International Journal of Radiation Oncology * Biology * Physics
Volume 73, Issue 4 , Pages 988-996 , 15 March 2009

On the Path to Seeking Novel Radiosensitizers

  • David Katz, M.Sc.

      Affiliations

    • Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
    • Division of Applied Molecular Oncology, University Health Network, Toronto, ON, Canada
  • ,
  • Emma Ito, M.Sc.

      Affiliations

    • Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
    • Division of Applied Molecular Oncology, University Health Network, Toronto, ON, Canada
  • ,
  • Fei-Fei Liu, M.D., F.R.C.P.C.

      Affiliations

    • Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
    • Division of Applied Molecular Oncology, University Health Network, Toronto, ON, Canada
    • Department of Radiation Oncology, Princess Margaret Hospital, University Health Network, Toronto, ON, Canada
    • Department of Radiation Oncology, University of Toronto, Toronto, ON, Canada
    • Corresponding Author InformationReprint requests to: Fei-Fei Liu, M.D., F.R.C.P.C., Department of Radiation Oncology, Princess Margaret Hospital/Ontario Cancer Institute, 610 University Avenue, Room 7-719, Toronto, ON, Canada M5G 2M9. Tel: (416) 946-2123; Fax: (416) 946-4586

Received 7 August 2008 ,Revised 29 November 2008 ,Accepted 2 December 2008.

References 

  1. Pow EH, Kwong DL, McMillan AS, et al. Xerostomia and quality of life after intensity-modulated radiotherapy vs. conventional radiotherapy for early-stage nasopharyngeal carcinoma: Initial report on a randomized controlled clinical trial. Int J Radiat Oncol Biol Phys. 2006;66:981–991
  2. DeVita VT, Hellman S, Rosenberg SA. Cancer, principles & practice of oncology. 7th ed.. Philadelphia, PA: Lippincott Williams & Wilkins; 2005;
  3. Riley PA. Free radicals in biology: Oxidative stress and the effects of ionizing radiation. Int J Radiat Biol. 1994;65:27–33
  4. Lewanski CR, Gullick WJ. Radiotherapy and cellular signalling. Lancet Oncol. 2001;2:366–370
  5. Falck J, Mailand N, Syljuasen RG, et al. The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis. Nature. 2001;410:842–847
  6. Hopfner KP, Putnam CD, Tainer JA. DNA double-strand break repair from head to tail. Curr Opin Struct Biol. 2002;12:115–122
  7. Bedford JS, Mitchell JB, Griggs HG, et al. Radiation-induced cellular reproductive death and chromosome aberrations. Radiat Res. 1978;76:573–586
  8. Watson GE, Lorimore SA, Macdonald DA, et al. Chromosomal instability in unirradiated cells induced in vivo by a bystander effect of ionizing radiation. Cancer Res. 2000;60:5608–5611
  9. Steel GG, Peckham MJ. Exploitable mechanisms in combined radiotherapy-chemotherapy: The concept of additivity. Int J Radiat Oncol Biol Phys. 1979;5:85–91
  10. Bentzen SM, Harari PM, Bernier J. Exploitable mechanisms for combining drugs with radiation: Concepts, achievements and future directions. Nat Clin Pract Oncol. 2007;4:172–180
  11. Belli JA, Dicus GJ, Bonte FJ. Radiation response of mammalian tumor cells. I. Repair of sublethal damage in vivo. J Natl Cancer Inst. 1967;38:673–682
  12. Shrieve DC, Harris JW. The in vitro sensitivity of chronically hypoxic EMT6/SF cells to X-radiation and hypoxic cell radiosensitizers. Int J Radiat Biol Relat Stud Phys Chem Med. 1985;48:127–138
  13. Pettersen EO, Wang H. Radiation-modifying effect of oxygen in synchronized cells pre-treated with acute or prolonged hypoxia. Int J Radiat Biol. 1996;70:319–326
  14. Moeller BJ, Dreher MR, Rabbani ZN, et al. Pleiotropic effects of HIF-1 blockade on tumor radiosensitivity. Cancer Cell. 2005;8:99–110
  15. Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003;3:721–732
  16. Moeller BJ, Cao Y, Li CY, et al. Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors: Role of reoxygenation, free radicals, and stress granules. Cancer Cell. 2004;5:429–441
  17. Williams KJ, Telfer BA, Xenaki D, et al. Enhanced response to radiotherapy in tumours deficient in the function of hypoxia-inducible factor-1. Radiother Oncol. 2005;75:89–98
  18. Dewhirst MW, Cao Y, Moeller B. Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response. Nat Rev Cancer. 2008;8:425–437
  19. Ryan HE, Lo J, Johnson RS. HIF-1 alpha is required for solid tumor formation and embryonic vascularization. EMBO J. 1998;17:3005–3015
  20. Geng L, Donnelly E, McMahon G, et al. Inhibition of vascular endothelial growth factor receptor signaling leads to reversal of tumor resistance to radiotherapy. Cancer Res. 2001;61:2413–2419
  21. Chapman JD. Hypoxic sensitizers—implications for radiation therapy. N Engl J Med. 1979;301:1429–1432
  22. Overgaard J, Hansen HS, Overgaard M, et al. A randomized double-blind phase III study of nimorazole as a hypoxic radiosensitizer of primary radiotherapy in supraglottic larynx and pharynx carcinoma. Results of the Danish Head and Neck Cancer Study (DAHANCA) Protocol 5-85. Radiother Oncol. 1998;46:135–146
  23. Overgaard J. Hypoxic radiosensitization: Adored and ignored. J Clin Oncol. 2007;25:4066–4074
  24. Brown JM. SR 4233 (tirapazamine): A new anticancer drug exploiting hypoxia in solid tumours. Br J Cancer. 1993;67:1163–1170
  25. Rischin D, Peters L, Fisher R, et al. 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. 2005;23:79–87
  26. Craighead PS, Pearcey R, Stuart G. A phase I/II evaluation of tirapazamine administered intravenously concurrent with cisplatin and radiotherapy in women with locally advanced cervical cancer. Int J Radiat Oncol Biol Phys. 2000;48:791–795
  27. Eastman A, Barry MA. Interaction of trans-diamminedichloroplatinum(II) with DNA: Formation of monofunctional adducts and their reaction with glutathione. Biochemistry. 1987;26:3303–3307
  28. Richmond RC, Khokhar AR, Teicher BA, et al. Toxic variability and radiation sensitization by Pt(II) analogs in Salmonella typhimurium cells. Radiat Res. 1984;99:609–626
  29. Yang LX, Douple EB, Wang HJ. Irradiation enhances cellular uptake of carboplatin. Int J Radiat Oncol Biol Phys. 1995;33:641–646
  30. Amorino GP, Freeman ML, Carbone DP, et al. Radiopotentiation by the oral platinum agent, JM216: Role of repair inhibition. Int J Radiat Oncol Biol Phys. 1999;44:399–405
  31. Marino P, Preatoni A, Cantoni A. Randomized trials of radiotherapy alone versus combined chemotherapy and radiotherapy in stages IIIa and IIIb nonsmall cell lung cancer. A meta-analysis. Cancer. 1995;76:593–601
  32. Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med. 2004;350:1945–1952
  33. Rose PG, Bundy BN, Watkins EB, et al. Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med. 1999;340:1144–1153
  34. Cividalli A, Ceciarelli F, Livdi E, et al. Radiosensitization by oxaliplatin in a mouse adenocarcinoma: Influence of treatment schedule. Int J Radiat Oncol Biol Phys. 2002;52:1092–1098
  35. Kraker AJ, Moore CW. Accumulation of cis-diamminedichloroplatinum(II) and platinum analogues by platinum-resistant murine leukemia cells in vitro. Cancer Res. 1988;48:9–13
  36. Raymond E, Faivre S, Woynarowski JM, et al. Oxaliplatin: Mechanism of action and antineoplastic activity. Semin Oncol. 1998;25:4–12
  37. Freyer G, Bossard N, Romestaing P, et al. Addition of oxaliplatin to continuous fluorouracil, l-folinic acid, and concomitant radiotherapy in rectal cancer: The Lyon R 97-03 phase I trial. J Clin Oncol. 2001;19:2433–2438
  38. Hickman MJ, Samson LD. Role of DNA mismatch repair and p53 in signaling induction of apoptosis by alkylating agents. Proc Natl Acad Sci U S A. 1999;96:10764–10769
  39. Hermisson M, Klumpp A, Wick W, et al. O6-methylguanine DNA methyltransferase and p53 status predict temozolomide sensitivity in human malignant glioma cells. J Neurochem. 2006;96:766–776
  40. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987–996
  41. Grem JL. 5-Fluorouracil: Forty-plus and still ticking. A review of its preclinical and clinical development. Invest New Drugs. 2000;18:299–313
  42. Lawrence TS, Davis MA, Chang EY, et al. Lack of dependence of 5-fluorodeoxyuridine-mediated radiosensitization on cytotoxicity. Radiat Res. 1995;143:281–285
  43. Davis MA, Tang HY, Maybaum J, et al. Dependence of fluorodeoxyuridine-mediated radiosensitization on S phase progression. Int J Radiat Biol. 1995;67:509–517
  44. Cooper JS, Guo MD, Herskovic A, et al. Chemoradiotherapy of locally advanced esophageal cancer: Long-term follow-up of a prospective randomized trial (RTOG 85-01). Radiation Therapy Oncology Group. J Am Med Assoc. 1999;281:1623–1627
  45. Morris M, Eifel PJ, Lu J, et al. Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med. 1999;340:1137–1143
  46. Bartelink H, Roelofsen F, Eschwege F, et al. Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: Results of a phase III randomized trial of the European Organization for Research and Treatment of Cancer Radiotherapy and Gastrointestinal Cooperative Groups. J Clin Oncol. 1997;15:2040–2049
  47. Sawada N, Ishikawa T, Sekiguchi F, et al. X-ray irradiation induces thymidine phosphorylase and enhances the efficacy of capecitabine (Xeloda) in human cancer xenografts. Clin Cancer Res. 1999;5:2948–2953
  48. Blackstock AW, Lesser GJ, Fletcher-Steede J, et al. Phase I study of twice-weekly gemcitabine and concurrent thoracic radiation for patients with locally advanced non-small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2001;51:1281–1289
  49. Talamonti MS, Small W, Mulcahy MF, et al. A multi-institutional phase II trial of preoperative full-dose gemcitabine and concurrent radiation for patients with potentially resectable pancreatic carcinoma. Ann Surg Oncol. 2006;13:150–158
  50. Shewach DS, Hahn TM, Chang E, et al. Metabolism of 2',2'-difluoro-2'-deoxycytidine and radiation sensitization of human colon carcinoma cells. Cancer Res. 1994;54:3218–3223
  51. Flanagan SA, Robinson BW, Krokosky CM, et al. Mismatched nucleotides as the lesions responsible for radiosensitization with gemcitabine: A new paradigm for antimetabolite radiosensitizers. Mol Cancer Ther. 2007;6:1858–1868
  52. Winterbourn CC. Reconciling the chemistry and biology of reactive oxygen species. Nat Chem Biol. 2008;4:278–286
  53. 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;49:1381–1390
  54. Mehta MP, Rodrigus P, Terhaard CH, et al. Survival and neurologic outcomes in a randomized trial of motexafin gadolinium and whole-brain radiation therapy in brain metastases. J Clin Oncol. 2003;21:2529–2536
  55. Sartor CI. Biological modifiers as potential radiosensitizers: Targeting the epidermal growth factor receptor family. Semin Oncol. 2000;27:15–20discussion 92–100
  56. Barrett DM, Black SM, Todor H, et al. Inhibition of protein-tyrosine phosphatases by mild oxidative stresses is dependent on S-nitrosylation. J Biol Chem. 2005;280:14453–14461
  57. Dent P, Reardon DB, Park JS, et al. Radiation-induced release of transforming growth factor alpha activates the epidermal growth factor receptor and mitogen-activated protein kinase pathway in carcinoma cells, leading to increased proliferation and protection from radiation-induced cell death. Mol Cell Biol. 1999;10:2493–2506
  58. Harari PM, Huang SM. Radiation response modification following molecular inhibition of epidermal growth factor receptor signaling. Semin Radiat Oncol. 2001;11:281–289
  59. Nasu S, Ang KK, Fan Z, et al. C225 antiepidermal growth factor receptor antibody enhances tumor radiocurability. Int J Radiat Oncol Biol Phys. 2001;51:474–477
  60. 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
  61. Huang SM, Bock JM, Harari PM. Epidermal growth factor receptor blockade with C225 modulates proliferation, apoptosis, and radiosensitivity in squamous cell carcinomas of the head and neck. Cancer Res. 1999;59:1935–1940
  62. Gupta AK, Bakanauskas VJ, Cerniglia GJ, et al. The Ras radiation resistance pathway. Cancer Res. 2001;61:4278–4282
  63. Rowinsky EK, Windle JJ, Von Hoff DD. Ras protein farnesyltransferase: A strategic target for anticancer therapeutic development. J Clin Oncol. 1999;17:3631–3652
  64. Cohen-Jonathan E, Muschel RJ, Gillies McKenna W, et al. Farnesyltransferase inhibitors potentiate the antitumor effect of radiation on a human tumor xenograft expressing activated HRAS. Radiat Res. 2000;154:125–132
  65. Bernhard EJ, McKenna WG, Hamilton AD, et al. Inhibiting Ras prenylation increases the radiosensitivity of human tumor cell lines with activating mutations of ras oncogenes. Cancer Res. 1998;58:1754–1761
  66. Hahn SM, Bernhard EJ, Regine W, et al. A Phase I trial of the farnesyltransferase inhibitor L-778,123 and radiotherapy for locally advanced lung and head and neck cancer. Clin Cancer Res. 2002;8:1065–1072
  67. Jain RK. Normalization of tumor vasculature: An emerging concept in antiangiogenic therapy. Science. 2005;307:58–62
  68. Murata R, Nishimura Y, Hiraoka M. An antiangiogenic agent (TNP-470) inhibited reoxygenation during fractionated radiotherapy of murine mammary carcinoma. Int J Radiat Oncol Biol Phys. 1997;37:1107–1113
  69. Corvo R. Evidence-based radiation oncology in head and neck squamous cell carcinoma. Radiother Oncol. 2007;85:156–170
  70. Pignon JP, Bourhis J, Domenge C, et al. Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: Three meta-analyses of updated individual data. MACH-NC Collaborative Group. Meta-Analysis of Chemotherapy on Head and Neck Cancer. Lancet. 2000;355:949–955
  71. Bourhis J, Calais G, Lapeyre M, et al. Concomitant radiochemotherapy or accelerated radiotherapy: Analysis of two randomized trials of the French Head and Neck Cancer Group (GORTEC). Semin Oncol. 2004;31:822–826
  72. Stockwell BR. Chemical genetics: Ligand-based discovery of gene function. Nat Rev Genet. 2000;1:116–125
  73. Friedman A, Perrimon N. A functional RNAi screen for regulators of receptor tyrosine kinase and ERK signalling. Nature. 2006;444:230–234
  74. Yip KW, Mao X, Au PY, et al. Benzethonium chloride: A novel anticancer agent identified by using a cell-based small-molecule screen. Clin Cancer Res. 2006;12:5557–5569
  75. Kolas NK, Chapman JR, Nakada S, et al. Orchestration of the DNA-damage response by the RNF8 ubiquitin ligase. Science. 2007;318:1637–1640
  76. Nieland TJ, Penman M, Dori L, et al. Discovery of chemical inhibitors of the selective transfer of lipids mediated by the HDL receptor SR-BI. Proc Natl Acad Sci U S A. 2002;99:15422–15427
  77. Katz D, Ito E, Lau KS, et al. Increased efficiency for performing colony formation assays in 96-well plates: Novel applications to combination therapies and high-throughput screening. Biotechniques. 2008;44:ix–xiv
  78. Lally BE, Geiger GA, Kridel S, et al. Identification and biological evaluation of a novel and potent small molecule radiation sensitizer via an unbiased screen of a chemical library. Cancer Res. 2007;67:8791–8799
  79. Hickson I, Zhao Y, Richardson CJ, et al. Identification and characterization of a novel and specific inhibitor of the ataxia-telangiectasia mutated kinase ATM. Cancer Res. 2004;64:9152–9159
  80. Zhao Y, Thomas HD, Batey MA, et al. Preclinical evaluation of a potent novel DNA-dependent protein kinase inhibitor NU7441. Cancer Res. 2006;66:5354–5362
  81. Lamb J. The Connectivity Map: A new tool for biomedical research. Nat Rev Cancer. 2007;7:54–60
  82. Lamb J, Crawford ED, Peck D, et al. The Connectivity Map: Using gene-expression signatures to connect small molecules, genes, and disease. Science. 2006;313:1929–1935
  83. Barrett T, Suzek TO, Troup DB, et al. NCBI GEO: Mining millions of expression profiles—database and tools. Nucleic Acids Res. 2005;33:D562–D566
  84. Hassane DC, Guzman ML, Corbett C, et al. Discovery of agents that eradicate leukemia stem cells using an in silico screen of public gene expression data. Blood. 2008;111:5654–5662
  85. Wei G, Twomey D, Lamb J, et al. Gene expression-based chemical genomics identifies rapamycin as a modulator of MCL1 and glucocorticoid resistance. Cancer Cell. 2006;10:331–342
  86. Hieronymus H, Lamb J, Ross KN, et al. Gene expression signature-based chemical genomic prediction identifies a novel class of HSP90 pathway modulators. Cancer Cell. 2006;10:321–330
  87. Owens J. The Internet in clinical trials: Breaking the bottleneck?. Drug Discov Today. 2001;6:241–243
  88. Marks R, Bristol H, Conlon M, et al. Enhancing clinical trials on the internet: Lessons from INVEST. Clin Cardiol. 2001;24:V17–V23
  89. Lallas CD, Preminger GM, Pearle MS, et al. Internet based multi-institutional clinical research: A convenient and secure option. J Urol. 2004;171:1880–1885

 Conflict of interest: none.

PII: S0360-3016(08)03811-X

doi: 10.1016/j.ijrobp.2008.12.002

International Journal of Radiation Oncology * Biology * Physics
Volume 73, Issue 4 , Pages 988-996 , 15 March 2009