Skip to main content

Advertisement

SpringerLink
Log in

Biomarkers for DNA DSB inhibitors and radiotherapy clinical trials

  • Published:
Cancer and Metastasis Reviews Aims and scope Submit manuscript

Abstract

Major technical advances in radiotherapy, including IMRT and image-guided radiotherapy, have allowed for improved physical precision and increased dose delivery to the tumor, with better sparing of surrounding normal tissue. The development of inhibitors of the sensing and repair of DNA double-strand breaks (DSBs) is exciting and could be combined with precise radiotherapy targeting to improve local control following radiotherapy. However, caution must be exercised in order that DSB inhibitors are combined with radiotherapy in such a manner as to preserve the therapeutic ratio by exploiting repair deficiencies in malignant cells over that of normal cells. In this review, we discuss the rationale and current approaches to targeting DSB sensing and repair pathways in combined modality with radiotherapy. We also describe potential biomarkers that could be useful in detecting functional inhibition of DSB repair in a patient’s tissues during clinical radiotherapy trials. Finally, we examine a number of issues relating to the use of DSB-inhibiting molecular agents and radiotherapy in the context of the tumor microenvironment, effects on normal tissues and the optimal timing and duration of the agent in relation to fractionated radiotherapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Helleday, T., Petermann, E., Lundin, C., Hodgson, B., & Sharma, R. A. (2008). DNA repair pathways as targets for cancer therapy. Nature Reviews Cancer, 8, 193–204.

    Google Scholar 

  2. Bristow, R. G., & Harrington, L. (2005). Genetic instability and DNA repair. In I. F. Tannock, R. P. Hill, R. G. Bristow, & L. Harrington (Eds.) The basic science of oncology ((pp. 77–99)4th ed.). New York: McGraw-Hill.

    Google Scholar 

  3. Faulhaber, O., & Bristow, R. G. (2005). Basis of cell kill following clinical radiotherapy. In M. Sluyser (Ed.) Application of apoptosis to cancer treatment, vol. 7 (pp. 293–320). Amsterdam: Kluwer–Springer.

    Chapter  Google Scholar 

  4. Fernet, M., & Hall, J. (2004). Genetic biomarkers of therapeutic radiation sensitivity. DNA Repair (Amst), 3(8–9), 1237–1243.

    Article  CAS  Google Scholar 

  5. Andreassen, C. N., Alsner, J., Overgaard, M., Sorensen, F. B., & Overgaard, J. (2006). Risk of radiation-induced subcutaneous fibrosis in relation to single nucleotide polymorphisms in TGFB1, SOD2, XRCC1, XRCC3, APEX and ATM–a study based on DNA from formalin fixed paraffin embedded tissue samples. International Journal of Radiation Biology, 82(8), 577–586.

    Article  PubMed  CAS  Google Scholar 

  6. Olive, P. L., Vikse, C. M., & Durand, R. E. (1994). Hypoxic fractions measured in murine tumors and normal tissues using the comet assay. International Journal of Radiation Oncology, Biology, Physics, 29(3), 487–491.

    PubMed  CAS  Google Scholar 

  7. Bristow, R. G., Ozcelik, H., Jalali, F., Chan, N., & Vesprini, D. (2007). Homologous recombination and prostate cancer: A model for novel DNA repair targets and therapies. Radiotherapy and Oncology, 83(3), 220–230.

    Article  PubMed  CAS  Google Scholar 

  8. Choudhury, A., Cuddihy, A., & Bristow, R. G. (2006). Radiation and new molecular agents part I: Targeting ATM-ATR checkpoints, DNA repair, and the proteasome. Seminars on Radiattion Oncology, 16(1), 51–58.

    Article  Google Scholar 

  9. Olive, P. L. (1999). DNA damage and repair in individual cells: Applications of the comet assay in radiobiology. International Journal of Radiation Biology, 75(4), 395–405.

    Article  PubMed  CAS  Google Scholar 

  10. Bartek, J., & Lukas, J. (2007). DNA damage checkpoints: From initiation to recovery or adaptation. Current Opinion in Cell Biology, 19(2), 238–245.

    Article  PubMed  CAS  Google Scholar 

  11. Jeggo, P. A., & Lobrich, M. (2007). DNA double-strand breaks: Their cellular and clinical impact? Oncogene, 26(56), 7717–7719.

    Article  PubMed  CAS  Google Scholar 

  12. Helleday, T., Lo, J., van Gent, D. C., & Engelward, B. P. (2007). DNA double-strand break repair: From mechanistic understanding to cancer treatment. DNA Repair (Amst), 6(7), 923–935.

    Article  CAS  Google Scholar 

  13. O’Connor, M. J., Martin, N. M., & Smith, G. C. (2007). Targeted cancer therapies based on the inhibition of DNA strand break repair. Oncogene, 26(56), 7816–7824.

    Article  PubMed  CAS  Google Scholar 

  14. Yu, T., MacPhail, S. H., Banath, J. P., Klokov, D., & Olive, P. L. (2006). Endogenous expression of phosphorylated histone H2AX in tumors in relation to DNA double-strand breaks and genomic instability. DNA Repair (Amst), 5(8), 935–946.

    Article  CAS  Google Scholar 

  15. Cuddihy, A. R., & Bristow, R. G. (2004). The p53 protein family and radiation sensitivity: Yes or no? Cancer and Metastasis Reviews, 23(3–4), 237–257.

    Article  PubMed  CAS  Google Scholar 

  16. Bucher, N., & Britten, C. D. (2008). G2 checkpoint abrogation and checkpoint kinase-1 targeting in the treatment of cancer. British Journal of Cancer, 98(3), 523–528.

    Article  PubMed  CAS  Google Scholar 

  17. Harrington, K., Jankowska, P., & Hingorani, M. (2007). Molecular biology for the radiation oncologist: The 5Rs of radiobiology meet the hallmarks of cancer. Clinical Oncology, 19(8), 561–571.

    Article  PubMed  CAS  Google Scholar 

  18. Gordon, A. T., & McMillan, T. J. (1997). A role for molecular radiobiology in radiotherapy? Clinical Oncology, 9(2), 70–78.

    Article  PubMed  CAS  Google Scholar 

  19. Bindra, R. S., Crosby, M. E., & Glazer, P. M. (2007). Regulation of DNA repair in hypoxic cancer cells. Cancer and Metastasis Reviews, 26(2), 249–260.

    Article  PubMed  CAS  Google Scholar 

  20. Chan, N., Koritzinsky, M., Zhao, H., Bindra, R., Glazer, P. M., Powell, S., et al. (2008). Chronic hypoxia decreases synthesis of homologous recombination proteins to offset chemoresistance and radioresistance. Cancer Research, 68(2), 605–614.

    Article  PubMed  CAS  Google Scholar 

  21. Bristow, R. G., & Hill, R. P. (2008). Hypoxia and metabolism: Hypoxia, DNA repair and genetic instability. Nature Reviews Cancer, 8, 180–192.

    Google Scholar 

  22. Elshaikh, M., Ljungman, M., Ten Haken, R., & Lichter, A. S. (2006). Advances in radiation oncology. Annual Review of Medicine, 57, 19–31.

    Article  PubMed  CAS  Google Scholar 

  23. Bentzen, S. M., & Trotti, A. (2007). Evaluation of early and late toxicities in chemoradiation trials. Journal of Clinical Oncology, 25(26), 4096–4103.

    Article  PubMed  CAS  Google Scholar 

  24. Bentzen, S. M. (2006). Preventing or reducing late side effects of radiation therapy: Radiobiology meets molecular pathology. Nature Reviews Cancer, 6(9), 702–713.

    Article  PubMed  CAS  Google Scholar 

  25. Hill, R. P., Rodemann, H. P., Hendry, J. H., Roberts, S. A., & Anscher, M. S. (2001). Normal tissue radiobiology: From the laboratory to the clinic. International Journal of Radiation Oncology, Biology, Physics, 49(2), 353–365.

    Article  PubMed  CAS  Google Scholar 

  26. Chen, D. J., & Nirodi, C. S. (2007). The epidermal growth factor receptor: A role in repair of radiation-induced DNA damage. Clinical Cancer Research, 13(22 Pt 1), 6555–6560.

    Article  PubMed  CAS  Google Scholar 

  27. Rochester, M. A., Riedemann, J., Hellawell, G. O., Brewster, S. F., & Macaulay, V. M. (2005). Silencing of the IGF1R gene enhances sensitivity to DNA-damaging agents in both PTEN wild-type and mutant human prostate cancer. Cancer Gene Therapy, 12(1), 90–100.

    Article  PubMed  CAS  Google Scholar 

  28. Dupre, A., Boyer-Chatenet, L., Sattler, R. M., Modi, A. P., Lee, J. H., Nicolette, M. L., et al. (2008). A forward chemical genetic screen reveals an inhibitor of the Mre11-Rad50-Nbs1 complex. Nature Chemical Biology, 4(2), 119–125.

    Article  PubMed  CAS  Google Scholar 

  29. Olive, P. L., & Banath, J. P. (2004). Phosphorylation of histone H2AX as a measure of radiosensitivity. International Journal of Radiation Oncology, Biology, Physics, 58(2), 331–335.

    PubMed  CAS  Google Scholar 

  30. Hammond, E. M., Kaufmann, M. R., & Giaccia, A. J. (2007). Oxygen sensing and the DNA-damage response. Current Opinion in Cell Biology, 19(6), 680–684.

    Article  PubMed  CAS  Google Scholar 

  31. Dalton, W. S., & Friend, S. H. (2006). Cancer biomarkers—An invitation to the table. Science, 312(5777), 1165–1168.

    Article  PubMed  CAS  Google Scholar 

  32. Lavin, M. F., Delia, D., & Chessa, L. (2006). ATM and the DNA damage response. Workshop on ataxia-telangiectasia and related syndromes. EMBO Reports, 7(2), 154–160.

    Article  PubMed  CAS  Google Scholar 

  33. Canman, C. E., Lim, D. S., Cimprich, K. A., Taya, Y., Tamai, K., Sakaguchi, K., et al. (1998). Activation of the ATM kinase by ionizing radiation and phosphorylation of p53. Science, 281(5383), 1677–1679.

    Article  PubMed  CAS  Google Scholar 

  34. Banin, S., Moyal, L., Shieh, S., Taya, Y., Anderson, C. W., Chessa, L., et al. (1998). Enhanced phosphorylation of p53 by ATM in response to DNA damage. Science, 281(5383), 1674–1677.

    Article  PubMed  CAS  Google Scholar 

  35. Hall-Jackson, C. A., Cross, D. A., Morrice, N., & Smythe, C. (1999). ATR is a caffeine-sensitive, DNA-activated protein kinase with a substrate specificity distinct from DNA-PK. Oncogene, 18(48), 6707–6713.

    Article  PubMed  CAS  Google Scholar 

  36. Collis, S. J., DeWeese, T. L., Jeggo, P. A., & Parker, A. R. (2005). The life and death of DNA-PK. Oncogene, 24(6), 949–961.

    Article  PubMed  CAS  Google Scholar 

  37. Chen, B. P., Chan, D. W., Kobayashi, J., Burma, S., Asaithamby, A., Morotomi-Yano, K., et al. (2005). Cell cycle dependence of DNA-dependent protein kinase phosphorylation in response to DNA double strand breaks. Journal of Biological Chemistry, 280(15), 14709–14715.

    Article  PubMed  CAS  Google Scholar 

  38. Madhusudan, S., & Middleton, M. R. (2005). The emerging role of DNA repair proteins as predictive, prognostic and therapeutic targets in cancer. Cancer Treatment Reviews, 31(8), 603–617.

    Article  PubMed  CAS  Google Scholar 

  39. Lord, C. J., Garrett, M. D., & Ashworth, A. (2006). Targeting the double-strand DNA break repair pathway as a therapeutic strategy. Clinical Cancer Research, 12(15), 4463–4468.

    Article  PubMed  CAS  Google Scholar 

  40. Hickson, I., Zhao, Y., Richardson, C. J., Green, S. J., Martin, N. M., Orr, A. I., et al. (2004). Identification and characterization of a novel and specific inhibitor of the ataxia-telangiectasia mutated kinase ATM. Cancer Research, 64(24), 9152–9159.

    Article  PubMed  CAS  Google Scholar 

  41. Chalmers, A. J. (2004). Poly(ADP-ribose) polymerase-1 and ionizing radiation: Sensor, signaller and therapeutic target. Clinical Oncology, 16(1), 29–39.

    Article  PubMed  CAS  Google Scholar 

  42. Schraufstatter, I. U., Hyslop, P. A., Hinshaw, D. B., Spragg, R. G., Sklar, L. A., & Cochrane, C. G. (1986). Hydrogen peroxide-induced injury of cells and its prevention by inhibitors of poly(ADP-ribose) polymerase. Proceedings of the National Academy of Sciences of the United States of America, 83(13), 4908–4912.

    Article  PubMed  CAS  Google Scholar 

  43. Bakkenist, C. J., & Kastan, M. B. (2003). DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature, 421(6922), 499–506.

    Article  PubMed  CAS  Google Scholar 

  44. Bartek, J., & Lukas, J. (2003). DNA repair: Damage alert. Nature, 421(6922), 486–488.

    Article  PubMed  CAS  Google Scholar 

  45. Chan, D. W., Chen, B. P., Prithivirajsingh, S., Kurimasa, A., Story, M. D., Qin, J., et al. (2002). Autophosphorylation of the DNA-dependent protein kinase catalytic subunit is required for rejoining of DNA double-strand breaks. Genes & Development, 16(18), 2333–2338.

    Article  CAS  Google Scholar 

  46. Matsuoka, S., Ballif, B. A., Smogorzewska, A., McDonald 3rd, E. R., Hurov, K. E., Luo, J., et al. (2007). ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science, 316(5828), 1160–1166.

    Article  PubMed  CAS  Google Scholar 

  47. Kawamitsu, H., Hoshino, H., Okada, H., Miwa, M., Momoi, H., & Sugimura, T. (1984). Monoclonal antibodies to poly(adenosine diphosphate ribose) recognize different structures. Biochemistry, 23(16), 3771–3777.

    Article  PubMed  CAS  Google Scholar 

  48. Plummer, E. R., Middleton, M. R., Jones, C., Olsen, A., Hickson, I., McHugh, P., et al. (2005). Temozolomide pharmacodynamics in patients with metastatic melanoma: DNA damage and activity of repair enzymes O6-alkylguanine alkyltransferase and poly(ADP-ribose) polymerase-1. Clinical Cancer Research, 11(9), 3402–3409.

    Article  PubMed  CAS  Google Scholar 

  49. Kinders, R. J., Palma, J., Liu, X., Colon-Lopez, M., Luo, Y., Rodriguez, L. E., et al. (2006). Development of a quantitative enzyme immunoassay for measurement of PAR as a pharmacodynamic biomarker of PARP activity. AACR Meeting Abstracts, 2006(2), A5.

  50. Plummer, R., Middleton, M., Wilson, R., Jones, C., Evans, L., Robson, L., et al. (2005). First in human phase I trial of the PARP inhibitor AG-014699 with temozolomide (TMZ) in patients (pts) with advanced solid tumors. Journal of Clinical Oncology, 23(16S), 3065.

    Google Scholar 

  51. Ratnam, K., & Low, J. A. (2007). Current development of clinical inhibitors of poly(ADP-ribose) polymerase in oncology. Clinical Cancer Research, 13(5), 1383–1388.

    Article  PubMed  CAS  Google Scholar 

  52. Sreekumar, A., Nyati, M. K., Varambally, S., Barrette, T. R., Ghosh, D., Lawrence, T. S., et al. (2001). Profiling of cancer cells using protein microarrays: Discovery of novel radiation-regulated proteins. Cancer Research, 61(20), 7585–7593.

    PubMed  CAS  Google Scholar 

  53. Dainiak, N., Schreyer, S. K., & Albanese, J. (2005). The search for mRNA biomarkers: Global quantification of transcriptional and translational responses to ionising radiation. BJR Supplement, 27, 114–122.

    PubMed  CAS  Google Scholar 

  54. Menard, C., Johann, D., Lowenthal, M., Muanza, T., Sproull, M., Ross, S., et al. (2006). Discovering clinical biomarkers of ionizing radiation exposure with serum proteomic analysis. Cancer Research, 66(3), 1844–1850.

    Article  PubMed  CAS  Google Scholar 

  55. Lukas, C., Bartek, J., & Lukas, J. (2005). Imaging of protein movement induced by chromosomal breakage: Tiny ‘local’ lesions pose great ‘global’ challenges. Chromosoma, 114(3), 146–154.

    Article  PubMed  CAS  Google Scholar 

  56. Rogakou, E. P., Pilch, D. R., Orr, A. H., Ivanova, V. S., & Bonner, W. M. (1998). DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. Journal of Biological Chemistry, 273(10), 5858–5868.

    Article  PubMed  CAS  Google Scholar 

  57. Paull, T. T., Rogakou, E. P., Yamazaki, V., Kirchgessner, C. U., Gellert, M., & Bonner, W. M. (2000). A critical role for histone H2AX in recruitment of repair factors to nuclear foci after DNA damage. Current Biology, 10(15), 886–895.

    Article  PubMed  CAS  Google Scholar 

  58. Essers, J., Houtsmuller, A. B., van Veelen, L., Paulusma, C., Nigg, A. L., Pastink, A., et al. (2002). Nuclear dynamics of RAD52 group homologous recombination proteins in response to DNA damage. EMBO Journal, 21(8), 2030–2037.

    Article  PubMed  CAS  Google Scholar 

  59. Shiloh, Y. (2003). ATM and related protein kinases: Safeguarding genome integrity. Nature Reviews Cancer, 3(3), 155–168.

    Article  PubMed  CAS  Google Scholar 

  60. Lukas, C., Falck, J., Bartkova, J., Bartek, J., & Lukas, J. (2003). Distinct spatiotemporal dynamics of mammalian checkpoint regulators induced by DNA damage. Nature Cell Biology, 5(3), 255–260.

    Article  PubMed  CAS  Google Scholar 

  61. Bekker-Jensen, S., Lukas, C., Kitagawa, R., Melander, F., Kastan, M. B., Bartek, J., et al. (2006). Spatial organization of the mammalian genome surveillance machinery in response to DNA strand breaks. Journal of Cell Biology, 173(2), 195–206.

    Article  PubMed  CAS  Google Scholar 

  62. Haaf, T., Golub, E. I., Reddy, G., Radding, C. M., & Ward, D. C. (1995). Nuclear foci of mammalian Rad51 recombination protein in somatic cells after DNA damage and its localization in synaptonemal complexes. Proceedings of the National Academy of Sciences of the United States of America, 92(6), 2298–2302.

    Article  PubMed  CAS  Google Scholar 

  63. Olive, P. L., Banath, J. P., & Keyes, M. (2008). Residual gammaH2AX after irradiation of human lymphocytes and monocytes in vitro and its relation to late effects after prostate brachytherapy. Radiotherapy and Oncology, 86(3), 336–346.

    Google Scholar 

  64. van Veelen, L. R., Cervelli, T., van de Rakt, M. W., Theil, A. F., Essers, J., & Kanaar, R. (2005). Analysis of ionizing radiation-induced foci of DNA damage repair proteins. Mutation Research, 574(1–2), 22–33.

    PubMed  Google Scholar 

  65. Sedelnikova, O. A., Rogakou, E. P., Panyutin, I. G., & Bonner, W. M. (2002). Quantitative detection of (125)IdU-induced DNA double-strand breaks with gamma-H2AX antibody. Radiation Research, 158(4), 486–492.

    Article  PubMed  CAS  Google Scholar 

  66. Banath, J. P., & Olive, P. L. (2003). Expression of phosphorylated histone H2AX as a surrogate of cell killing by drugs that create DNA double-strand breaks. Cancer Research, 63(15), 4347–4350.

    PubMed  CAS  Google Scholar 

  67. Klokov, D., MacPhail, S. M., Banath, J. P., Byrne, J. P., & Olive, P. L. (2006). Phosphorylated histone H2AX in relation to cell survival in tumor cells and xenografts exposed to single and fractionated doses of X-rays. Radiotherapy and Oncology, 80(2), 223–229.

    Article  PubMed  CAS  Google Scholar 

  68. Rothkamm, K., Balroop, S., Shekhdar, J., Fernie, P., & Goh, V. (2007). Leukocyte DNA damage after multi-detector row CT: A quantitative biomarker of low-level radiation exposure. Radiology, 242(1), 244–251.

    Article  PubMed  Google Scholar 

  69. Hamasaki, K., Imai, K., Nakachi, K., Takahashi, N., Kodama, Y., & Kusunoki, Y. (2007). Short-term culture and gammaH2AX flow cytometry determine differences in individual radiosensitivity in human peripheral T lymphocytes. Environmental and Molecualr Mutagenesis, 48(1), 38–47.

    Article  CAS  Google Scholar 

  70. Tanaka, T., Huang, X., Halicka, H. D., Zhao, H., Traganos, F., Albino, A. P., et al. (2007). Cytometry of ATM activation and histone H2AX phosphorylation to estimate extent of DNA damage induced by exogenous agents. Cytometry A, 71(9), 648–661.

    PubMed  Google Scholar 

  71. MacPhail, S. H., Banath, J. P., Yu, T. Y., Chu, E. H., Lambur, H., & Olive, P. L. (2003). Expression of phosphorylated histone H2AX in cultured cell lines following exposure to X-rays. International Journal of Radiation Biology, 79(5), 351–358.

    Article  PubMed  CAS  Google Scholar 

  72. Olive, P. L. (2004). Detection of DNA damage in individual cells by analysis of histone H2AX phosphorylation. Methods in Cell Biology, 75, 355–373.

    Article  PubMed  CAS  Google Scholar 

  73. Lobrich, M., & Kiefer, J. (2006). Assessing the likelihood of severe side effects in radiotherapy. International Journal of Cancer, 118(11), 2652–2656.

    Article  CAS  Google Scholar 

  74. Taneja, N., Davis, M., Choy, J. S., Beckett, M. A., Singh, R., Kron, S. J., et al. (2004). Histone H2AX phosphorylation as a predictor of radiosensitivity and target for radiotherapy. Journal of Biological Chemistry, 279(3), 2273–2280.

    Article  PubMed  CAS  Google Scholar 

  75. Rogakou, E. P., Nieves-Neira, W., Boon, C., Pommier, Y., & Bonner, W. M. (2000). Initiation of DNA fragmentation during apoptosis induces phosphorylation of H2AX histone at serine 139. Journal of Biological Chemistry, 275(13), 9390–9395.

    Article  PubMed  CAS  Google Scholar 

  76. Kumaravel, T. S., & Jha, A. N. (2006). Reliable Comet assay measurements for detecting DNA damage induced by ionising radiation and chemicals. Mutation Research, 605(1–2), 7–16.

    PubMed  CAS  Google Scholar 

  77. Dorie, M. J., Kovacs, M. S., Gabalski, E. C., Adam, M., Le, Q. T., Bloch, D. A., et al. (1999). DNA damage measured by the comet assay in head and neck cancer patients treated with tirapazamine. Neoplasia, 1(5), 461–467.

    Article  PubMed  CAS  Google Scholar 

  78. Terris, D. J., Ho, E. Y., Ibrahim, H. Z., Dorie, M. J., Kovacs, M. S., Le, Q. T., et al. (2002). Estimating DNA repair by sequential evaluation of head and neck tumor radiation sensitivity using the comet assay. Archives of Otolaryngology Head & Neck Surgery, 128(6), 698–702.

    Google Scholar 

  79. Francis, R. J., Sharma, S. K., Springer, C., Green, A. J., Hope-Stone, L. D., Sena, L., et al. (2002). A phase I trial of antibody directed enzyme prodrug therapy (ADEPT) in patients with advanced colorectal carcinoma or other CEA producing tumours. British Journal of Cancer, 87(6), 600–607.

    Article  PubMed  CAS  Google Scholar 

  80. Prise, K. M., Ahnstrom, G., Belli, M., Carlsson, J., Frankenberg, D., Kiefer, J., et al. (1998). A review of dsb induction data for varying quality radiations. International Journal of Radiation Biology, 74(2), 173–184.

    Article  PubMed  CAS  Google Scholar 

  81. Bohm, L. (2006). Inhibition of homologous recombination repair with Pentoxifylline targets G2 cells generated by radiotherapy and induces major enhancements of the toxicity of cisplatin and melphalan given after irradiation. Radiation Oncology, 1, 12.

    Article  PubMed  CAS  Google Scholar 

  82. Grem, J. L., Harold, N., Keith, B., Chen, A. P., Kao, V., Takimoto, C. H., et al. (2002). A phase I pharmacologic and pharmacodynamic study of pyrazoloacridine given as a weekly 24-hour continuous intravenous infusion in adult cancer patients. Clinical Cancer Research, 8(7), 2149–2156.

    PubMed  CAS  Google Scholar 

  83. Kumaravel, T. S., & Bristow, R. G. (2005). Detection of genetic instability at HER-2/neu and p53 loci in breast cancer cells using Comet-FISH. Breast Cancer Research and Treatment, 91(1), 89–93.

    Article  PubMed  CAS  Google Scholar 

  84. Bayani, J., & Squire, J. A. (2007). Application and interpretation of FISH in biomarker studies. Cancer Letters, 249(1), 97–109.

    Article  PubMed  CAS  Google Scholar 

  85. Ma, B. B., Bristow, R. G., Kim, J., & Siu, L. L. (2003). Combined-modality treatment of solid tumors using radiotherapy and molecular targeted agents. Journal of Clinical Oncology, 21(14), 2760–2776.

    Article  PubMed  CAS  Google Scholar 

  86. Parulekar, W. R., & Eisenhauer, E. A. (2004). Phase I trial design for solid tumor studies of targeted, non-cytotoxic agents: Theory and practice. Journal of National Cancer Institute, 96(13), 990–997.

    CAS  Google Scholar 

  87. Deutsch, E., Soria, J. C., & Armand, J. P. (2005). New concepts for phase I trials: Evaluating new drugs combined with radiation therapy. Nature Clinical Practice Oncology, 2(9), 456–465.

    Article  PubMed  CAS  Google Scholar 

  88. Dowlati, A., Haaga, J., Remick, S. C., Spiro, T. P., Gerson, S. L., Liu, L., et al. (2001). Sequential tumor biopsies in early phase clinical trials of anticancer agents for pharmacodynamic evaluation. Clinical Cancer Research, 7(10), 2971–2976.

    PubMed  CAS  Google Scholar 

  89. Agulnik, M., Oza, A. M., Pond, G. R., & Siu, L. L. (2006). Impact and perceptions of mandatory tumor biopsies for correlative studies in clinical trials of novel anticancer agents. Journal of Clinical Oncology, 24(30), 4801–4807.

    Article  PubMed  Google Scholar 

  90. Helft, P. R., & Daugherty, C. K. (2006). Are we taking without giving in return? The ethics of research-related biopsies and the benefits of clinical trial participation. Journal of Clinical Oncology, 24(30), 4793–4795.

    Article  PubMed  Google Scholar 

  91. Cannistra, S. A. (2007). Performance of biopsies in clinical research. Journal of Clinical Oncology, 25(11), 1454–1455.

    Article  PubMed  Google Scholar 

  92. Rockett, J. C., Burczynski, M. E., Fornace, A. J., Herrmann, P. C., Krawetz, S. A., & Dix, D. J. (2004). Surrogate tissue analysis: Monitoring toxicant exposure and health status of inaccessible tissues through the analysis of accessible tissues and cells. Toxicology and Applied Pharmacology, 194(2), 189–199.

    Article  PubMed  CAS  Google Scholar 

  93. Rehman, S., & Jayson, G. C. (2005). Molecular imaging of antiangiogenic agents. Oncologist, 10(2), 92–103.

    Article  PubMed  CAS  Google Scholar 

  94. Cullinane, C., Dorow, D. S., Kansara, M., Conus, N., Binns, D., Hicks, R. J., et al. (2005). An in vivo tumor model exploiting metabolic response as a biomarker for targeted drug development. Cancer Research, 65(21), 9633–9636.

    Article  PubMed  CAS  Google Scholar 

  95. Yang, D. J., Kim, E. E., & Inoue, T. (2006). Targeted molecular imaging in oncology. Annals of Nuclear Medicine, 20(1), 1–11.

    PubMed  CAS  Google Scholar 

  96. Boothman, D. A., Bouvard, I., & Hughes, E. N. (1989). Identification and characterization of X-ray-induced proteins in human cells. Cancer Research, 49(11), 2871–2878.

    PubMed  CAS  Google Scholar 

  97. Einspahr, J. G., Alberts, D. S., Gapstur, S. M., Bostick, R. M., Emerson, S. S., & Gerner, E. W. (1997). Surrogate end-point biomarkers as measures of colon cancer risk and their use in cancer chemoprevention trials. Cancer Epidemiology Biomarkers & Prevention, 6(1), 37–48.

    CAS  Google Scholar 

  98. Pepe, M. S., Etzioni, R., Feng, Z., Potter, J. D., Thompson, M. L., Thornquist, M., et al. (2001). Phases of biomarker development for early detection of cancer. Journal of National Cancer Institute, 93(14), 1054–1061.

    Article  CAS  Google Scholar 

  99. Sharma, R. A., & Farmer, P. B. (2004). Biological relevance of adduct detection to the chemoprevention of cancer. Clinical Cancer Research, 10(15), 4901–4912.

    Article  PubMed  CAS  Google Scholar 

  100. Hede, K. (2005). NCI’s National Biospecimen Network: Too early or too late? Journal of National Cancer Institute, 97(4), 247–248.

    Article  Google Scholar 

  101. Maruvada, P., & Srivastava, S. (2006). Joint National Cancer Institute-Food and Drug Administration workshop on research strategies, study designs, and statistical approaches to biomarker validation for cancer diagnosis and detection. Cancer Epidemiology Biomarkers & Prevention, 15(6), 1078–1082.

    Article  Google Scholar 

  102. Bartek, J., Bartkova, J., & Lukas, J. (2007). DNA damage signalling guards against activated oncogenes and tumour progression. Oncogene, 26(56), 7773–7779.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

Work in the author’s laboratories is supported by grants from National Cancer Institute of Canada, the Terry Fox Foundation and the Canadian Institutes of Health Research (PO, RGB). RGB is a Canadian Cancer Society Research Scientist.

Author information

Authors and Affiliations

  1. Radiation Medicine Program, Princess Margaret Hospital (University Health Network), 610 University Avenue, Toronto, Ontario, M5G 2M9, Canada

    Stanley K. Liu & Robert G. Bristow

  2. Department of Radiation Oncology, University of Toronto, 610 University Avenue, Toronto, Ontario, M5G 2M9, Canada

    Stanley K. Liu & Robert G. Bristow

  3. Medical Biophysics Department, British Columbia Cancer Research Centre, 675 W. 10th Avenue, Vancouver, British Columbia, V5Z 1L3, Canada

    Peggy L. Olive

  4. Department of Medical Biophysics, University of Toronto, 610 University Avenue, Toronto, Ontario, M5G 2M9, Canada

    Robert G. Bristow

Authors
  1. Stanley K. Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peggy L. Olive
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Robert G. Bristow
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Robert G. Bristow.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Liu, S.K., Olive, P.L. & Bristow, R.G. Biomarkers for DNA DSB inhibitors and radiotherapy clinical trials. Cancer Metastasis Rev 27, 445–458 (2008). https://doi.org/10.1007/s10555-008-9137-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10555-008-9137-8

Keywords

Search

Navigation