Drug Resistance Updates
Volume 13, Issue 1 , Pages 29-43 , February 2010

Novel therapeutics in combination with radiotherapy to improve cancer treatment: Rationale, mechanisms of action and clinical perspective

  • Marcel Verheij

      Affiliations

    • Department of Radiotherapy, The Netherlands Cancer Institute–Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
    • Division of Experimental Therapy, The Netherlands Cancer Institute–Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
    • Corresponding Author InformationCorresponding author at: Department of Radiotherapy, The Netherlands Cancer Institute–Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. Tel.: +31 20 5122120; fax: +31 20 6691101.
  • ,
  • Conchita Vens

      Affiliations

    • Division of Experimental Therapy, The Netherlands Cancer Institute–Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
  • ,
  • Baukelien van Triest

      Affiliations

    • Department of Radiotherapy, The Netherlands Cancer Institute–Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands

Received 29 December 2009 ,Revised 21 January 2010 ,Accepted 22 January 2010.

References 

  1. Anon . BiPar Sciences presents interim phase 2 results for PARP inhibitor BSI-201 at San Antonio Breast Cancer Symposium. Cancer Biol. Ther. 2009;8:2–3
  2. Abdollahi A, Lipson KE, Han X, et al. SU5416 and SU6668 attenuate the angiogenic effects of radiation-induced tumor cell growth factor production and amplify the direct anti-endothelial action of radiation in vitro. Cancer Res. 2003;63:3755–3763
  3. Adams RR, Eckley DM, Vagnarelli P, et al. Human INCENP colocalizes with the Aurora-B/AIRK2 kinase on chromosomes and is overexpressed in tumour cells. Chromosoma. 2001;110:65–74
  4. Adjei AA, Cohen RB, Franklin W, et al. Phase I pharmacokinetic and pharmacodynamic study of the oral, small-molecule mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancers. J. Clin. Oncol. 2008;26:2139–2146
  5. Aguilar-Quesada R, Munoz-Gamez JA, Martin-Oliva D, et al. Modulation of transcription by PARP-1: consequences in carcinogenesis and inflammation. Curr. Med. Chem. 2007;14:1179–1187
  6. Albert JM, Cao C, Kim KW, et al. Inhibition of poly(ADP-ribose) polymerase enhances cell death and improves tumor growth delay in irradiated lung cancer models. Clin. Cancer Res. 2007;13:3033–3042
  7. Ali M, Telfer BA, McCrudden C, et al. Vasoactivity of AG014699, a clinically active small molecule inhibitor of poly(ADP-ribose) polymerase: a contributory factor to chemopotentiation in vivo?. Clin. Cancer Res. 2009;15:6106–6112
  8. Arizono Y, Yoshikawa H, Naganuma H, Hamada Y, Nakajima Y, Tasaka K. A mechanism of resistance to TRAIL/Apo2L-induced apoptosis of newly established glioma cell line and sensitisation to TRAIL by genotoxic agents. Br. J. Cancer. 2003;88:298–306
  9. Ashkenazi A, Herbst RS. To kill a tumor cell: the potential of proapoptotic receptor agonists. J. Clin. Invest. 2008;118:1979–1990
  10. Ashkenazi A, Pai RC, Fong S, et al. Safety and antitumor activity of recombinant soluble Apo2 ligand. J. Clin. Invest. 1999;104:155–162
  11. Ashworth A. A synthetic lethal therapeutic approach: poly(ADP) ribose polymerase inhibitors for the treatment of cancers deficient in DNA double-strand break repair. J. Clin. Oncol. 2008;26:3785–3790
  12. Augello C, Caruso L, Maggioni M, et al. Inhibitors of apoptosis proteins (IAPs) expression and their prognostic significance in hepatocellular carcinoma. BMC Cancer. 2009;9:125
  13. 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
  14. Beckert S, Farrahi F, Perveen Ghani Q, et al. IGF-I-induced VEGF expression in HUVEC involves phosphorylation and inhibition of poly(ADP-ribose)polymerase. Biochem. Biophys. Res. Commun. 2006;341:67–72
  15. Belka C, Jendrossek V, Pruschy M, Vink S, Verheij M, Budach W. Apoptosis-modulating agents in combination with radiotherapy-current status and outlook. Int. J. Radiat. Oncol. Biol. Phys. 2004;58:542–554
  16. Belka C, Schmid B, Marini P, et al. Sensitization of resistant lymphoma cells to irradiation-induced apoptosis by the death ligand TRAIL. Oncogene. 2001;20:2190–2196
  17. Bennett M, Macdonald K, Chan SW, Luzio JP, Simari R, Weissberg P. Cell surface trafficking of Fas: a rapid mechanism of p53-mediated apoptosis. Science. 1998;282:290–293
  18. Bernier J, Bentzen SM, Vermorken JB. Molecular therapy in head and neck oncology. Nat. Rev. Clin. Oncol. 2009;6:266–277
  19. Bianco C, Tortora G, Bianco R, et al. Enhancement of antitumor activity of ionizing radiation by combined treatment with the selective epidermal growth factor receptor-tyrosine kinase inhibitor ZD1839 (Iressa). Clin. Cancer Res. 2002;8:3250–3258
  20. Bischoff JR, Anderson L, Zhu Y, et al. A homologue of Drosophila aurora kinase is oncogenic and amplified in human colorectal cancers. EMBO J. 1998;17:3052–3065
  21. Boehm AL, Sen M, Seethala R, et al. Combined targeting of epidermal growth factor receptor, signal transducer and activator of transcription-3, and Bcl-X(L) enhances antitumor effects in squamous cell carcinoma of the head and neck. Mol. Pharmacol. 2008;73:1632–1642
  22. 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
  23. Bonner, J.A., Harari, P.M., Giralt, J. et al., 2009. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol. doi:10.1016/S1470-2045(09)70311-0.
  24. Bowman KJ, White A, Golding BT, Griffin RJ, Curtin NJ. Potentiation of anti-cancer agent cytotoxicity by the potent poly(ADP-ribose) polymerase inhibitors NU1025 and NU1064. Br. J. Cancer. 1998;78:1269–1277
  25. Brock WA, Milas L, Bergh S, Lo R, Szabo C, Mason KA. Radiosensitization of human and rodent cell lines by INO-1001, a novel inhibitor of poly(ADP-ribose) polymerase. Cancer Lett. 2004;205:155–160
  26. Brunet A, Roux D, Lenormand P, Dowd S, Keyse S, Pouyssegur J. Nuclear translocation of p42/p44 mitogen-activated protein kinase is required for growth factor-induced gene expression and cell cycle entry. EMBO J. 1999;18:664–674
  27. Bryant HE, Schultz N, Thomas HD, et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature. 2005;434:913–917
  28. Buchsbaum DJ, Zhou T, Grizzle WE, Oliver PG, Hammond CJ, Zhang S, et al. Antitumor efficacy of TRA-8 anti-DR5 monoclonal antibody alone or in combination with chemotherapy and/or radiation therapy in a human breast cancer model. Clin. Cancer Res. 2003;9:3731–3741
  29. Bushunow P, Reidenberg MM, Wasenko J, et al. Gossypol treatment of recurrent adult malignant gliomas. J. Neurooncol. 1999;43:79–86
  30. 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
  31. Calais G, Alfonsi M, Bardet E, et al. Randomized trial of radiation therapy versus concomitant chemotherapy and radiation therapy for advanced-stage oropharynx carcinoma. J. Natl. Cancer Inst. 1999;91:2081–2086
  32. Camphausen K, Cerna D, Scott T, Sproull M, Burgan WE, Cerra MA, et al. Enhancement of in vitro and in vivo tumor cell radiosensitivity by valproic acid. Int. J. Cancer. 2005;114:380–386
  33. Camphausen K, Tofilon PJ. Inhibition of histone deacetylation: a strategy for tumor radiosensitization. J. Clin. Oncol. 2007;25:4051–4056
  34. Camus P, Kudoh S, Ebina M. Interstitial lung disease associated with drug therapy. Br. J. Cancer. 2004;91(Suppl. 2):S18–S23
  35. Cao C, Albert JM, Geng L, Ivy PS, Sandler A, Johnson DH, et al. Vascular endothelial growth factor tyrosine kinase inhibitor AZD2171 and fractionated radiotherapy in mouse models of lung cancer. Cancer Res. 2006;66:11409–11415
  36. Caudell JJ, Sawrie SM, Spencer SA, et al. Locoregionally advanced head and neck cancer treated with primary radiotherapy: a comparison of the addition of cetuximab or chemotherapy and the impact of protocol treatment. Int. J. Radiat. Oncol. Biol. Phys. 2008;71:676–681
  37. Chalmers AJ. The potential role and application of PARP inhibitors in cancer treatment. Br. Med. Bull. 2009;89:23–40
  38. Chapman JD, Dugle DL, Reuvers AP, Meeker BE, Borsa J. Letter: studies on the radiosensitizing effect of oxygen in Chinese hamster cells. Int. J. Radiat. Biol. Relat. Stud. Phys. Chem. Med. 1974;26:383–389
  39. Chinnaiyan AM, Prasad U, Shankar S, Hamstra DA, Shanaiah M, Chenevert TL, et al. Combined effect of tumor necrosis factor-related apoptosis-inducing ligand and ionizing radiation in breast cancer therapy. Proc. Natl. Acad. Sci. (U.S.A.). 2000;97:1754–1759
  40. Chinnaiyan P, Vallabhaneni G, Armstrong E, Huang SM, Harari PM. Modulation of radiation response by histone deacetylase inhibition. Int. J. Radiat. Oncol. Biol. Phys. 2005;62:223–229
  41. Clarke MJ, Mulligan EA, Grogan PT, et al. Effective sensitization of temozolomide by ABT-888 is lost with development of temozolomide resistance in glioblastoma xenograft lines. Mol. Cancer Ther. 2009;8:407–414
  42. Colquhoun AJ, Mchugh LA, Tulchinsky E, Kriajevska M, Mellon JK. Combination treatment with ionising radiation and gefitinib (‘Iressa’, ZD1839), an epidermal growth factor receptor (EGFR) inhibitor, significantly inhibits bladder cancer cell growth in vitro and in vivo. J. Radiat. Res. (Tokyo). 2007;48:351–360
  43. Crane CH, Winter K, Regine WF, Safran H, Rich TA, Curran W, et al. Phase II study of bevacizumab with concurrent capecitabine and radiation followed by maintenance gemcitabine and bevacizumab for locally advanced pancreatic cancer: Radiation Therapy Oncology Group RTOG 0411. J. Clin. Oncol. 2009;27:4096–4102
  44. Curtin NJ, Wang LZ, Yiakouvaki A, et al. Novel poly(ADP-ribose) polymerase-1 inhibitor. AG14361, restores sensitivity to temozolomide in mismatch repair-deficient cells. Clin. Cancer Res. 2004;10:881–889
  45. Czito BG, Willett CG, Bendell JC, et al. Increased toxicity with gefitinib, capecitabine, and radiation therapy in pancreatic and rectal cancer: phase I trial results. J. Clin. Oncol. 2006;24:656–662
  46. Dai Y, Liu M, Tang W, et al. Molecularly targeted radiosensitization of human prostate cancer by modulating inhibitor of apoptosis. Clin. Cancer Res. 2008;14:7701–7710
  47. de Vries EG, Gietema JA, de Jong S. Tumor necrosis factor-related apoptosis-inducing ligand pathway and its therapeutic implications. Clin. Cancer Res. 2006;12:2390–2393
  48. Dean E, Jodrell D, Connolly K, et al. Phase I trial of AEG35156 administered as a 7-day and 3-day continuous intravenous infusion in patients with advanced refractory cancer. J. Clin. Oncol. 2009;27:1660–1666
  49. Dent P, Curiel DT, Fisher PB, Grant S. Synergistic combinations of signaling pathway inhibitors: mechanisms for improved cancer therapy. Drug Resist. Updat. 2009;12:65–73
  50. Dittmann K, Mayer C, Fehrenbacher B, et al. Radiation-induced epidermal growth factor receptor nuclear import is linked to activation of DNA-dependent protein kinase. J. Biol. Chem. 2005;280:31182–31189
  51. Dittmann K, Mayer C, Kehlbach R, Rodemann HP. Radiation-induced caveolin-1 associated EGFR internalization is linked with nuclear EGFR transport and activation of DNA-PK. Mol. Cancer. 2008;7:69
  52. Dittmann K, Mayer C, Rodemann HP. Inhibition of radiation-induced EGFR nuclear import by C225 (Cetuximab) suppresses DNA-PK activity. Radiother. Oncol. 2005;76:157–161
  53. Donawho CK, Luo Y, Luo Y, et al. ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models. Clin. Cancer Res. 2007;13:2728–2737
  54. Downs JA. Chromatin structure and DNA double-strand break responses in cancer progression and therapy. Oncogene. 2007;26:7765–7772
  55. Drew Y, Plummer R. PARP inhibitors in cancer therapy: two modes of attack on the cancer cell widening the clinical applications. Drug Resist. Updat. 2009;12:153–156
  56. Dungey FA, Loser DA, Chalmers AJ. Replication-dependent radiosensitization of human glioma cells by inhibition of poly(ADP-Ribose) polymerase: mechanisms and therapeutic potential. Int. J. Radiat. Oncol. Biol. Phys. 2008;72:1188–1197
  57. Eller JL, Longo SL, Kyle MM, Bassano D, Hicklin DJ, Canute GW. Anti-epidermal growth factor receptor monoclonal antibody cetuximab augments radiation effects in glioblastoma multiforme in vitro and in vivo. Neurosurgery. 2005;56:155–162
  58. Farmer H, McCabe N, Lord CJ, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434:917–921
  59. Feng FY, Lopez CA, Normolle DP, et al. Effect of epidermal growth factor receptor inhibitor class in the treatment of head and neck cancer with concurrent radiochemotherapy in vivo. Clin. Cancer Res. 2007;13:2512–2518
  60. Flack MR, Pyle RG, Mullen NM, Lorenzo B, Wu YW, Knazek RA, et al. Oral gossypol in the treatment of metastatic adrenal cancer. J. Clin. Endocrinol. Metab. 1993;76:1019–1024
  61. Folkman J. Tumor angiogenesis: therapeutic implications. N. Engl. J. Med. 1971;285:1182–1186
  62. Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N. Engl. J. Med. 2009;361:123–134
  63. Gallo O, Chiarelli I, Boddi V, Bocciolini C, Bruschini L, Porfirio B. Cumulative prognostic value of p53 mutations and bcl-2 protein expression in head-and-neck cancer treated by radiotherapy. Int. J. Cancer. 1999;84:573–579
  64. Garcia-Barros M, Paris F, Cordon-Cardo C, Lyden D, Rafii S, Haimovitz-Friedman A, et al. Tumor response to radiotherapy regulated by endothelial cell apoptosis. Science. 2003;300:1155–1159
  65. Geng L, Donnelly E, McMahon G, Lin PC, Sierra-Rivera E, Oshinka H, et al. Inhibition of vascular endothelial growth factor receptor signaling leads to reversal of tumor resistance to radiotherapy. Cancer Res. 2001;61:2413–2419
  66. Geoerger B, Gaspar N, Opolon P, et al. EGFR tyrosine kinase inhibition radiosensitizes and induces apoptosis in malignant glioma and childhood ependymoma xenografts. Int. J. Cancer. 2008;123:209–216
  67. Gero D, Szabo C. Poly(ADP-ribose) polymerase: a new therapeutic target?. Curr. Opin. Anaesthesiol. 2008;21:111–121
  68. Giaccone G, Zatloukal P, Roubec J, et al. Multicenter phase II trial of YM155, a small-molecule suppressor of survivin, in patients with advanced, refractory, non-small-cell lung cancer. J. Clin. Oncol. 2009;27:4481–4486
  69. Glozak MA, Seto E. Histone deacetylases and cancer. Oncogene. 2007;26:5420–5432
  70. Gorski DH, Beckett MA, Jaskowiak NT, et al. Blockage of the vascular endothelial growth factor stress response increases the antitumor effects of ionizing radiation. Cancer Res. 1999;59:3374–3378
  71. Greco FA, Bonomi P, Crawford J, et al. Phase 2 study of mapatumumab, a fully human agonistic monoclonal antibody which targets and activates the TRAIL receptor-1, in patients with advanced non-small cell lung cancer. Lung Cancer. 2008;61:82–90
  72. Guan B, Yue P, Clayman GL, Sun SY. Evidence that the death receptor DR4 is a DNA damage-inducible, p53-regulated gene. J. Cell. Physiol. 2001;188:98–105
  73. Gupta AK, McKenna WG, Weber CN, et al. Local recurrence in head and neck cancer: relationship to radiation resistance and signal transduction. Clin. Cancer Res. 2002;8:885–892
  74. Gutin PH, Iwamoto FM, Beal K, et al. Safety and efficacy of bevacizumab with hypofractionated stereotactic irradiation for recurrent malignant gliomas. Int. J. Radiat. Oncol. Biol. Phys. 2009;75:156–163
  75. Haas RL, de JD, Valdes Olmos RA, Hoefnagel CA, van dHI, Zerp SF, et al. In vivo imaging of radiation-induced apoptosis in follicular lymphoma patients. Int. J. Radiat. Oncol. Biol. Phys. 2004;59:782–787
  76. Hall EJ, Chapman JD. Letter: radiosensitization of hypoxic cells with metronidazole. Br. J. Radiol. 1974;47:513–514
  77. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57–70
  78. Hay T, Matthews JR, Pietzka L, et al. Poly(ADP-ribose) polymerase-1 inhibitor treatment regresses autochthonous Brca2/p53-mutant mammary tumors in vivo and delays tumor relapse in combination with carboplatin. Cancer Res. 2009;69:3850–3855
  79. Hengartner MO. The biochemistry of apoptosis. Nature. 2000;407:770–776
  80. Herbst, R.S., Mendolson, D.S., Ebbinghaus, S. et al., 2006. A phase I safety and pharmacokinetic (PK) study of recombinant Apo2L/TRAIL, an apoptosis-inducing protein in patients with advanced cancer. J. Clin. Oncol. 24 (18S), Abstract 3013.
  81. Hillman RE, Walsh MJ, Wolf GT, Fisher SG, Hong WK. Functional outcomes following treatment for advanced laryngeal cancer. Part I--Voice preservation in advanced laryngeal cancer. Part II--Laryngectomy rehabilitation: the state of the art in the VA System. Research Speech-Language Pathologists. Department of Veterans Affairs Laryngeal Cancer Study Group. Ann. Otol. Rhinol. Laryngol. (Suppl). 1998;172:1–27
  82. Hoebers FJ, Kartachova M, de BJ, et al. 99mTc Hynic-rh-Annexin V scintigraphy for in vivo imaging of apoptosis in patients with head and neck cancer treated with chemoradiotherapy. Eur. J. Nucl. Med. Mol. Imaging. 2008;35:509–518
  83. Horsman MR, Murata R. Combination of vascular targeting agents with thermal or radiation therapy. Int. J. Radiat. Oncol. Biol. Phys. 2002;54:1518–1523
  84. Hotte SJ, Hirte HW, Chen EX, et al. A phase 1 study of mapatumumab (fully human monoclonal antibody to TRAIL-R1) in patients with advanced solid malignancies. Clin. Cancer Res. 2008;14:3450–3455
  85. 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
  86. Huang SM, Harari PM. Modulation of radiation response after epidermal growth factor receptor blockade in squamous cell carcinomas: inhibition of damage repair, cell cycle kinetics, and tumor angiogenesis. Clin. Cancer Res. 2000;6:2166–2174
  87. Inoue A, Saijo Y, Maemondo M, et al. Severe acute interstitial pneumonia and gefitinib. Lancet. 2003;361:137–139
  88. Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science. 2005;307:58–62
  89. Jain RK, Duda DG, Willett CG, Sahani DV, Zhu AX, Loeffler JS, et al. Biomarkers of response and resistance to antiangiogenic therapy. Nat. Rev. Clin. Oncol. 2009;6:327–338
  90. Jiang BH, Liu LZ. Role of mTOR in anticancer drug resistance: perspectives for improved drug treatment. Drug Resist. Updat. 2008;11:63–76
  91. Kang MH, Reynolds CP. Bcl-2 inhibitors: targeting mitochondrial apoptotic pathways in cancer therapy. Clin. Cancer Res. 2009;15:1126–1132
  92. Karikari CA, Roy I, Tryggestad E, et al. Targeting the apoptotic machinery in pancreatic cancers using small-molecule antagonists of the X-linked inhibitor of apoptosis protein. Mol. Cancer Ther. 2007;6:957–966
  93. Kartachova M, Haas RL, Olmos RA, Hoebers FJ, van ZN, Verheij M. In vivo imaging of apoptosis by 99mTc-Annexin V scintigraphy: visual analysis in relation to treatment response. Radiother. Oncol. 2004;72:333–339
  94. Kartachova M, van ZN, Burgers S, van TH, Verheij M, Valdes Olmos RA. Prognostic significance of 99mTc Hynic-rh-annexin V scintigraphy during platinum-based chemotherapy in advanced lung cancer. J. Clin. Oncol. 2007;25:2534–2539
  95. Kartachova MS, Valdes Olmos RA, Haas RL, Hoebers FJ, van HM, Verheij M. 99mTc-HYNIC-rh-annexin-V scintigraphy: visual and quantitative evaluation of early treatment-induced apoptosis to predict treatment outcome. Nucl. Med. Commun. 2008;29:39–44
  96. Kasten-Pisula U, Windhorst S, hm-Daphi J, Mayr G, Dikomey E. Radiosensitization of tumour cell lines by the polyphenol Gossypol results from depressed double-strand break repair and not from enhanced apoptosis. Radiother. Oncol. 2007;83:296–303
  97. Keen N, Taylor S. Aurora-kinase inhibitors as anticancer agents. Nat. Rev. Cancer. 2004;4:927–936
  98. Kelland LR, Burgess L, Steel GG. Differential radiosensitization by the poly(ADP-ribose) transferase inhibitor 3-aminobenzamide in human tumor cells of varying radiosensitivity. Int. J. Radiat. Oncol. Biol. Phys. 1988;14:1239–1246
  99. Kelley SK, Harris LA, Xie D, DeForge L, Totpal K, Bussiere J, et al. Preclinical studies to predict the disposition of Apo2L/tumor necrosis factor-related apoptosis-inducing ligand in humans: characterization of in vivo efficacy, pharmacokinetics, and safety. J. Pharmacol. Exp. Ther. 2001;299:31–38
  100. Kitada S, Leone M, Sareth S, Zhai D, Reed JC, Pellecchia M. Discovery, characterization, and structure-activity relationships studies of proapoptotic polyphenols targeting B-cell lymphocyte/leukemia-2 proteins. J. Med. Chem. 2003;46:4259–4264
  101. Kline MP, Rajkumar SV, Timm MM, Kimlinger TK, Haug JL, Lust JA, et al. R-(−)-gossypol (AT-101) activates programmed cell death in multiple myeloma cells. Exp. Hematol. 2008;36:568–576
  102. Koukourakis MI, Giatromanolaki A, Sheldon H, Buffa FM, Kouklakis G, Ragoussis I, et al. Phase I/II trial of bevacizumab and radiotherapy for locally advanced inoperable colorectal cancer: vasculature-independent radiosensitizing effect of bevacizumab. Clin. Cancer Res. 2009;15:7069–7076
  103. Krause M, Ostermann G, Petersen C, et al. Decreased repopulation as well as increased reoxygenation contribute to the improvement in local control after targeting of the EGFR by C225 during fractionated irradiation. Radiother. Oncol. 2005;76:162–167
  104. Krause M, Schutze C, Petersen C, Pimentel N, Hessel F, Harstrick A, et al. Different classes of EGFR inhibitors may have different potential to improve local tumour control after fractionated irradiation: a study on C225 in FaDu hSCC. Radiother. Oncol. 2005;74:109–115
  105. Krepela E, Dankova P, Moravcikova E, et al. Increased expression of inhibitor of apoptosis proteins, survivin and XIAP, in non-small cell lung carcinoma. Int. J. Oncol. 2009;35:1449–1462
  106. Kuijlen JM, Mooij JJ, Platteel I, Hoving EW, van der Graaf WT, Span MM, et al. TRAIL-receptor expression is an independent prognostic factor for survival in patients with a primary glioblastoma multiforme. J. Neurooncol. 2006;78:161–171
  107. Kummar S, Kinders R, Gutierrez ME, et al. Phase 0 clinical trial of the poly (ADP-ribose) polymerase inhibitor ABT-888 in patients with advanced malignancies. J. Clin. Oncol. 2009;27:2705–2711
  108. LaCasse EC, Mahoney DJ, Cheung HH, Plenchette S, Baird S, Korneluk RG. IAP-targeted therapies for cancer. Oncogene. 2008;27:6252–6275
  109. Lai A, Filka E, McGibbon B, et al. Phase II pilot study of bevacizumab in combination with temozolomide and regional radiation therapy for up-front treatment of patients with newly diagnosed glioblastoma multiforme: interim analysis of safety and tolerability. Int. J. Radiat. Oncol. Biol. Phys. 2008;71:1372–1380
  110. Lee CG, Heijn M, di Tomaso E, et al. Anti-vascular endothelial growth factor treatment augments tumor radiation response under normoxic or hypoxic conditions. Cancer Res. 2000;60:5565–5570
  111. Leong S, Cohen RB, Gustafson DL, et al. Mapatumumab, an antibody targeting TRAIL-R1, in combination with paclitaxel and carboplatin in patients with advanced solid malignancies: results of a phase I and pharmacokinetic study. J. Clin. Oncol. 2009;27:4413–4421
  112. Le Tourneau C, Vidal L, Siu LL. Progress and challenges in the identification of biomarkers for EGFR and VEGFR targeting anticancer agents. Drug Resist. Updat. 2008;11:99–109
  113. Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science. 1989;246:1306–1309
  114. Liu G, Kelly WK, Wilding G, Leopold L, Brill K, Somer B. An open-label, multicenter, phase I/II study of single-agent AT-101 in men with castrate-resistant prostate cancer. Clin. Cancer Res. 2009;15:3172–3176
  115. Liu S, Kulp SK, Sugimoto Y, Jiang J, Chang HL, Dowd MK, et al. The (−)-enantiomer of gossypol possesses higher anticancer potency than racemic gossypol in human breast cancer. Anticancer Res. 2002;22:33–38
  116. Liu X, Han EK, Anderson M, et al. Acquired resistance to combination treatment with temozolomide and ABT-888 is mediated by both base excision repair and homologous recombination DNA repair pathways. Mol. Cancer Res. 2009;7:1686–1692
  117. LoPiccolo J, Blumenthal GM, Bernstein WB, Dennis PA. Targeting the PI3K/Akt/mTOR pathway: effective combinations and clinical considerations. Drug Resist. Updat. 2008;11:32–50
  118. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N. Engl. J. Med. 2004;350:2129–2139
  119. Macdonald JS, Smalley SR, Benedetti J, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N. Engl. J. Med. 2001;345:725–730
  120. Manegold PC, Paringer C, Kulka U, et al. Antiangiogenic therapy with mammalian target of rapamycin inhibitor RAD001 (Everolimus) increases radiosensitivity in solid cancer. Clin. Cancer Res. 2008;14:892–900
  121. Marini P, Budach W, Niyazi M, Junginger D, Stickl S, Jendrossek V, et al. Combination of the pro-apoptotic TRAIL-receptor antibody mapatumumab with ionizing radiation strongly increases long-term tumor control under ambient and hypoxic conditions. Int. J. Radiat. Oncol. Biol. Phys. 2009;75:198–202
  122. Marini P, Schmid A, Jendrossek V, Faltin H, Daniel PT, Budach W, et al. Irradiation specifically sensitises solid tumour cell lines to TRAIL mediated apoptosis. BMC Cancer. 2005;5:5
  123. Marquardt F, Rodel F, Capalbo G, Weiss C, Rodel C. Molecular targeted treatment and radiation therapy for rectal cancer. Strahlenther. Onkol. 2009;185:371–378
  124. Milas L, Fan Z, Andratschke NH, Ang KK. Epidermal growth factor receptor and tumor response to radiation: in vivo preclinical studies. Int. J. Radiat. Oncol. Biol. Phys. 2004;58:966–971
  125. Milas L, Mason K, Hunter N, Petersen S, Yamakawa M, Ang K, et al. In vivo enhancement of tumor radioresponse by C225 antiepidermal growth factor receptor antibody. Clin. Cancer Res. 2000;6:701–708
  126. Millauer B, Wizigmann-Voos S, Schnurch H, Martinez R, Moller NP, Risau W, et al. High affinity VEGF binding and developmental expression suggest Flk-1 as a major regulator of vasculogenesis and angiogenesis. Cell. 1993;72:835–846
  127. Mohammad RM, Wang S, Aboukameel A, Chen B, Wu X, Chen J, et al. Preclinical studies of a nonpeptidic small-molecule inhibitor of Bcl-2 and Bcl-X(L) [(−)-gossypol] against diffuse large cell lymphoma. Mol. Cancer Ther. 2005;4:13–21
  128. Mom CH, Verweij J, Oldenhuis CN, et al. Mapatumumab, a fully human agonistic monoclonal antibody that targets TRAIL-R1, in combination with gemcitabine and cisplatin: a phase I study. Clin. Cancer Res. 2009;15:5584–5590
  129. Mukherjee B, McEllin B, Camacho CV, et al. EGFRvIII and DNA double-strand break repair: a molecular mechanism for radioresistance in glioblastoma. Cancer Res. 2009;69:4252–4259
  130. Muller M, Wilder S, Bannasch D, et al. p53 activates the CD95 (APO-1/Fas) gene in response to DNA damage by anticancer drugs. J. Exp. Med. 1998;188:2033–2045
  131. Ng QS, Goh V, Carnell D, Meer K, Padhani AR, Saunders MI, et al. Tumor antivascular effects of radiotherapy combined with combretastatin a4 phosphate in human non-small-cell lung cancer. Int. J. Radiat. Oncol. Biol. Phys. 2007;67:1375–1380
  132. Nieder C, Wiedenmann N, Andratschke NH, Astner ST, Molls M. Radiation therapy plus angiogenesis inhibition with bevacizumab: rationale and initial experience. Rev. Recent Clin. Trials. 2007;2:163–168
  133. Nigg EA. Mitotic kinases as regulators of cell division and its checkpoints. Nat. Rev. Mol. Cell Biol. 2001;2:21–32
  134. Noel G, Godon C, Fernet M, Giocanti N, Megnin-Chanet F, Favaudon V. Radiosensitization by the poly(ADP-ribose) polymerase inhibitor 4-amino-1,8-naphthalimide is specific of the S phase of the cell cycle and involves arrest of DNA synthesis. Mol. Cancer Ther. 2006;5:564–574
  135. Nyati MK, Maheshwari D, Hanasoge S, et al. Radiosensitization by pan ErbB inhibitor CI-1033 in vitro and in vivo. Clin. Cancer Res. 2004;10:691–700
  136. O’Brien SM, Claxton DF, Crump M, Faderl S, Kipps T, Keating MJ, et al. Phase I study of obatoclax mesylate (GX15-070), a small molecule pan-Bcl-2 family antagonist, in patients with advanced chronic lymphocytic leukemia. Blood. 2009;113:299–305
  137. O'Shaughnessy, J., Osborne, C., Pippen, J. et al., 2009. Efficacy of BSI-201, a poly (ADP-ribose) polymerase-1 (PARP1) inhibitor, in combination with gemcitabine/carboplatin (G/C) in patients with metastatic triple-negative breast cancer (TNBC): results of a randomized phase II trial. J. Clin. Oncol (ASCO Annual Meeting Abstracts) 27, p. 3.
  138. Ogasawara J, Watanabe-Fukunaga R, Adachi M, et al. Lethal effect of the anti-Fas antibody in mice. Nature. 1993;364:806–809
  139. Oliver CL, Bauer JA, Wolter KG, et al. In vitro effects of the BH3 mimetic. (−)-gossypol, on head and neck squamous cell carcinoma cells. Clin. Cancer Res. 2004;10:7757–7763
  140. Oltersdorf T, Elmore SW, Shoemaker AR, et al. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature. 2005;435:677–681
  141. Ong F, Moonen LM, Gallee MP, ten BC, Zerp SF, Hart AA, et al. Prognostic factors in transitional cell cancer of the bladder: an emerging role for Bcl-2 and p53. Radiother. Oncol. 2001;61:169–175
  142. Perez-Galan P, Roue G, Villamor N, Campo E, Colomer D. The BH3-mimetic GX15-070 synergizes with bortezomib in mantle cell lymphoma by enhancing Noxa-mediated activation of Bak. Blood. 2007;109:4441–4449
  143. Peter ME, Krammer PH. The CD95(APO-1/Fas) DISC and beyond. Cell Death Differ. 2003;10:26–35
  144. Peters NA, Richel DJ, Verhoeff JJ, Stalpers LJ. Bowel perforation after radiotherapy in a patient receiving sorafenib. J. Clin. Oncol. 2008;26:2405–2406
  145. Pfister DG, Su YB, Kraus DH, et al. Concurrent cetuximab, cisplatin and concomitant boost radiotherapy for locoregionally advanced, squamous cell head and neck cancer: a pilot phase II study of a new combined-modality paradigm. J. Clin. Oncol. 2006;24:1072–1078
  146. Pignon JP, Bourhis J, Domenge C, Designe L. 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
  147. Plastaras JP, Kim SH, Liu YY, et al. Cell cycle dependent and schedule-dependent antitumor effects of sorafenib combined with radiation. Cancer Res. 2007;67:9443–9454
  148. Plummer R, Attard G, Pacey S, et al. Phase 1 and pharmacokinetic study of lexatumumab in patients with advanced cancers. Clin. Cancer Res. 2007;13:6187–6194
  149. Plummer R, Jones C, Middleton M, et al. Phase I study of the poly(ADP-ribose) polymerase inhibitor. AG014699, in combination with temozolomide in patients with advanced solid tumors. Clin. Cancer Res. 2008;14:7917–7923
  150. Plummer, R., Lorigan, P., Evans, J. et al., 2006. First and final report of a phase II study of the poly(ADP-ribose) polymerase (PARP) inhibitor, AG014699, in combination with temozolomide (TMZ) in patients with metastatic malignant melanoma (MM). J. Clin. Oncol. (ASCO Annual Meeting Abstracts) 24, p. 8013.
  151. Puthalakath H, Strasser A. Keeping killers on a tight leash: transcriptional and post-translational control of the pro-apoptotic activity of BH3-only proteins. Cell Death Differ. 2002;9:505–512
  152. Pyriochou A, Olah G, Deitch EA, Szabo C, Papapetropoulos A. Inhibition of angiogenesis by the poly(ADP-ribose) polymerase inhibitor PJ-34. Int. J. Mol. Med. 2008;22:113–118
  153. Qayum N, Muschel RJ, Im JH, Balathasan L, Koch CJ, Patel S, et al. Tumor vascular changes mediated by inhibition of oncogenic signaling. Cancer Res. 2009;69:6347–6354
  154. Qiao L, Wong BCY. Targeting apoptosis as an approach for gastrointestinal cancer therapy. Drug Resist. Updat. 2009;12:55–64
  155. Raben D, Helfrich B, Chan DC, et al. The effects of cetuximab alone and in combination with radiation and/or chemotherapy in lung cancer. Clin. Cancer Res. 2005;11:795–805
  156. Reed JC. Mechanisms of Bcl-2 family protein function and dysfunction in health and disease. Behring Inst. Mitt. 1996;72–100
  157. Riesterer O, Honer M, Jochum W, Oehler C, Ametamey S, Pruschy M. Ionizing radiation antagonizes tumor hypoxia induced by antiangiogenic treatment. Clin. Cancer Res. 2006;12:3518–3524
  158. Roh MS, Colangelo LH, O’Connell MJ, et al. Preoperative multimodality therapy improves disease-free survival in patients with carcinoma of the rectum: NSABP R-03. J. Clin. Oncol. 2009;27:5124–5130
  159. Rose PG, Bundy BN, Watkins EB, Thigpen JT, Deppe G, Maiman MA, et al. Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N. Engl. J. Med. 1999;340:1144–1153
  160. Rottenberg S, Jaspers JE, Kersbergen A, et al. High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs. Proc. Natl. Acad. Sci. (U.S.A.). 2008;105:17079–17084
  161. Saleh MN, Raisch KP, Stackhouse MA, et al. Combined modality therapy of A431 human epidermoid cancer using anti-EGFR antibody C225 and radiation. Cancer Biother. Radiopharm. 1999;14:451–463
  162. Satoh T, Okamoto I, Miyazaki M, et al. Phase I study of YM155, a novel survivin suppressant, in patients with advanced solid tumors. Clin. Cancer Res. 2009;15:3872–3880
  163. Schaake-Koning C, van den Bogaert W, Dalesio O, et al. Effects of concomitant cisplatin and radiotherapy on inoperable non-small-cell lung cancer. N. Engl. J. Med. 1992;326:524–530
  164. Schimmer AD, O’Brien S, Kantarjian H, et al. A phase I study of the pan bcl-2 family inhibitor obatoclax mesylate in patients with advanced hematologic malignancies. Clin. Cancer Res. 2008;14:8295–8301
  165. Seiwert TY, Haraf DJ, Cohen EE, et al. Phase I study of bevacizumab added to fluorouracil- and hydroxyurea-based concomitant chemoradiotherapy for poor-prognosis head and neck cancer. J. Clin. Oncol. 2008;26:1732–1741
  166. Shannon AM, Telfer BA, Smith PD, et al. The mitogen-activated protein/extracellular signal-regulated kinase kinase 1/2 inhibitor AZD6244 (ARRY-142886) enhances the radiation responsiveness of lung and colorectal tumor xenografts. Clin. Cancer Res. 2009;15:6619–6629
  167. She Y, Lee F, Chen J, Haimovitz-Friedman A, Miller VA, Rusch VR, et al. The epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 selectively potentiates radiation response of human tumors in nude mice, with a marked improvement in therapeutic index. Clin. Cancer Res. 2003;9:3773–3778
  168. Shibata T, Noguchi T, Takeno S, Gabbert HE, Ramp U, Kawahara K. Disturbed XIAP and XAF1 expression balance is an independent prognostic factor in gastric adenocarcinomas. Ann. Surg. Oncol. 2008;15:3579–3587
  169. Shintani S, Kiyota A, Mihara M, Sumida T, Kayahara H, Nakashiro K, et al. Enhancement of radiosensitivity in head and neck cancer cells by ZD1839 (’IRESSA’), a selective epidermal growth factor receptor tyrosine kinase inhibitor. Am. J. Clin. Oncol. 2003;26:e150–e156
  170. Singh TR, Shankar S, Chen X, Asim M, Srivastava RK. Synergistic interactions of chemotherapeutic drugs and tumor necrosis factor-related apoptosis-inducing ligand/Apo-2 ligand on apoptosis and on regression of breast carcinoma in vivo. Cancer Res. 2003;63:5390–5400
  171. Stea B, Falsey R, Kislin K, et al. Time and dose-dependent radiosensitization of the glioblastoma multiforme U251 cells by the EGF receptor tyrosine kinase inhibitor ZD1839 (‘Iressa’). Cancer Lett. 2003;202:43–51
  172. Stegehuis JH, de Wilt LH, de Vries EG, Groen HJ, de Jong S, Kruyt FA. TRAIL receptor targeting therapies for non-small cell lung cancer: current status and perspectives. Drug Resist. Updat. 2010;13:2–15
  173. Straughn JM, Oliver PG, Zhou T, Wang W, Alvarez RD, Grizzle WE, et al. Anti-tumor activity of TRA-8 anti-death receptor 5 (DR5) monoclonal antibody in combination with chemotherapy and radiation therapy in a cervical cancer model. Gynecol. Oncol. 2006;101:46–54
  174. Stupp R, Hegi ME, Mason WP, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009;10:459–466
  175. Taira N, Doihara H, Oota T, et al. Gefitinib, an epidermal growth factor receptor blockade agent, shows additional or synergistic effects on the radiosensitivity of esophageal cancer cells in vitro. Acta Med. Okayama. 2006;60:25–34
  176. Takano T, Ohe Y, Kusumoto M, et al. Risk factors for interstitial lung disease and predictive factors for tumor response in patients with advanced non-small cell lung cancer treated with gefitinib. Lung Cancer. 2004;45:93–104
  177. Tao Y, Zhang P, Girdler F, Frascogna V, Castedo M, Bourhis J, et al. Enhancement of radiation response in p53-deficient cancer cells by the Aurora-B kinase inhibitor AZD1152. Oncogene. 2008;27:3244–3255
  178. Tentori L, Leonetti C, Scarsella M, et al. Inhibition of poly(ADP-ribose) polymerase prevents irinotecan-induced intestinal damage and enhances irinotecan/temozolomide efficacy against colon carcinoma. FASEB J. 2006;20:1709–1711
  179. Tentori L, Lacal PM, Muzi A, et al. Poly(ADP-ribose) polymerase (PARP) inhibition or PARP-1 gene deletion reduces angiogenesis. Eur. J. Cancer. 2007;43:2124–2133
  180. Thomas GM. Improved treatment for cervical cancer—concurrent chemotherapy and radiotherapy. N. Engl. J. Med. 1999;340:1198–1200
  181. Thomas HD, Calabrese CR, Batey MA, et al. Preclinical selection of a novel poly(ADP-ribose) polymerase inhibitor for clinical trial. Mol. Cancer Ther. 2007;6:945–956
  182. Thorburn A, Behbakht K, Ford H. TRAIL receptor-targeted therapeutics: resistance mechanisms and strategies to avoid them. Drug Resist. Updat. 2008;11:17–24
  183. Thraves P, Mossman KL, Brennan T, Dritschilo A. Radiosensitization of human fibroblasts by 3-aminobenzamide: an inhibitor of poly(ADP-ribosylation). Radiat. Res. 1985;104:119–127
  184. Tolcher AW, Mita M, Meropol NJ, et al. Phase I pharmacokinetic and biologic correlative study of mapatumumab, a fully human monoclonal antibody with agonist activity to tumor necrosis factor-related apoptosis-inducing ligand receptor-1. J. Clin. Oncol. 2007;25:1390–1395
  185. Tolcher AW, Mita A, Lewis LD, et al. Phase I and pharmacokinetic study of YM155, a small-molecule inhibitor of survivin. J. Clin. Oncol. 2008;26:5198–5203
  186. Tong Y, Bouska JJ, Ellis PA, et al. Synthesis and evaluation of a new generation of orally efficacious benzimidazole-based poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors as anticancer agents. J. Med. Chem. 2009;52:6803–6813
  187. Trudel S, Stewart AK, Li Z, et al. The Bcl-2 family protein inhibitor. ABT-737, has substantial antimyeloma activity and shows synergistic effect with dexamethasone and melphalan. Clin. Cancer Res. 2007;13:621–629
  188. Turner N, Tutt A, Ashworth A. Hallmarks of ‘BRCAness’ in sporadic cancers. Nat. Rev. Cancer. 2004;4:814–819
  189. Van Poznak C, Seidman AD, Reidenberg MM, et al. Oral gossypol in the treatment of patients with refractory metastatic breast cancer: a phase I/II clinical trial. Breast Cancer Res. Treat. 2001;66:239–248
  190. Verbrugge I, de VE, Tait SW, Wissink EH, Walczak H, Verheij M, et al. Ionizing radiation modulates the TRAIL death-inducing signaling complex, allowing bypass of the mitochondrial apoptosis pathway. Oncogene. 2008;27:574–584
  191. Verbrugge, I., Maas, C., Heijkoop, M., Verheij, M., Borst, J., 2009a. Radiation and anticancer drugs can facilitate mitochondrial bypass by CD95/Fas via c-FLIP downregulation. Cell Death Differ. doi:10.1038/cdd.2009.141.
  192. Verbrugge I, Wissink EH, Rooswinkel RW, Jongsma J, Beltraminelli N, Dupuis M, et al. Combining radiotherapy with APO010 in cancer treatment. Clin. Cancer Res. 2009;15:2031–2038
  193. Verheij M, van Blitterswijk WJ, Bartelink H. Radiation-induced apoptosis—the ceramide-SAPK signaling pathway and clinical aspects. Acta Oncol. 1998;37:575–581
  194. Veuger SJ, Curtin NJ, Smith GC, Durkacz BW. Effects of novel inhibitors of poly(ADP-ribose) polymerase-1 and the DNA-dependent protein kinase on enzyme activities and DNA repair. Oncogene. 2004;23:7322–7329
  195. Wakelee, H.A., Patnaik, A., Sikic, B.I. et al., 2009. Phase I and pharmacokinetic study of lexatumumab (HGS-ETR2) given every 2 weeks in patients with advanced solid tumors. Ann. Oncol. doi:10.1093/annonc/mdp292.
  196. Walczak H, Miller RE, Ariail K, et al. Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo. Nat. Med. 1999;5:157–163
  197. Wang C, Abe S, Matsuda K, Yu C, Li Y, Usuki J, et al. Effects of gefitinib on radiation-induced lung injury in mice. J. Nippon Med. Sch. 2008;75:96–105
  198. Wang X. The expanding role of mitochondria in apoptosis. Genes Dev. 2001;15:2922–2933
  199. Weppler SA, Li Y, Dubois L, Lieuwes N, Jutten B, Lambin P, et al. Expression of EGFR variant vIII promotes both radiation resistance and hypoxia tolerance. Radiother. Oncol. 2007;83:333–339
  200. Wickenden JA, Jin H, Johnson M, et al. Colorectal cancer cells with the BRAF(V600E) mutation are addicted to the ERK1/2 pathway for growth factor-independent survival and repression of BIM. Oncogene. 2008;27:7150–7161
  201. Willett CG, Boucher Y, di Tomaso E, et al. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat. Med. 2004;10:145–147
  202. Willett CG, Duda DG, di Tomaso E, et al. Efficacy, safety, and biomarkers of neoadjuvant bevacizumab, radiation therapy, and fluorouracil in rectal cancer: a multidisciplinary phase II study. J. Clin. Oncol. 2009;27:3020–3026
  203. Williams KJ, Telfer BA, Brave S, Kendrew J, Whittaker L, Stratford IJ, 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
  204. Williams KJ, Telfer BA, Shannon AM, Babur M, Stratford IJ, Wedge SR. Combining radiotherapy with AZD2171, a potent inhibitor of vascular endothelial growth factor signaling: pathophysiologic effects and therapeutic benefit. Mol. Cancer Ther. 2007;6:599–606
  205. Williams KJ, Telfer BA, Stratford IJ, Wedge SR. ZD1839 (‘Iressa’), a specific oral epidermal growth factor receptor-tyrosine kinase inhibitor, potentiates radiotherapy in a human colorectal cancer xenograft model. Br. J. Cancer. 2002;86:1157–1161
  206. Wissink EH, Verbrugge I, Vink SR, Schader MB, Schaefer U, Walczak H, et al. TRAIL enhances efficacy of radiotherapy in a p53 mutant. Bcl-2 overexpressing lymphoid malignancy. Radiother. Oncol. 2006;80:214–222
  207. Wollman R, Yahalom J, Maxy R, Pinto J, Fuks Z. Effect of epidermal growth factor on the growth and radiation sensitivity of human breast cancer cells in vitro. Int. J. Radiat. Oncol. Biol. Phys. 1994;30:91–98
  208. Wolter KG, Wang SJ, Henson BS, et al. (−)-gossypol inhibits growth and promotes apoptosis of human head and neck squamous cell carcinoma in vivo. Neoplasia. 2006;8:163–172
  209. Wright CW, Duckett CS. Reawakening the cellular death program in neoplasia through the therapeutic blockade of IAP function. J. Clin. Invest. 2005;115:2673–2678
  210. Wu GS, Burns TF, McDonald ER, et al. KILLER/DR5 is a DNA damage-inducible p53-regulated death receptor gene. Nat. Genet. 1997;17:141–143
  211. Xu L, Yang D, Wang S, et al. (−)-Gossypol enhances response to radiation therapy and results in tumor regression of human prostate cancer. Mol. Cancer Ther. 2005;4:197–205
  212. Zaidi SH, Huddart RA, Harrington KJ. Novel targeted radiosensitisers in cancer treatment. Curr. Drug Discov. Technol. 2009;6:103–134
  213. Zerp SF, Stoter R, Kuipers G, et al. AT-101, a small molecule inhibitor of anti-apoptotic Bcl-2 family members, activates the SAPK/JNK pathway and enhances radiation-induced apoptosis. Radiat. Oncol. 2009;4:47
  214. Zhang M, Liu H, Guo R, et al. Molecular mechanism of gossypol-induced cell growth inhibition and cell death of HT-29 human colon carcinoma cells. Biochem. Pharmacol. 2003;66:93–103
  215. Zhang M, Liu H, Tian Z, Griffith BN, Ji M, Li QQ. Gossypol induces apoptosis in human PC-3 prostate cancer cells by modulating caspase-dependent and caspase-independent cell death pathways. Life Sci. 2007;80:767–774
  216. Zhang N, Erjala K, Kulmala J, Qiu X, Sundvall M, Elenius K, et al. Concurrent cetuximab, cisplatin, and radiation for squamous cell carcinoma of the head and neck in vitro. Radiother. Oncol. 2009;92:388–392

PII: S1368-7646(10)00003-8

doi: 10.1016/j.drup.2010.01.002

Drug Resistance Updates
Volume 13, Issue 1 , Pages 29-43 , February 2010