung cancer and with chemoradiotherapy with advanced head and neck cancer demonstrate the potential of this approach. There is a good reason to expect that future drugs or strategies will do better: indeed advances made in experimental models identifying the determinants of the efficacy of these hypoxia-targeting compounds, together with other strategies to exploit tumor hypoxia, auger well for the future of this field.

Keywords

Radiat Oncol Biol Phys Hypoxic Cell Cytochrome P450 Reductase Hypoxic Tumor Cell Bioreductive Drug 
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.

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References

  1. Adams GE, Cooke MS (1969) Electron-affinic sensitization. I. A structural basis for chemical radiosensitizers in bacteria. Int J Radiat Biol Relat Stud Phys Chem Med 15:457–471PubMedGoogle Scholar
  2. Adams GE, Ahmed I, Sheldon PW, Stratford IJ (1984) Radiation sensitization and chemopotentiation: RSU 1069, a compound more efficient than misonidazole in vitro and in vivo. Br J Cancer 49:571–577PubMedGoogle Scholar
  3. Ahn G (2003) Investigation of an aza-chloromethylbenzindoline cobalt(III) complex as a hypoxia-activated prodrug for cancer therapy. Pathology Auckland, University of Auckland, New ZealandGoogle Scholar
  4. Ahn G, Ware DC, Botting KJ, Kriste AG, Denny WA, Wilson WR (2002) A novel Co(III) complex of the DNA minor-groove binder aza-seco-CBI-TMI as a hypoxia-selective prodrug that is activated by enzymatic or radiolytic reduction. Proc Am Assoc Cancer Res 43:656Google Scholar
  5. Ahn G, Liu SC, Menke D, Dorie MJ, Brown JM (2004a) Enhanced antitumor activity of 5-FC by genetically engineered anaerobic bacteria C. sporogenes expressing cytosine deaminase when combined with a vascular targeting agent, ZD6126 or DMXAA. Second International Conference on Vascular Targeting, Miami, FloridaGoogle Scholar
  6. Ahn GO, Ware DC, Denny WA, Wilson WR (2004b) Optimization of the auxiliary ligand shell of cobalt(III)(8-hydroxyquinoline) complexes as model hypoxia-selective radiation-activated prodrugs. Radiat Res 162:315–325PubMedCrossRefGoogle Scholar
  7. Anderson RF, Denny WA, LI W, Packer JE, Tercel M, Wilson WR (1997) Pulse radiolysis studies on the fragmentation of arylmethyl quaternary nitrogen mustards by one-electron reduction in aqueous solution. J Phys Chem 101:9704–9709Google Scholar
  8. Anderson RF, Shinde SS, Hay MP, Gamage SA, Denny WA (2003) Activation of 3-amino-1,2,4-benzotriazine 1,4-dioxide antitumor agents to oxidizing species following their one-electron reduction. J Am Chem Soc 125 748–756PubMedCrossRefGoogle Scholar
  9. Anlezark GM, Melton RG, Sherwood RF, Wilson WR, Denny WA, Palmer BD, Knox RJ, Friedlos F, Williams A (1995) Bioactivation of dinitrobenzamide mustards by an E. coli B nitroreductase. Biochem Pharmacol 50:609–618PubMedCrossRefGoogle Scholar
  10. Bachur NR, Gordon SL, Gee MV (1978) A general mechanism for microsomal activation of quinone anticancer agents to free radicals. Cancer Res 38:1745–1750PubMedGoogle Scholar
  11. Bachur NR, Gordon SL, Gee MV, Kon H (1979) NADPH-cytochrome P-450 reductase activation of quinone anticancer agents to free radicals. Proc Natl Acad Sci USA 76:954–957PubMedCrossRefGoogle Scholar
  12. Bailey SM, Lewis AD, Patterson LH, Fischer GR, Workman P (1993) Free radical generation following reduction of EO9: involvement in cytotoxicity. Br J Cancer 67:8Google Scholar
  13. Baker MA, Zeman EM, Hirst VK, Brown JM (1988) Metabolism of SR 4233 by Chinese hamster ovary cells: basis of selective hypoxic cytotoxicity. Cancer Res 48:5947–5952PubMedGoogle Scholar
  14. Beard C, Buswell L, Rose MA, Noql L, Johnson D, Coleman CN (1994) Phase-II trial of external beam radiation with etanidazole (SR 2508) for the treatment of locally advanced prostate cancer. Int J Radiat Oncol Biol Phys 29:611–616PubMedGoogle Scholar
  15. Beidermann KA, Wang J, Graham RP, Brown JM (1991) SR 4233 cytotoxicity and metabolism in DNA repair-competent and repair-deficient cell cultures. Br J Cancer 63:358–362Google Scholar
  16. Biaglow JE, Varnes ME, Koch CJ, Sridhar R (1982) Metabolic activation of carcinogenic nitro-compounds to oxygen reactive intermediates. In: Floyd RA (ed) Free radicals and cancer. Marcel Dekker, New YorkGoogle Scholar
  17. Bos R, Van der Groep P, Greijer AE, Shvarts A, Meijer S, Pinedo HM, Semenza GL, Van Diest PJ, Van der Wall E (2003) Levels of hypoxia-inducible factor-1α independently predict prognosis in patients with lymph node negative breast carcinoma. Cancer 97:1573–1581PubMedCrossRefGoogle Scholar
  18. Breider MA, Pilcher GD, Graziano MJ, Gough AW (1998) Retinal degeneration in rats induced by CI-1010, a 2-nitroimidazole radiosensitizer. Toxicol Pathol 26:234–239PubMedGoogle Scholar
  19. Bridgewater JA, Springer CJ, Knox RJ, Minton NP, Michael NP, Collins MK (1995) Expression of the bacterial nitroreductase enzyme in mammalian cells renders them selectively sensitive to killing by the prodrug CB1954. Eur J Cancer 31A:2362–2370PubMedCrossRefGoogle Scholar
  20. Brizel DM, Sibley GS, Prosnitz LR, Scher RL, Dewhirst MW (1997) Tumor hypoxia adversely affects the prognosis of carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 38:285–289PubMedCrossRefGoogle Scholar
  21. Brown JM (1979) Evidence for acutely hypoxic cells in mouse tumours, and a possible mechanism of reoxygenation. Br J Radiol 52:650–656PubMedGoogle Scholar
  22. Brown JM (1993) SR 4233 (tirapazamine): a new anticancer drug exploiting hypoxia in solid tumours. Br J Cancer 67:1163–1170PubMedGoogle Scholar
  23. Brown JM (1999) The hypoxic cell: a target for selective cancer therapy. Eighteenth Bruce F. Cain Memorial Award Lecture. Cancer Res 59:5863–5870PubMedGoogle Scholar
  24. Brown JM, Giaccia AJ (1998) The unique physiology of solid tumors: opportunities (and problems) for cancer therapy. Cancer Res 58:1408–1416PubMedGoogle Scholar
  25. Brown JM, Koong A (1991) Therapeutic advantage of hypoxic cells in tumors: a theoretical study. J Natl Cancer Inst 83:178–185PubMedGoogle Scholar
  26. Brown JM, Lemmon MJ (1990) Potentiation by the hypoxic cytotoxin SR 4233 of cell killing produced by fractionated irradiation of mouse tumors. Cancer Res 50:7745–7749PubMedGoogle Scholar
  27. Brown JM, Wang LH (1998) Tirapazamine: laboratory data relevant to clinical activity. Anticancer Drug Des 13:529–539PubMedGoogle Scholar
  28. Brown JM, Wilson WR (2004) Exploiting tumour hypoxia in cancer treatment. Nat Rev Cancer 4:437–447PubMedCrossRefGoogle Scholar
  29. Brown JM, Yu NY (1984) Radiosensitization of hypoxic cells in vivo by SR 2508 at low radiation doses: a preliminary report. Int J Radiat Oncol Biol Phys 10:1207–1212PubMedGoogle Scholar
  30. Brown JM, Yu NY, Brown DM, Lee WW (1981) SR-2508: A 2-nitroimidazole amide which should be superior to misonidazole as a radiosensitizer for clinical use. Int J Radiat Oncol Biol Phys 7:695–703PubMedGoogle Scholar
  31. Bush RS, Jenkin RDT, Allt WEC, Beale FA, Bean H, Dembo AJ, Pringle JF (1978) Definitive evidence for hypoxic cells influencing cure in cancer therapy. Br J Cancer 37:302–306Google Scholar
  32. Cahill A, White IN (1990) Reductive metabolism of 3-amino-1,2,4-benzotriazine-1,4-dioxide (SR 4233) and the induction of unscheduled DNA synthesis in rat and human derived cell lines. Carcinogenesis 11:1407–1411PubMedGoogle Scholar
  33. Carey RW, Holland JF, Whang HY, Neter E, Bryant B (1967) Clostridial oncolysis in man. Eur J Cancer 3:37–46Google Scholar
  34. Carmeliet P, Dor Y, Herbert JM, Fukumura D, Brusselmans K, Dewerchin M, Neeman M, Bono F, Abramovitch R, Maxwell P, Koch CJ, Ratcliffe P, Moons L, Jain RK, Collen D, Keshert E (1998) Role of HIF-1 alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature 394:485–490PubMedCrossRefGoogle Scholar
  35. Chadderton N, Cowen RL, Sheppard FCD, Robinson S, Greco O, Scott SD, Stratford IJ, Patterson AV, Williams KJ (2005) Dual responsive promoters to target therapeutic gene expression to radiation-resistant hypoxic tumor cells. Int J Radiat Oncol Biol Phys 62:213–222PubMedCrossRefGoogle Scholar
  36. Chan P, Milosevic M, Fyles AW, Carson J, Pintilie M, Rauth M, Thomas G (2004) A phase III randomized study of misonidazole plus radiation vs radiation alone for cervix cancer. Radiother Oncol 70:295–299PubMedCrossRefGoogle Scholar
  37. Chaplin DJ, Durand RE, Olive PL (1986) Acute hypoxia in tumors: implications for modifiers of radiation effects. Int J Radiat Oncol Biol Phys 12:1279–1282PubMedGoogle Scholar
  38. Chaplin DJ, Horsman MR, Aoki DS (1991) Nicotinamide, Fluosol DA and carbogen: a strategy to oxygenate acutely and chronically hypoxic cells in vivo. Br J Cancer 63:109–113PubMedGoogle Scholar
  39. Chapman JD, Raleigh JA, Pederson L, Ngan J, Shum FY, Meeker BE, Urtasun RC (1979) Potentially three distinct roles for hypoxic cell radiosensitizers in the clinic. Proc 6th Int Congr Radiat Res, TokyoGoogle Scholar
  40. Chen J, Zhao S, Nakada K, Kuge Y, Tamaki N, Okada F, Wang J, Shindo M, Higashiro F, Takeda K, Asaka M, Katoh H, Sugiyama T, Hosokawa M, Kobayashi M (2003) Dominant-negative hypoxia-inducible factor-1α reduces tumorigenicity of pancreatic cancer cells through the suppression of glucose metabolism. Am J Pathol 1162:1283–1291PubMedGoogle Scholar
  41. Choy H, Nabid A, Stea B, Scott C, Roa W, Kleinberg L, Ayoub J, Smith C, Souhami L, Hamburg S, Spanos W, Kreisman H, Boyd AP, Cagnoni PJ, Curran WJ (2005) Phase II multicenter study of induction chemotherapy followed by concurrent efaproxiral (RSR13) and thoracic radiotherapy for patients with locally advanced non-small-cell lung cancer. J Clin Oncol 23:5918–5928PubMedCrossRefGoogle Scholar
  42. Chung-Faye G, Palmer D, Anderson D, Clark J, Downes M, Baddeley J, Hussain S, Murray PI, Searle P, Seymour L, Harris PA, Ferry D, Kerr DJ (2001) Virus-directed, enzyme prodrug therapy with nitroimidazole reductase: a phase I and pharmacokinetic study of its prodrug, CB1954. Clin Cancer Res 7:2662–2668PubMedGoogle Scholar
  43. Cole S, Stratford IJ, Adams GE, Fielden EM, Jenkins TC (1990) Dual-function 2-nitroimidazoles as hypoxic cell radiosensitizers and bioreductive cytotoxins: in vivo evaluation in KHT murine sarcomas. Radiat Res 124:S38–S43PubMedGoogle Scholar
  44. Corry J, Rischin D (2004) Strategies to overcome accelerated repopulation and hypoxia: What have we learned from clinical trials? Semin Oncol 31:802–808PubMedCrossRefGoogle Scholar
  45. Cowan DS, Panicucci R, Mcclelland RA, Rauth AM (1991) Targeting radiosensitizers to DNA by attachment of an intercalating group: nitroimidazole-linked phenanthridines. Radiat Res 127:81–89PubMedGoogle Scholar
  46. Cowen RL, Williams KJ, Chinje EC, Jaffar M, Sheppard FCD, Telfer BA, Wind NS, Stratford IJ (2004) Hypoxia targeted gene therapy to increase the efficacy of tirapazamine as an adjuvant to radiotherapy: reversing tumor resistance and effecting cure. Cancer Res 64:1396–1402PubMedCrossRefGoogle Scholar
  47. Dachs GU, Patterson AV, Firth JD, Ratcliffe PJ, Townsend KMS, Stratford IJ, Harris AL (1997) Targeting gene expression to hypoxic tumor cells. Nat Med 3:515–520PubMedCrossRefGoogle Scholar
  48. Dachs GU, Tupper J, Tozer GM (2005) From bench to bedside for gene-directed enzyme prodrug therapy of cancer. Anti Cancer Drugs 16:349–359PubMedCrossRefGoogle Scholar
  49. Delahoussaye YM, Evans JW, Brown JM (2001) Metabolism of tirapazamine by multiple reductases in the nucleus. Biochem Pharmacol 62:1201–1209PubMedCrossRefGoogle Scholar
  50. Denekamp J, Stewart FA (1978) Sensitization of mouse tumours using fractionated X-irradiation. Br J Cancer 37:259–263Google Scholar
  51. Denny WA, Wilson WR (1993) Bioreducible mustards: a paradigm for hypoxia-selective prodrugs of diffusible cytotoxins (HPDCs). Cancer Met Rev 12:135–151CrossRefGoogle Scholar
  52. Denny WA, Roberts PB, Anderson RF, Brown JM, Phil D, Wilson WR (1992) NLA-1: A 2-nitroimidazole radiosensitizer targeted to DNA by intercalation. Int J Radiat Oncol Biol Phys 22:553–556PubMedGoogle Scholar
  53. Dirix LY, Tonnesen F, Cassidy J, Epelbaum R, Bokkel Huinink WW, Pavlidis N, Sorio R, Gamucci T, Wolff I, Te VA, Lan J, Verweij J (1996) EO9 Phase II study in advanced breast, gastric, pancreatic and colorectal carcinoma by the EORTC Early Clinical Studies Group. Eur J Cancer 32A:2019–2022PubMedCrossRefGoogle Scholar
  54. Dische S (1985) Chemical sensitisers for hypoxic cells: a decade of experience in clinical radiotherapy. Radiother Oncol 3:97–115PubMedGoogle Scholar
  55. Dische S, Anderson PJ, Sealy R, Watson ER (1983) Carcinoma of the cervix: anaemia, radiotherapy and hyperbaric oxygen. Br J Radiol 56:251–255PubMedGoogle Scholar
  56. Dische S, Chassagne D, Hope-Stone HF, Dawes PJDK, Roberts JT, Yosef H, Bey P, Horiot J-C, Jacobson A, Frankendal B, Gonzales Gonzales D, Nguyen TD, Daly NJ, Le Floch O, Newman H, Vieiro E, Bennett MH, Bichel P, Duvillard P, Jacobson A, Cook PA, Everett V, Machin D (1993) A trial of Ro 03-8799 (pimonidazole) in carcinoma of the uterine cervix: an interim report from the Medical Research Council Working Party on advanced carcinoma of the cervix. Radiother Oncol 26:93–103CrossRefGoogle Scholar
  57. Dische S, Saunders MI, Lee ME, Adams GE, Flockhart IR (1977) Clinical testing of the radiosensitizer Ro 07-0582: experience with multiple doses. Br J Cancer 35:567–579PubMedGoogle Scholar
  58. Dorie MJ, Brown JM (1993) Tumor-specific, schedule-dependent interaction between tirapazamine (SR 4233) and cisplatin. Personal communicationGoogle Scholar
  59. Douglas RS, Patterson AV, Yang S, Wilson WR, Siim BG (2005) Induction of DNA damage and repair responses by the hypoxia-activated prodrug PR-104. AACR-NCI-EORTC Conference on Molecular Targets and Cancer Therapeutics: Discovery, Biology, and Clinical Applications. PhiladelphiaGoogle Scholar
  60. Eschwege F, Sancho-Garnier H, Chassagne D, Brisgand D, Guerra M, Malaise EP, Bey P, Busutti L, Cionini L, N’guyen T, Romanini A, Chavaudra J, Hill C (1997) Results of an European randomized trial of etanidazole combined with radiotherapy in head and neck carcinomas. Int J Radiat Oncol Biol Phys 39:275–281PubMedCrossRefGoogle Scholar
  61. Evans JW, Yudoh K, DeLahoussaye YM, Brown JM (1998) Tirapazamine is metabolized to its DNA-damaging radical by intranuclear enzymes. Cancer Res 58:2098–2101PubMedGoogle Scholar
  62. Fang J, Yan L, Shing Y, Moses MA (2001) HIF-1 alpha-mediated up-regulation of vascular endothelial growth factor, independent of basic fibroblast growth factor, is important in the switch to the angiogenic phenotype during early tumorigenesis. Cancer Res 61:5731–5735PubMedGoogle Scholar
  63. Fang J, Xia C, Cao Z, Zheng JZ, Reed E, Jiang B-H (2005) Apigenin inhibits VEGF and HIF-1 expression via PI3K/AKT/p70S6K1 and HDM2/p53 pathways. FASEB J 19:342–353PubMedCrossRefGoogle Scholar
  64. Flockhart IR, Large P, Troup D, Malcolm SH, Marten TR (1978) Pharmacokinetic and metabolic studies of the hypoxic cell radiosensitizer misonidazole. Xenobiotica 8:97–105PubMedCrossRefGoogle Scholar
  65. Fox ME, Lemmon MJ, Mauchline ML, Davis TO, Giaccia AJ, Minton NP, Brown JM (1996) Anaerobic bacteria as a delivery system for cancer gene therapy: activation of 5-fluorocytosine by genetically engineered clostridia. Gene Therapy 3:173–178PubMedGoogle Scholar
  66. Fracasso PM, Sartorelli AC (1986) Cytotoxicity and DNA lesions produced by mitomycin C and porfiromycin in hypoxic and aerobic EMT6 and Chinese hamster ovary cells. Cancer Res 46:3939–3944PubMedGoogle Scholar
  67. Fyles AW, Milosevic M, Pintilie M, Hill RP (1998) Cervix cancer oxygenation measured following external radiation therapy. Int J Radiat Oncol Biol Phys 42:751–753PubMedCrossRefGoogle Scholar
  68. Giaccia A, Siim BG, Johnson RS (2003) HIF-1 as a target for drug development. Nat Rev Drug Discovery 2:1–9CrossRefGoogle Scholar
  69. Graeber TG, Osmanian C, Jacks T, Housman DE, Koch CJ, Lowe SW, Giaccia AJ (1996) Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature 379:88–91PubMedCrossRefGoogle Scholar
  70. Grahams MA, Senan S, Robin HJ, Eckhardt N, Lendrem D, Hinks J, Greenslade D, Rampling R, Kaye SB, Roemeling R von, Workman P (1997) Pharmacokinetics of the hypoxic cell cytotoxic agent tirapazamine and its major bioreductive metabolites in mice and humans: retrospective analysis of a pharmacokinetically guided dose-escalation strategy in a phase I trial. Cancer Chemother Pharmacol 40:1–10CrossRefGoogle Scholar
  71. Greco O, Marples B, Dachs GU, Williams KJ, Patterson AV, Scott SD (2002) Novel chimeric gene promoters responsive to hypoxia and ionizing radiation. Gene Ther 9:1403–1411PubMedCrossRefGoogle Scholar
  72. Green NK, Youngs DJ, Neoptolemos JP, Friedlos F, Knox RJ, Springer CJ, Anlezark GM, Michael NP, Melton RG, Ford MJ, Young LS, Kerr DJ, Searle PF (1997) Sensitization of colorectal and pancreatic cancer cell lines to the prodrug 5-(aziridin-1-yl)-2,4-dinitrobenzamide (CB1954) by retroviral transduction and expression of the E. coli nitroreductase gene. Cancer Gene Ther 4:229–238PubMedGoogle Scholar
  73. Grigsby PW, Winter K, Wasserman TH, Marcial VA, Rotman M, Cooper JS, Keys H, Asbell SO, Phillips TL (1999) Irradiation with or without misonidazole for patients with stages IIIB and IVA carcinoma of the cervix: final results of RTOG 80-05. Int J Radiat Oncol Biol Phys 44:513–517PubMedCrossRefGoogle Scholar
  74. Haffty BG, Son YH, Sasaki CT, Papac R, Fischer D, Rockwell S, Sartorelli AC, Fischer JJ (1993) Mitomycin C as an adjunct to postoperative radiation therapy in squamous cell carcinoma of the head and neck: results from two randomized clinical trials. Int J Radiat Oncol Biol Phys 27:241–250PubMedGoogle Scholar
  75. Haffty BG, Son YH, Papac R, Sasaki CT, Weissberg JB, Fischer D, Rockwell S, Sartorelli AC, Fischer JJ (1997) Chemotherapy as an adjunct to radiation in the treatment of squamous cell carcinoma of the head and neck: results of the Yale Mitomycin Randomized Trials. J Clin Oncol 15:268–276PubMedGoogle Scholar
  76. Haffty BG, Wilson LD, Son YH, Cho EI, Papac RJ, Fischer DB, Rockwell S, Sartorelli AC, Ross DA, Sasaki CT, Fischer JJ (2005) Concurrent chemo-radiotherapy with mitomycin C compared with porfiromycin in squamous cell cancer of the head and neck: final results of a randomized clinical trial. Int J Radiat Oncol Biol Phys 61:119–128PubMedCrossRefGoogle Scholar
  77. Hall EJ, Roizon-Towle L (1975) Hypoxic radiosensitisers: radiobiological studies at the cellular level. Radiology 117:453–457PubMedGoogle Scholar
  78. Hay MP, Wilson WR, Moselen JW, Palmer BD and Denny WA (1994) Hypoxia-selective antitumor agents. 8. Bis (nitroimi dazolyl)alkanecarboxamides: a new class of hypoxia-selective cytotoxins and hypoxic cell radiosensitisers. J Med Chem 37 381–391PubMedCrossRefGoogle Scholar
  79. Heimbrook DC, Sartorelli AC (1986) Biochemistry of misonidazole by NADPH-cytochrome c (P-450) reductase. Mol Pharmacol 29:168–172PubMedGoogle Scholar
  80. Helsby NA, Wheeler SJ, Pruijn FB, Palmer BD, Yang S, Denny WA, Wilson WR (2003) Effect of nitroreduction on the alkylating reactivity and cytotoxicity of the 2,4-dinitrobenzamide-5-aziridine CB1954 and the corresponding nitrogen mustard SN 23862: distinct mechanisms of bioreductive activation. Chem Res Toxicol 16:469–478PubMedCrossRefGoogle Scholar
  81. Helsby NA, Ferry DM, Patterson AV, Pullen SM, Wilson WR (2004) 2-Amino metabolites are key mediators of CB 1954 and SN 23862 bystander effects in nitroreductase GDEPT. Br J Cancer 90:1084–1092PubMedCrossRefGoogle Scholar
  82. Henk JM (1986) Late results of a trial of hyperbaric oxygen and radiotherapy in head and neck cancer: a rationale for hypoxic cell radiosensitizers. Int J Radiat Oncol Biol Phys 12:1339–1341PubMedGoogle Scholar
  83. Henk JM, Bishop K and Shepherd SF (2003) Treatment of head and neck cancer with CHART and nimorazole: phase II study. Radiother Oncol 66:65–70PubMedCrossRefGoogle Scholar
  84. Heppner F, Mose JR (1978) The liquefaction (oncolysis) of malignant gliomas by a non pathogenic clostridium. Acta Neuro 12 123–125CrossRefGoogle Scholar
  85. Heppner F, Mose J, Ascher PW, Walter G (1983) Oncolysis of malignant gliomas of the brain. Thirteenth Int Cong Chemother 226:38–45Google Scholar
  86. Hicks KO, Pruijn FB, Sturman JR, Denny WA, Wilson WR (2003) Multicellular resistance to tirapazamine is due to restricted extravascular transport: a pharmacokinetic/pharmacodynamic study in HT29 multicellular layer cultures. Cancer Res 63:5970–5977PubMedGoogle Scholar
  87. Hicks KO, Siim BG, Pruijn FB, Wilson WR (2004) Oxygen dependence of the metabolic activation and cytotoxicity of tirapazamine: implications for extravascular transport and activity in tumors. Radiat Res 161:656–666PubMedCrossRefGoogle Scholar
  88. Hill RP, Bush RS (1978) The effect of misonidazole in combination with radiation dose fractionation. Br J Cancer 37:255–258Google Scholar
  89. Hill RP, Gulyas S, Whitmore GF (1986) Studies of the in vivo and in vitro cytotoxicity of the drug RSU-1069. Br J Cancer 53:743–751PubMedGoogle Scholar
  90. Hill SA, Pigott KH, Saunders MI, Powell ME, Arnold S, Obeid A, Ward G, Leahy M, Hoskin PJ, Chaplin DJ (1996) Microregional blood flow in murine and human tumours assessed using laser Doppler microprobes. Br J Cancer 27(Suppl):S260–S263Google Scholar
  91. Hirst DG, Wood PJ (1989) Altered radiosensitivity in a mouse carcinoma after administration of clofibrate and benzafibrate. Radiother Oncol 15:55–61PubMedCrossRefGoogle Scholar
  92. Hockel M, Knoop C, Schlenger K, Vorndran B, Baussmann E, Mitze M, Knapstein PG, Vaupel P (1993) Intratumoral pO2 predicts survival in advanced cancer of the uterine cervix. Radiother Oncol 26:45–50PubMedCrossRefGoogle Scholar
  93. Hodgkiss RJ (1998) Use of 2-nitroimidazoles as bioreductive markers for tumour hypoxia. Anticancer Drug Des 13:687–702PubMedGoogle Scholar
  94. Horsman MR, Chaplin DJ, Brown JM (1987) Radiosensitization by nicotinamide in vivo: a greater enhancement of tumor damage compared to that of normal tissues. Radiat Res 109:479–489PubMedGoogle Scholar
  95. Horwich A, Holliday SB, Deacon JM, Peckham MJ (1986) A toxicity and pharmacokinetic study in man of the hypoxic-cell radiosensitizer RSU-1069. Br J Radiol 59:1238–1240PubMedGoogle Scholar
  96. Iyanagi T, Yamazaki I (1970) One-electron reactions in biochemical systems. V. Differences in the mechanism of quinone reduction by the NADP dehydrogenase and the HAD(P)H dehydrogenase (DT-diaphorase). Biochim Biophys Acta 216:282–294PubMedCrossRefGoogle Scholar
  97. Iyer NV, Szybalski W (1963) Mitomycins and porfiromycin: chemical mechanisms of activation and cross-linking of DNA. Microbiology 50:355–362Google Scholar
  98. Jenkins TC, Naylor MA, O’Neill P, Threadgill MD, Cole S, Stratford IJ, Adams GE, Fielden EM, Suto MJ, Stier MA (1990) Synthesis and evaluation of alpha-[[(2-haloethyl)amino]methyl]-2-nitro-1H-imidazole-1-ethanols as prodrugs of alpha-[[(2-aziridinyl)methyl]2-nitro-1H-imidazole-1-ethanol (RSU-1069) and its analogues which are radiosensitizers and bioreductively activated cytotoxins. J Med Chem 33:2603–2610PubMedCrossRefGoogle Scholar
  99. Jirtle R (1988) Chemical modification of tumour blood flow. Int J Hyperthermia 4:355–371PubMedGoogle Scholar
  100. Keyes SR, Fracasso PM, Heimbrook DC, Rockwell S, Sligar SG, Sartorelli AC (1984) Role of NADPH:cytochrome c reductase and DT-diaphorase in the biotransformation of mitomycin C. Cancer Res 44:5638–5643PubMedGoogle Scholar
  101. Keyes SR, Rockwell S, Sartorelli AC (1985) Porfiromycin as a bioreductive alkylating agent with selective toxicity to hypoxic EMT6 tumor cells in vivo and in vitro. Cancer Res 45:3642–3645PubMedGoogle Scholar
  102. Kimura H, Braun RD, Ong ET, Hsu R, Secomb TW, Papahadjopoulos D, Hong K, Dewhirst MW (1996) Fluctuations in red cell flux in tumor microvessels can lead to transient hypoxia and reoxygenation in tumor parenchyma. Cancer Res 56:5522–5528PubMedGoogle Scholar
  103. Kjellen E, Joiner MC, Collier JM, Johns J and Rojas A (1991) A therapeutic benefit from combining normobaric carbogen or oxygen with nicotinamide in fractionated X-ray treatments. Radiother Oncol 22:81–91PubMedCrossRefGoogle Scholar
  104. Knox RJ, Boland MP, Friedlos F, Coles B, Southan C, Roberts JJ (1988a) The nitroreductase enzyme in Walker cells that activates 5-(aziridin-1-yl)-2,4-dinitrobenzamide (CB 1954) to 5-(aziridin-1-yl)-4-hydroxylamino-2-nitrobenzamide is a form of NAD(P)H dehydrogenase (quinone) (EC 1.6.99.2). Biochem Pharmacol 37:4671–4677PubMedCrossRefGoogle Scholar
  105. Knox RJ, Friedlos F, Jarman M, Roberts JJ (1988b) A new cytotoxic, DNA interstrand crosslinking agent, 5-(aziridin-1-yl)-4-hydroxylamino-2-nitrobenzamide, is formed from 5-(aziridin-1-yl)-2,4-dinitrobenzamide (CB 1954) by nitroreductase enzyme in Walker carcinoma cells. Biochem Pharmacol 37:4661PubMedCrossRefGoogle Scholar
  106. Knox RJ, Friedlos F, Marchbank T, Roberts JJ (1991) Bioactivation of CB 1954: reaction of the active 4-hydroxylamino derivative with thioesters to form the ultimate DNA-DNA interstrand crosslinking species. Biochem Pharmacol 42:1691–1697PubMedCrossRefGoogle Scholar
  107. Koch CJ (1993) Unusual oxygen concentration dependence of toxicity of SR-4233, a hypoxic cell toxin. Cancer Res 53:3992–3997PubMedGoogle Scholar
  108. Kong D, Park EJ, Stephen AG, Calvani M, Cardellina JH, Monks A, Fisher RJ, Shoemaker RH, Melillo G (2005) Echinomycin, a small-molecule inhibitor of hypoxia-inducible factor-1 DNA-binding activity. Cancer Res 65:9047–9055PubMedCrossRefGoogle Scholar
  109. Kung AL, Zabludoff SD, France DS, Freedman SJ, Tanner EA, Vieira A, Cornell-Kennon S, Lee J, Wang B, Wang J, Memmert K, Naegeli H-U, Petersen F, Eck MJ, Bair KW, Wood AW, Livingston DM (2004) Small molecule blockade of transcriptional coactivation of the hypoxia-inducible factor pathway. Cancer Cell 6:33–43PubMedCrossRefGoogle Scholar
  110. Laderoute K, Wardman P, Rauth AM (1988) Molecular mechanisms for the hypoxia-dependent activation of 3-amino-1,2,4-benzotriazine-1,4-dioxide (SR 4233). Biochem Pharmacol 37:1487–1495PubMedCrossRefGoogle Scholar
  111. Lawton CA, Coleman CN, Buzydlowski JW, Forman JD, Marcial VA, Delrowe JD, Rotman M (1996) Results of a Phase-II trial of external beam radiation with etanidazole (SR 2508) for the treatment of locally advanced prostate cancer (RTOG protocol 90-20). Int J Radiat Oncol Biol Phys 36:673–680PubMedCrossRefGoogle Scholar
  112. Lee D-J, Cosmatos D, Marcial VA, Fu KK, Rotman M, Cooper JS, Ortiz HG, Beitler JJ, Abrams RA, Curran WJ, Coleman CN, Wasserman TH (1995) Results of an RTOG phase III trial (RTOG 85-27) comparing radiotherapy plus etanidazole with radiotherapy alone for locally advanced head and neck carcinomas. Int J Radiat Oncol Biol Phys 32:567–576PubMedCrossRefGoogle Scholar
  113. Lee HH, Wilson WR, Ferry DM, Van Zijl P, Pullen SM, Denny WA (1996) Hypoxia-selective antitumour agents. 13. Effects of acridine substitution on the hypoxia-selective cytotoxicity and metabolic reduction of the bis-bioreductive agent nitracrine N-oxide. J Med Chem 39:2508–2517PubMedCrossRefGoogle Scholar
  114. Lemmon MJ, Elwell JH, Brehm JK, Mauchline ML, Minton NP, Giaccia AJ, Brown JM (1994) Anaerobic bacteria as a gene delivery system to tumors. Proc Am Assoc Cancer Res 35:374Google Scholar
  115. Li M-H, Miao Z-H, Tan W-F, Yue J-M, Zhang C, Lin L-P, Zhang X-W, Ding J (2004) Pseudolaric acid B inhibits angiogenesis and reduces hypoxia-inducible factor 1α by promoting proteasome-mediated degradation. Clin Cancer Res 10:8266–8274PubMedCrossRefGoogle Scholar
  116. Li YM, Zhou BP, Deng J, Pan Y, Hay N, Hung M-C (2005) A hypoxia-independent hypoxia-inducible factor-1 activation pathway induced by phophatidylinositol-3 kinase/Akt in HER2 overexpressing cells. Cancer Res 65:3257–3263PubMedGoogle Scholar
  117. Liu SC, Minton NP, Giaccia AJ, Brown JM (2002) Anticancer efficacy of systemically delivered anaerobic bacteria as gene therapy vectors targeting tumor hypoxia/necrosis. Gene Ther 9:291–296PubMedCrossRefGoogle Scholar
  118. Lloyd RV, Duling DR, Rumyantseva GV, Mason RP, Bridson PK (1991) Microsomal reduction of 3-amino-1,2,4-benzotriazine-1,4-dioxide to a free radical. Mol Pharmacol 40:440–445PubMedGoogle Scholar
  119. Majumder PK, Febbo PG, Bikoff R, Berger R, Xue Q, Mcmahon LM, Manola J, Brugarolas J, Mcdonnell TJ, Golub TR, Loda M, Lane HA, Sellers WR (2004) mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nat Med 10:594–601PubMedCrossRefGoogle Scholar
  120. Maliepaard M, Wolfs A, Groot SE, De Mol NJ, Janssen LHM (1995) Indoloquinone EO9: DNA interstrand cross-linking upon reduction by DT-diaphorase or xanthine oxidase. Br J Cancer 71:836–839PubMedGoogle Scholar
  121. Mason RP, Holtzman JL (1975) The mechanism of microsomal and mitochondrial nitroreductase. Biochemistry 14:1626–1632PubMedCrossRefGoogle Scholar
  122. McClelland RA, Fuller JR, Seaman NE, Rauth AM, Battistella R (1984) 2-hydroxylaminoimidazoles: unstable intermediates in the reduction of 2-nitroimidazoles. Biochem Pharmacol 33:303–309PubMedCrossRefGoogle Scholar
  123. McKeown SR, Friery OP, Mcintyre IA, Hejmadi MV, Patterson LH, Hirst DG (1996) Evidence for a therapeutic gain when AQ4N or tirapazamine is combined with radiation. Br J Cancer 27(Suppl):S39–S42Google Scholar
  124. McKeown SR, Hejmadi MV, Mcintyre IA, Mcaleer JJ, Patterson LH (1995) AQ4N: an alkylaminoanthraquinone N-oxide showing bioreductive potential and positive interaction with radiation in vivo. Br J Cancer 72:76–81PubMedGoogle Scholar
  125. Miller VA, Ng KK, Grant SC, Kindler H, Pizzo B, Heelan RT, Roemeling R von, Kris MG (1997) Phase II study of the combination of the novel bioreductive agent, tirapazamine, with cisplatin in patients with advanced non-small-cell lung cancer. Ann Oncol 8:1269–1271PubMedCrossRefGoogle Scholar
  126. Moeller BJ, Cao Y, Li CY, Dewhirst MW (2004) Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors: role of reoxygenation, free radicals, and stress granules. Cancer Cell 5:429–441PubMedCrossRefGoogle Scholar
  127. Moeller BJ, Dreher MR, Rabbani ZN, Schroeder T, Cao Y, Li CY, Dewhirst MW (2005) Pleiotropic effects of HIF-1 blockade on tumor radiosensitivity. Cancer Cell 8:99–110PubMedCrossRefGoogle Scholar
  128. Moselen JW, Hay MP, Denny WA, Wilson WR (1995) N-[2-(2-methyl-5-nitroimidazolyl)ethyl]-4-(2-nitroimidazolyl)but anamide (NSC 639862), a bisnitroimidazole with enhanced selectivity as a bioreductive drug. Cancer Res 55:574–580PubMedGoogle Scholar
  129. Nakanishi K, Hiroi S, Tominaga S, Aida S, Kasamatsu H, Matsuyama S, Matsuyama T, Kawai T (2005) Expression of hypoxia-inducible factor-1α protein predicts survival in patients with transitional cell carcinoma of the upper urinary tract. Clin Cancer Res 11:2583–2590PubMedCrossRefGoogle Scholar
  130. Nishimoto SI, Hatta H, Ureshima H, Kagiya T (1992) 1-(5′-fluoro-6′-hydroxy-5′, 6′-dihydrouracil-5′-yl)-5-fluorouracil, a novel N(1)-C(5)-linked dimer that releases 5-fluorouracil by radiation activation under hypoxic conditions. J Med Chem 35:2711–2712PubMedCrossRefGoogle Scholar
  131. Nordsmark M, Overgaard M, Overgaard J (1996) Pretreatment oxygenation predicts radiation response in advanced squamous cell carcinoma of the head and neck. Radiother Oncol 41:31–39PubMedGoogle Scholar
  132. Oostveen EA, Speckamp WN (1987) Mitomycin analogs. I. Indoloquinones as (potential) bisalkylating agents. Tetrahedron 43:255–262CrossRefGoogle Scholar
  133. Overgaard J (1994) Clinical evaluation of nitroimidazoles as modifiers of hypoxia in solid tumors. Oncol Res 6:509–518PubMedGoogle Scholar
  134. Overgaard J, Bentzen SM, Kolstad P, Kjoerstad K, Davy M, Bertelsen K, Mantyla M, Frankendal B, Skryten A, Loftquist I, Pedersen M, Sell A, Hammer R (1989a) Misonidazole combined with radiotherapy in the treatment of carcinoma of the uterine cervix. Int J Radiat Oncol Biol Phys 16:1069–1072PubMedGoogle Scholar
  135. Overgaard J, Hansen HS, Anderson AP, Hjelm-Hansen M, Jorgensen K, Sandberg E, Berthelsen A, Hammer R, Pedersen M (1989b) Misonidazole combined with split-course radiotherapy in the treatment of invasive carcinoma of larynx and pharynx: report from the DAHANCA 2 study. Int J Radiat Oncol Biol Phys 16:1065–1068PubMedGoogle Scholar
  136. Overgaard J, Hansen HS, Overgaard M, Bastholt L, Berthelsen A, Specht L, Lindelov B, Jorgensen KA (1998) A randomized double-blind phase III study of nimorazole as a hypoxic radiosensitizer of primary radiotherapy in supraglottic larynx and pharynx carcinoma. Results of Danish Head and Neck Cancer Study (DAHANCA) Protocol 5–85. Radiother Oncol 46:135–146PubMedCrossRefGoogle Scholar
  137. Overgaard J, Eriksen JG, Nordsmark M, Alsner J, Horsman MR (2005) 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 6:757–764PubMedCrossRefGoogle Scholar
  138. Palmer BD, Van Zijl P, Denny WA, Wilson WR (1995) Reductive chemistry of the novel hypoxia-selective cytotoxin 5-[N,N-bis(2-chloroethyl)amino]-2,4-dinitrobenzamide. J Med Chem 38 1229–1241PubMedCrossRefGoogle Scholar
  139. Pan SS, Andrews PA, Glover CJ, Bachur NR (1984) Reductive activation of mitomycin C and mitomycin C metabolites catalysed by NADPH-cytochrome P-450 reductase and xanthine oxidase. J Biol Chem 259:959–966PubMedGoogle Scholar
  140. Papadopoulou MV, Epperly MW, Shields DS, Bloomer WD (1992) Radiosensitization and hypoxic cell toxicity of NLA-1 and NLA-2, two bioreductive compounds. Jpn J Cancer Res 83:410–414PubMedGoogle Scholar
  141. Papadopoulou MV, Rosenzweig HS, Doddi M, Bloomer WD (1994) 9-[3-)2-nitro-1-imidazolyl)propylamino]-1,2,3,4-tetrahydroacridine hydrochloride. A novel DNA-affinic hypoxic cell cytotoxin and radiosensitizer. Comparison with NLA-1. Oncol Res 6:439–448PubMedGoogle Scholar
  142. Papadopoulou MV, JI M, Bloomer WD (1996) THNLA-1 as radio/chemosensitiser of EMT-6 tumours in mice. Br J Cancer 74:S267–S270Google Scholar
  143. Papadopoulou MV, Ji M, Rao MK, Bloomer WD (2000) 4-[3-(2-nitro-1-imidazolyl)propylamino]-7-chloroquinoline hydrochloride (NLCQ-1), a novel bioreductive agent as radiosensitizer in vitro and in vivo: comparison with tirapazamine. Oncol Res 12:325–333PubMedGoogle Scholar
  144. Papadopoulou MV, Bloomer WD, Hollingshead MG (2005) NLCQ-1 (NSC 709257) in combination with radiation against human glioma U251 xenografts. Anticancer Res 25:1865–1869PubMedGoogle Scholar
  145. Parker RF, Vincent PW, Elliot WL (1996) Alkylating property of nitro-imidazole radiosensitizers is required for induction of murine retinal degeneration. Vet Pathol 33:625Google Scholar
  146. Parker LL, Lacy SM, Farrugia LJ, Evans C, Robins DJ, O’Hare CC, Hartley JA, Jaffar M, Stratford IJ (2004) A novel design strategy for stable metal complexes of nitrogen mustards as bioreductive prodrugs. J Med Chem 47:5683–5689PubMedCrossRefGoogle Scholar
  147. Patterson AV, Barham HM, Chinje EC, Adams GE, Harris AL, Stratford IJ (1995) Importance of P450 reductase activity in determining sensitivity of breast tumour cells to the bioreductive drug, tirapazamine (SR 4233). Br J Cancer 72:1144–1150PubMedGoogle Scholar
  148. Patterson AV, Saunders MP, Chinje EC, Talbot DA, Harris AL, Stratford IJ (1997) Overexpression of human NADPH:cytochrome c (P450) reductase confers enhanced sensitivity to both tirapazamine (SR 4233) and RSU 1069. Br J Cancer 76:1338–1347PubMedGoogle Scholar
  149. Patterson AV, Williams KJ, Cowen RL, Jaffar M, Telfer BA, Saunders M, Airley R, Honess D, Van der Kogel AJ, Wolf CR, Stratford IJ (2002) Oxygen-sensitive enzyme-prodrug gene therapy for the eradication of radiation-resistant solid tumours. Gene Ther 9:946–954PubMedCrossRefGoogle Scholar
  150. Patterson LH (1993) Rationale for the use of aliphatic N-oxides of cytotoxic anthraquinones as prodrug DNA binding agents: a new class of bioreductive agent. Cancer Met Rev 12:119–134CrossRefGoogle Scholar
  151. Patterson LH, McKeown SR (2000) AQ4N: a new approach to hypoxia-activated cancer chemotherapy. Br J Cancer 83:1589–1593PubMedCrossRefGoogle Scholar
  152. Patterson LH, Craven MR, Fisher GR, Teesdale-Spittle P (1994) Aliphatic amine N-oxides of DNA binding agents as bioreductive drugs. Oncol Res 6:533–538PubMedGoogle Scholar
  153. Patterson LH, McKeown SR, Robson T, Gallagher R, Raleigh SM, Orr S (1999) Antitumour prodrug development using cytochrome P450 (CYP) mediated activation. Anticancer Drug Des 14:473–486PubMedGoogle Scholar
  154. Patterson LH, McKeown SR, Ruparelia K, Double JA, Bibby MC, Cole S, Stratford IJ (2000) Enhancement of chemotherapy and radiotherapy of murine tumours by AQ4N, a bioreductively activated anti-tumour agent. Br J Cancer 82:1984–1990PubMedCrossRefGoogle Scholar
  155. Perez-Reyez E, Kalyanaraman B, Mason RP (1980) The reductive metabolism of metronidazole and ronidazole by aerobic liver microsomes. Mol Pharmacol 17:239–244Google Scholar
  156. Peters KB, Brown JM (2002) Tirapazamine: a hypoxia-activated topoisomerase II poison. Cancer Res 62:5248–5253PubMedGoogle Scholar
  157. Peters KB, Wang H, Brown JM, Iliakis G (2001) Inhibition of DNA replication by tirapazamine. Cancer Res 61:5425–5431PubMedGoogle Scholar
  158. Phillips RM (1996) Bioreductive activation of a series of analogues of 5-aziridinyl-3-hydroxymethyl-1-methyl-2-[1Hindole-4,7-dione]prop-beta-en-alpha-ol (EO9) by human DT-diaphorase. Biochem Pharmacol 52:1711–1718PubMedCrossRefGoogle Scholar
  159. Plumb JA, Gerritsen M, Workman P (1994) DT-diaphorase protects cells from the hypoxic cytotoxicity of indoloquinone EO9. Br J Cancer 70:1136–1143PubMedGoogle Scholar
  160. Powel J von, Roemeling R von, Gatzemeier U, Boyer M, Elisson LO, Clark P, Talbot S, Rey A, Butler TW, Hirsh V, Olver I, Bergman B, Ayoub J, Ricahrdson G, Dunlop D, Arcenas A, Vescio R, Viallet J, Treat J (2000) Tirapazamine plus cisplatin versus cisplatin in advanced non-small-cell lung cancer: a report of the international CATAPULT I study group. J Clin Oncol 18:1351–1359Google Scholar
  161. Pritsos CA, Sartorelli AC (1986) Generation of reactive oxygen radicals through bioactivation of mitomycin antibiotics. Cancer Res 46:3528–3532PubMedGoogle Scholar
  162. Raleigh SM, Wanogho E, Burke MD, McKeown SR, Patterson LH (1998) Involvement of human cytochromes P450 (CYP) in the reductive metabolism of AQ4N, a hypoxia activated anthraquinone di-N-oxide prodrug. Int J Radiat Oncol Biol Phys 42:763–767PubMedCrossRefGoogle Scholar
  163. Raleigh SM, Wanogho E, Burke MD and Patterson LH (1999) Rat cytochromes P450 (CYP) specifically contribute to the reductive bioactivation of AQ4N, an alkylaminoanthraquinone-di-N-oxide anticancer drug. Xenobiotica 29:1115–1122PubMedCrossRefGoogle Scholar
  164. Rauth AM, McClelland RA, Michaels HB, Battistella R (1984) The oxygen dependence of the reduction of nitroimidazoles in a radiolytic model system. Int J Radiat Oncol Biol Phys 10:1323–1326PubMedGoogle Scholar
  165. Reynolds TY, Rockwell S, Glazer PM (1996) Genetic instability induced by the tumor microenvironment. Cancer Res 56:5754–5757PubMedGoogle Scholar
  166. Riley RJ, Workman P (1992) Enzymology of the reduction of the potent benzotriazine-di-N-oxide hypoxic cell cytotoxin SR 4233 (WIN 59075) by NAD(P)H: (quinone acceptor) oxidoreductase (EC 1.6.99.2) purified from Walker 256 rat tumour cells. Biochem Pharmacol 43:167–174PubMedCrossRefGoogle Scholar
  167. Riley RJ, Hemingway SA, Graham MA, Workman P (1993) Initial characterization of the major mouse cytochrome P450 enzymes involved in the reductive metabolism of the hypoxic cytotoxin 3-amino-1,2,4-benzotriazine-1,4-di-Noxide (tirapazamine, SR 4233, WIN 59075). Biochem Pharmacol 45:1065–1077PubMedCrossRefGoogle Scholar
  168. Rischin D, Peters L, Hicks R, Hughes P, Fisher R, Hart R, Sexton M, D’Costa I, Roemeling R von (2001) Phase I trial of concurrent tirapazamine, cisplatin, and radiotherapy in patients with advanced head and neck cancer. J Clin Oncol 19:535–542PubMedGoogle Scholar
  169. Rischin D, Peters L, Fisher R, Macann A, Danham J, Poulsen M, Jackson M, Kenny L, Penniment M, Corry J, Lamb D, McClure B (2005) Tirapazamine, cisplatin, and radiation versus fluorouracil, cisplatin, and radiation in patients with locally advanced head and neck cancer: a randomized Phase-II trial of the trans-Tasman radiation oncology group (TROG 98.02). J Clin Oncol 23:79–87PubMedCrossRefGoogle Scholar
  170. Roberts PB, Anderson RF, Wilson WR (1987) Hypoxia-selective radiosensitization of mammalian cells by nitracrine, an electron-affinic DNA intercalator. Int J Radiat Biol Relat Stud Phys Chem Med 51:641–654PubMedGoogle Scholar
  171. Roberts KB, Urdaneta N, Vera R, Vera A, Gutierrez E, Aguilar Y, Ott S, Medina I, Sempere P, Rockwell S, Sartorelli AC, Fischer DB, Fischer JJ (2000) Interim results of a randomized trial of mitomycin C as an adjunct to radical radiotherapy in the treatment of locally advanced squamous-cell carcinoma of the cervix. Int J Cancer 90:206–223PubMedCrossRefGoogle Scholar
  172. Rockwell S (1997) Oxygen delivery: implications for the biology and therapy of solid tumors. Oncol Res 9:383–390PubMedGoogle Scholar
  173. Rockwell S, Kennedy KA (1979) Combination therapy with radiation and mitomycin C: preliminary results with EMT6 tumor cells in vitro and in vivo. Int J Radiat Oncol Biol Phys 5:1673–1676PubMedGoogle Scholar
  174. Rockwell S, Kennedy KA, Sartorelli AC (1982) Mitomycin C as a prototype bioreductive alkylating agent: in vitro studies of metabolism and cytotoxicity. Int J Radiat Oncol Biol Phys 8:753–755PubMedGoogle Scholar
  175. Rockwell S, Mate TP, Irvin CG, Nierenburg M (1986) Reactions of tumors and normal tissues in mice to irradiation in the presence and absence of a perfluorochemical emulsion. Int J Radiat Oncol Biol Phys 12:1315–1318PubMedGoogle Scholar
  176. Rockwell S, Keyes SR, Sartorelli AC (1988) Preclinical studies of porfiromycin as adjunct to radiotherapy. Radiat Res 116:100–113PubMedGoogle Scholar
  177. Rodriguez GI, Valdivieso M, Hoff DD von, Kraut M, Burris HA, Eckardt JR, Lockwood G, Kennedy H, Roemeling R von (1996) A phase I/II trial of the combination of tirapazamine and cisplatin in patients with non-small cell lung cancer (NSCLC). Proc Am Assoc Cancer Res 15:382Google Scholar
  178. Rofstad EK (2000) Microenvironment-induced cancer metastasis. Int J Radiat Biol:76 589–605PubMedCrossRefGoogle Scholar
  179. Ryan HE, Lo J, Johnson RS (1998) HIF-1 alpha is required for solid tumor formation and embryonic vascularization. EMBO J 17:3005–3015PubMedCrossRefGoogle Scholar
  180. Saarilahti K, Kajanti M, Atula T, Makitie A, Aaltonen L-M, Kouri M, Mantyla M (2004) Biweekly escalated, accelerated hyperfractionated radiotherapy with concomitant single-dose mitomycin C results in a high rate of local control in advanced laryngeal and hypopharyngeal cancer. Am J Clin Oncol 27:589–594PubMedCrossRefGoogle Scholar
  181. Schellens JHM, Planting AST, Van Acker BAC, Loos WJ, De Boer-Denert M, Van der Burg MEL, Koier I, Krediet RT, Stoter G, Verweij J (1994) Phase I and pharmacologic study of the novel indoloquinone bioreductive alkylating cytotoxic drug EO9. J Natl Cancer Inst 86:906–912PubMedGoogle Scholar
  182. Semenza GL (2001) Hypoxia-inducible factor 1: oxygen homeostasis and disease pathophysiology. Trends Mol Med 7:345–350PubMedCrossRefGoogle Scholar
  183. Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3:721–732PubMedCrossRefGoogle Scholar
  184. Sheldon PW, Fowler JF (1978) Radiosensitization by misonidazole (Ro-07-0582) of fractionated X-rays in murine tumour. Br J Cancer 37:243–245Google Scholar
  185. Shibaji T, Nagao M, Ikeda N, Kanehiro H, Hisanaga M, Ko S, Fukumoto A, Nakajima Y (2003) Prognostic significance of HIF-1 alpha overexpression in human pancreatic cancer. Anticancer Res 23:4721–4727PubMedGoogle Scholar
  186. Shibamoto Y, Zhou L, Hatta H, Mayuko M, Nishimoto S (2000) A novel class of antitumor prodrug, 1-(2’-oxopropyl)-5-fluorouracil (OFU001), that releases 5-fluorouracil upon hypoxic irradiation. Jpn J Cancer Res 91:433–438PubMedGoogle Scholar
  187. Shibamoto Y, Zhou L, Hatta H, Mori M, Nishimoto S (2001) In vivo evaluation of a novel antitumor prodrug, 1-(2′-oxopropyl)-5-fluorouracil (OFU001), which releases 5-fluorouracil upon hypoxic irradiation. Int J Radiat Biol Phys 49:407–413CrossRefGoogle Scholar
  188. Shibamoto Y, Tachi Y, Tanabe K, Hatta H, Nishimoto S (2004) In vitro and in vivo evaluation of novel antitumor prodrugs of 5-fluoro-2′-deoxyuridine activated by hypoxic irradiation. Int J Radiat Biol Phys 58:397–402CrossRefGoogle Scholar
  189. Shibata T, Giaccia AJ, Brown JM (2002) Hypoxia-inducible regulation of a prodrug-activating enzyme for tumor-specific gene therapy. Neoplasia 4:40–48PubMedCrossRefGoogle Scholar
  190. Shweiki D, Itin A, Soffer D, Keshet E (1992) Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 359:843–845PubMedCrossRefGoogle Scholar
  191. Siim BG, Van Zijl P, Brown JM (1996) Tirapazamine-induced DNA damage measured using the comet assay correlates with cytotoxicity towards hypoxic tumour cells in vitro. Br J Cancer 73:952–960PubMedGoogle Scholar
  192. Siim BG, Denny WA, Wilson WR (1997) Nitro reduction as an electronic switch for bioreductive drug activation. Oncol Res 9:357–369PubMedGoogle Scholar
  193. Simpson JR, Bauer M, Perez CA, Wasserman TH, Emami B, Doggett RL, Byhardt RW, Phillips TL, Mowry PA (1989) Radiation therapy alone or combined with misonidazole in the treatment of locally advanced non-small cell lung cancer: report of an RTOG prospective randomized trial. Int J Radiat Oncol Biol Phys 16:1483–1491PubMedGoogle Scholar
  194. Smith PJ, Blunt NJ, Desnoyers R, Giles Y, Patterson LH (1997a) DNA topoisomerase II-dependent cytotoxicity of alkyklaminoanthraquinones and their N-oxides. Cancer Chemother Pharmacol 39:455–461PubMedCrossRefGoogle Scholar
  195. Smith PJ, Desnoyers R, Blunt N, Giles Y, Patterson LH, Watson JV (1997b) Flow cytometric analysis and confocal imaging of the anticancer alkylaminoanthraquinones and their Noxides in intact human cells using 647-nm krypton laser excitation. Cytometry 27:43–53PubMedCrossRefGoogle Scholar
  196. Smithen CE, Clarke ED, Dale JA, Jacobs RS, Wardman P, Watts ME, Woodcock M (1980) Novel (nitro-1-imidazolyl)alkanolamines as potential radiosensitisers with improved therapeutic properties. In: Brady LW (ed) Radiation sensitizers: their use in the clinical management of cancer. Masson, New York, pp 22–32Google Scholar
  197. Song CW, Park H, Griffin R (2001) Improvement of tumor oxygenation by mild hyperthermia. Radiat Res 155:515–528PubMedCrossRefGoogle Scholar
  198. Squillace DP, Ruben SL, Reid JM, Ames MM (2000) HPLC analysis and murine pharmacokinetics of the cytotoxic bioreductive agent NLCQ-1 (NSC 709257). Proc Am Assoc Cancer Res 41:706Google Scholar
  199. Stoeltzing O, McCarty MF, Wey JS, Fan F, Liu W, Belcheva A, Bucana CD, Semenza GL, Ellis LM (2004) Role of hypoxia-inducible factor 1α in gastric cancer cell growth, angiogenesis, and vessel maturation. J Natl Cancer Inst 96:946–956PubMedCrossRefGoogle Scholar
  200. Stratford IJ (1982) Mechanisms of hypoxic cell radiosensitizers and the development of new sensitizers. Int J Radiat Oncol Biol Phys 8:391–398PubMedGoogle Scholar
  201. Stratford IJ, Walling JM, Silver ARJ (1986) The differential toxicity of RSU 1069: cell survival studies indicating interaction with DNA as possible mode of action. Br J Cancer 53:339–344PubMedGoogle Scholar
  202. Sun X, Liu M, Wei Y, Liu F, Zhi X, Xu R, Krissansen GW (2005) Overexpression of von Hippel-Lindau tumor suppressor protein and antisense HIF-1alpha eradicates glioma. Cancer Gene TherGoogle Scholar
  203. Sutherland RM (1974) Selective chemotherapy of noncycling cells in an in vitro tumor model. Cancer Res 34:3501–3503PubMedGoogle Scholar
  204. Tan C, Noronha RG de, Roecker AJ, Pyrzynska B, Khwaja F, Zhang Z, Zhang H, Teng Q, Nicholson AC, Giannakakou P, Zhou W, Olson JJ, Pereira MM, Nicolaou KC, Van Meir EG (2005) Identification of a novel small-molecule inhibitor of the hypoxia-inducible factor 1 pathway. Cancer Res 65:605–612PubMedGoogle Scholar
  205. Teicher BA, Rose CM (1984) Oxygen-carrying perfluorochemical emulsion as an adjuvant to radiation therapy in mice. Cancer Res 44:4285–4288PubMedGoogle Scholar
  206. Teicher BA, Herman TS, Holden SA, Rudolph MB (1991) Effect of oxygenation, pH and hyperthermia on RSU-1069 in vitro and in vivo with radiation in the FSaIIC murine fibrosarcoma. Cancer Lett 59:109–117PubMedCrossRefGoogle Scholar
  207. Tercel M, Lee AE, Hogg A, Anderson RF, Lee HH, Siim BG, Denny WA, Wilson WR (2001) Hypoxia-selective antitumor agents. 16. Nitroarylmethyl quaternary salts as bioreductive prodrugs of the alkylating agent mechlorethamine. J Med Chem 44:3511–3522PubMedCrossRefGoogle Scholar
  208. Theodoropoulos VE, Lazaris AC, Sofras F, Gerzelis I, Tsoukala V, Ghikonti I, Manikas K, Kastriotis I (2004) Hypoxia-inducible factor 1 alpha expression correlates with angiogenesis and unfavorable prognosis in bladder cancer. Eur Urol 46:200–208PubMedCrossRefGoogle Scholar
  209. Thomlinson RH, Gray LH (1955) The histological structure of some human lung cancers and the possible implications for radiotherapy. Br J Cancer 9:539–549PubMedGoogle Scholar
  210. Tomasz M, Lipman R, Chowdary D, Pawlak J, Verdine GL, Nakanishi K (1987) Isolation and structure of a covalent cross-link adduct between mitomycin C and DNA. Science 235:1204–1208PubMedGoogle Scholar
  211. Torre MH, Gambino D, Araujo J, Cerecetto H, Gonzalez M, Lavaggi ML, Azqueta A, Lopez De Cerain A, Vega AM, Abram U, Costa-Filho AJ (2005) Novel Cu(II) quinoxaline N1, N4-dioxide complexes as selective hypoxic cytotoxins. Eur J Med Chem 40:473–480PubMedCrossRefGoogle Scholar
  212. Treat J, Johnson E, Langer C, Belani C, Haynes B, Greenberg R, Rodriguez R, Drobins P, Miller W Jr, Meehan L, McKeon A, Devin J, Roemeling R von, Viallen R (1998) Tirapazamine with cisplatin in patients with advanced non-small-cell lung cancer: a phase II study. J Clin Oncol 16:3524–3527PubMedGoogle Scholar
  213. Trotter MJ, Chaplin DJ, Olive PL (1989) Use of a carbocyanine dye as a marker of functional vasculature in murine tumours. Br J Cancer 59:706–709PubMedGoogle Scholar
  214. Unruh A, Ressel A, Mohamed HG, Johnson RS, Nadrowitz R, Richter E, Katschinski DM, Wenger RH (2003) The hypoxiainducible factor-1α is a negative factor for tumor therapy. Oncogene 22:3213–3220PubMedCrossRefGoogle Scholar
  215. Urtasun RC, Band P, Chapman JD, Feldstein ML, Mielke B, Fryer C (1976) Radiation and high dose metronidazole in supratentorial glioblastomas. N Engl J Med 294:1364–1367PubMedGoogle Scholar
  216. Urtasun RC, Palmer M, Kinney B, Belch A, Hewit J, Hanson J (1998) Intervention with the hypoxic tumor cell sensitizer etanidazole in the combined modality treatment of limited stage small-cell lung cancer. A one-institution study. Int J Radiat Oncol Biol Phys 40:337–342PubMedCrossRefGoogle Scholar
  217. Van den Bogaert W, Van den Schueren E, Horiot J-C, De Vilhena M, Schraub S, Svoboda V, Arcangeli G, De Pauw M, van Glabbeke M (1995) The EORTC randomized trial on three fractions per day and misonidazole (trial no. 22811) in advanced head and neck cancer: long-term results and side effects. Radiother Oncol 35:91–99PubMedCrossRefGoogle Scholar
  218. Varghese AJ, Gulyas S, Mohindra JK (1976) Hypoxia-dependent reduction of 1-(2-nitro-1-imidazolyl)3-methoxy-2-propanol by Chinese hamster ovary cells and KHT tumor cells in vitro and in vivo. Cancer Res 36:3761–3765PubMedGoogle Scholar
  219. Volpato M, Seargent J, Loadman PM, Phillips RM (2005) Formation of DNA interstrand cross-links as a marker of mitomycin C bioreductive activation and chemosensitivity. Eur J Cancer 41:1331–1338PubMedCrossRefGoogle Scholar
  220. Walton MI, Workman P (1987) Nitroimidazole bioreductive metabolism. Quantitation and characterisation of mouse tissue benznidazole nitroreductases in vivo and in vitro. Biochem Pharmacol 36 887–896PubMedCrossRefGoogle Scholar
  221. Walton MI, Workman P (1993) Pharmacokinetics and bioreductive metabolism of the novel benzotriazine di-Noxide hypoxic cell cytotoxin tirapazamine (WIN 59075; SR 4233; NSC 130181) in mice. J Pharmacol Exp Ther 265:938–947PubMedGoogle Scholar
  222. Walton MI, Wolf CR, Workman P (1992) The role of cytochrome P450 and cytochrome P450 reductase in the reductive bioactivation of the novel benzotriazine di-N-oxide hypoxic cytotoxin 3-amino-1,2,4-benzotriazine-1,4-dioxide (SR 4233, WIN 59075) by mouse liver. Biochem Pharmacol 44:251–259PubMedCrossRefGoogle Scholar
  223. Wang J, Biedermann KA, Brown JM (1992) Repair of DNA and chromosome breaks in cells exposed to SR 4233 under hypoxia or to ionizing radiation. Cancer Res 52:4473–4477PubMedGoogle Scholar
  224. Wang J, Biedermann KA, Wolf CR, Brown JM (1993) Metabolism of the bioreductive cytotoxin SR 4233 by tumour cells: enzymatic studies. Br J Cancer 67:321–325PubMedGoogle Scholar
  225. Wardman P (2001) Electron transfer and oxidative stress as key factors in the design of drugs selectively active in hypoxia. Curr Med Chem 8:739–761PubMedGoogle Scholar
  226. Wardman P, Clarke ED (1976) Oxygen inhibition of nitroreductase: electron transfer from nitro radical-anions to oxygen. Biochem Biophys Res Commun 69:942–949PubMedCrossRefGoogle Scholar
  227. Wardman P, Dennis MF, Everett SA, Patel KB, Stratford MR, Tracy M (1995) Radicals from one-electron reduction of nitro compounds, aromatic N-oxides and quinones: the kinetic basis of hypoxia-selective, bioreductive drugs. Biochem Soc Symp 61:171–194PubMedGoogle Scholar
  228. Ware DC, Palmer BD, Wilson WR, Denny WA (1993) Hypoxia-selective antitumor agents. 7. Metal complexes of aliphatic mustards as a new class of hypoxia-selective cytotoxins. Synthesis and evaluation of cobalt(III) complexes of bidentate mustards. J Med Chem 36:1839–1846PubMedCrossRefGoogle Scholar
  229. Watson ER, Halnan KE, Dische S, Saunders MI, Cade IS, Mcewen JB, Wiernik G, Perrins DJD, Sutherland I (1978) Hyperbaric oxygen and radiotherapy: a Medical Research Council trial in carcinoma of the cervix. Br J Radiol 51:879–887PubMedCrossRefGoogle Scholar
  230. Weissberg JB, Son YH, Papac RJ, Sasaki CT, Fischer DB, Lawrence R, Rockwell S, Sartorelli AC, Fischer JJ (1989) Randomized clinical trial of mitomycin C as an adjunct to radiotherapy in head and neck cancer. Int J Radiat Oncol Biol Phys 17:3–9PubMedGoogle Scholar
  231. Whitmore GF, Gulyas S (1986) Studies on the toxicity of RSU-1069. Int J Radiat Oncol Biol Phys 12:1219–1222PubMedGoogle Scholar
  232. Widder J, Dobrowsky W, Schmid R, Pokrajac B, Selzer E, Potter R (2004) Hyperfractionated accelerated radiochemotherapy (HFA-RCT) with mitomycin C for advanced head and neck cancer. Radiother Oncol 73:173–177PubMedCrossRefGoogle Scholar
  233. Williams KJ, Telfer BA, Xenaki D, Sheridan MR, Desbaillets I, Peters HJW, Honess D, Harris AL, Dachs GU, Van der Kogel A, Stratford IJ (2005) Enhanced response to radiotherapy in tumours deficient in the function of hypoxia-inducible factor-1. Radiother Oncol 75:89–98PubMedCrossRefGoogle Scholar
  234. Wilson WR, Denny WA, Stewart GM, Fenn A, Probert JC (1986) Reductive metabolism and hypoxia-selective toxicity of nitracrine. Int J Radiat Oncol Biol Phys 12:1235–1238PubMedGoogle Scholar
  235. Wilson WR, Van Zijl P, Denny WA (1992) Bis-bioreductive agents as hypoxia-selective cytotoxins: nitracrine N-oxide. Int J Radiat Oncol Biol Phys 22:693–696PubMedGoogle Scholar
  236. Wilson WR, Moselen JW, Cliffe S, Denny WA, Ware DC (1994) Exploiting tumor hypoxia through bioreductive release of diffusible cytotoxins: the cobalt(III)-nitrogen mustard complex SN24771. Int J Radiat Oncol Biol Phys 29:323–327PubMedGoogle Scholar
  237. Wilson WR, Denny WA, Pullen SM, Thompson KM, Li AE, Patterson LH, Lee HH (1996) Tertiary amine N-oxides as bioreductive drugs: DACA N-oxide, nitracrine N-oxide and AQ4N. Br J Cancer 27(Suppl):S43–S47Google Scholar
  238. Wilson WR, Tercel M, Anderson RF, Denny WA (1998) Radiation-activated prodrugs as hypoxia-selective cytotoxins: model studies with nitroarylmetyl quaternary salts. Anticancer Drug Des 13 663–685PubMedGoogle Scholar
  239. Wilson WR, Pullen SM, Hogg A, Helsby NA, Hicks KO, Denny WA (2002) Quantitation of bystander effects in nitroreductase suicide gene therapy using three-dimensional cell cultures. Cancer Res 62:1425–1432PubMedGoogle Scholar
  240. Wilson WR, Edmunds SJ, Valentines S (2005) Mechanism of action and antitumour activity of PR-104, a dinitrobenzamide mustard pre-prodrug that is activated selectively under hypoxia. National Cancer Research Institute Conference, Birmingham, UKGoogle Scholar
  241. Workman P, Stratford IJ (1993) The experimental development of bioreductive drugs and their role in cancer therapy. Cancer Met Rev 12:73–82CrossRefGoogle Scholar
  242. Wouters BG, Brown JM (1997) Cells at intermediate oxygen levels can be more important than the “hypoxic fraction” in determining tumor response to fractionated radiotherapy. Radiat Res 147:541–55PubMedGoogle Scholar
  243. Zeman EM, Brown JM, Lemmon MJ, Hirst VK, Lee WW (1986) SR-4233: a new bioreductive agent with high selective toxicity for hypoxic mammalian cells. Int J Radiat Oncol Biol Phys 12:1239–1242PubMedGoogle Scholar
  244. Zhong XS, Zheng JZ, Reed E, Jiang B-H (2004) SU5416 inhibited VEGF and HIF-1alpha expression through the PI3K/AKT/p70S6K1 signaling pathway. Biochem Biophys Res Commun 324:471–480PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2006

Authors and Affiliations

  • G-One Ahn
    • 1
  • J. Martin Brown
    • 1
  1. 1.Division of Radiation and Cancer Biology, Department of Radiation OncologyStanford School of MedicineStanfordUSA

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