Advertisement

Cancer and Metastasis Reviews

, Volume 29, Issue 4, pp 677–685 | Cite as

DNA repair pathways and their implication in cancer treatment

  • Athanasios G. Pallis
  • Michalis V. Karamouzis
NON-THEMATIC REVIEW

Abstract

Many cytotoxic agents used in cancer treatment exert their effects through their ability to directly or indirectly damage DNA and thus resulting in cell death. Major types of DNA damage induced by anticancer treatment include strand breaks (double or single strand), crosslinks (inter-strand, intra-strand, DNA–protein crosslinks), and interference with nucleotide metabolism and DNA synthesis. On the other hand, cancer cells activate various DNA repair pathways and repair DNA damages induced by cytotoxic drugs. The purpose of the current review is to present the major types of DNA damage induced by cytotoxic agents, DNA repair pathways, and their role as predictive agents, as well as evaluate the future perspectives of the novel DNA repair pathways inhibitors in cancer therapeutics.

Keywords

DNA repair pathways Cancer treatment Cytotoxic drugs 

References

  1. 1.
    Vermund, H., & Gollin, F. F. (1968). Mechanisms of action of radiotherapy and chemotherapeutic adjuvants. A review. Cancer, 21, 58–76.CrossRefPubMedGoogle Scholar
  2. 2.
    Longley, D. B., & Johnston, P. G. (2005). Molecular mechanisms of drug resistance. The Journal of Pathology, 205, 275–292.CrossRefPubMedGoogle Scholar
  3. 3.
    Khanna, K. K., & Jackson, S. P. (2001). DNA double-strand breaks: Signaling, repair and the cancer connection. Nature Genetics, 27, 247–254.CrossRefPubMedGoogle Scholar
  4. 4.
    Caldecott, K. W. (2008). Single-strand break repair and genetic disease. Nature Reviews Genetics, 9, 619–631.PubMedGoogle Scholar
  5. 5.
    Hurley, L. H. (2002). DNA and its associated processes as targets for cancer therapy. Nature Reviews Cancer, 2, 188–200.CrossRefPubMedGoogle Scholar
  6. 6.
    Hakem, R. (2008). DNA-damage repair; the good, the bad, and the ugly. The EMBO Journal, 27, 589–605.CrossRefPubMedGoogle Scholar
  7. 7.
    Olaussen, K. A., Dunant, A., Fouret, P., Brambilla, E., Andre, F., Haddad, V., et al. (2006). DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy. The New England Journal of Medicine, 355, 983–991.CrossRefPubMedGoogle Scholar
  8. 8.
    Pallis, A. G., Serfass, L., Dziadziusko, R., van Meerbeeck, J. P., Fennell, D., Lacombe, D., et al. (2009). Targeted therapies in the treatment of advanced/metastatic NSCLC. European Journal of Cancer, 45, 2473–2487.CrossRefPubMedGoogle Scholar
  9. 9.
    Sedgwick, B., Bates, P. A., Paik, J., Jacobs, S. C., & Lindahl, T. (2007). Repair of alkylated DNA: Recent advances. DNA Repair (Amst), 6, 429–442.CrossRefGoogle Scholar
  10. 10.
    Middleton, M. R., & Margison, G. P. (2003). Improvement of chemotherapy efficacy by inactivation of a DNA-repair pathway. The Lancet Oncology, 4, 37–44.CrossRefPubMedGoogle Scholar
  11. 11.
    Sharma, S., Salehi, F., Scheithauer, B. W., Rotondo, F., Syro, L. V., & Kovacs, K. (2009). Role of MGMT in tumor development, progression, diagnosis, treatment and prognosis. Anticancer Research, 29, 3759–3768.PubMedGoogle Scholar
  12. 12.
    Leibeling, D., Laspe, P., & Emmert, S. (2006). Nucleotide excision repair and cancer. Journal of Molecular Histology, 37, 225–238.CrossRefPubMedGoogle Scholar
  13. 13.
    Hanawalt, P. C. (2002). Subpathways of nucleotide excision repair and their regulation. Oncogene, 21, 8949–8956.CrossRefPubMedGoogle Scholar
  14. 14.
    de Laat, W. L., Jaspers, N. G., & Hoeijmakers, J. H. (1999). Molecular mechanism of nucleotide excision repair. Genes & Development, 13, 768–785.CrossRefGoogle Scholar
  15. 15.
    Aboussekhra, A., Biggerstaff, M., Shivji, M. K., Vilpo, J. A., Moncollin, V., Podust, V. N., et al. (1995). Mammalian DNA nucleotide excision repair reconstituted with purified protein components. Cell, 80, 859–868.CrossRefPubMedGoogle Scholar
  16. 16.
    van Steeg, H., & Kraemer, K. H. (1999). Xeroderma pigmentosum and the role of UV-induced DNA damage in skin cancer. Molecular Medicine Today, 5, 86–94.CrossRefPubMedGoogle Scholar
  17. 17.
    Niedernhofer, L. J., Odijk, H., Budzowska, M., van Drunen, E., Maas, A., Theil, A. F., et al. (2004). The structure-specific endonuclease Ercc1-Xpf is required to resolve DNA interstrand cross-link-induced double-strand breaks. Molecular and Cellular Biology, 24, 5776–5787.CrossRefPubMedGoogle Scholar
  18. 18.
    Sharma, R. A., & Dianov, G. L. (2007). Targeting base excision repair to improve cancer therapies. Molecular Aspects of Medicine, 28, 345–374.CrossRefPubMedGoogle Scholar
  19. 19.
    Chan, K. K., Zhang, Q. M., & Dianov, G. L. (2006). Base excision repair fidelity in normal and cancer cells. Mutagenesis, 21, 173–178.CrossRefPubMedGoogle Scholar
  20. 20.
    Wilson, D. M., III, & Bohr, V. A. (2007). The mechanics of base excision repair, and its relationship to aging and disease. DNA Repair (Amst), 6, 544–559.CrossRefGoogle Scholar
  21. 21.
    Ame, J. C., Spenlehauer, C., & de Murcia, G. (2004). The PARP superfamily. Bioessays, 26, 882–893.CrossRefPubMedGoogle Scholar
  22. 22.
    Min, W., & Wang, Z. Q. (2009). Poly (ADP-ribose) glycohydrolase (PARG) and its therapeutic potential. Frontiers in Bioscience, 14, 1619–1626.CrossRefPubMedGoogle Scholar
  23. 23.
    Hoeijmakers, J. H. (2001). Genome maintenance mechanisms for preventing cancer. Nature, 411, 366–374.CrossRefPubMedGoogle Scholar
  24. 24.
    Malanga, M., & Althaus, F. R. (2005). The role of poly(ADP-ribose) in the DNA damage signaling network. Biochemistry and Cell Biology, 83, 354–364.CrossRefPubMedGoogle Scholar
  25. 25.
    Chalmers, A. J. (2009). The potential role and application of PARP inhibitors in cancer treatment. British Medical Bulletin, 89, 23–40.CrossRefPubMedGoogle Scholar
  26. 26.
    Jiricny, J. (2006). The multifaceted mismatch-repair system. Nature Reviews Molecular Cell Biology, 7, 335–346.CrossRefPubMedGoogle Scholar
  27. 27.
    Li, G. M. (2008). Mechanisms and functions of DNA mismatch repair. Cell Research, 18, 85–98.CrossRefPubMedGoogle Scholar
  28. 28.
    Sonoda, E., Hochegger, H., Saberi, A., Taniguchi, Y., & Takeda, S. (2006). Differential usage of non-homologous end-joining and homologous recombination in double strand break repair. DNA Repair (Amst), 5, 1021–1029.CrossRefGoogle Scholar
  29. 29.
    Lieber, M. R. (2008). The mechanism of human nonhomologous DNA end joining. The Journal of Biological Chemistry, 283, 1–5.CrossRefPubMedGoogle Scholar
  30. 30.
    Johnson, R. D., & Jasin, M. (2001). Double-strand-break-induced homologous recombination in mammalian cells. Biochemical Society Transactions, 29, 196–201.CrossRefPubMedGoogle Scholar
  31. 31.
    Andegeko, Y., Moyal, L., Mittelman, L., Tsarfaty, I., Shiloh, Y., & Rotman, G. (2001). Nuclear retention of ATM at sites of DNA double strand breaks. The Journal of Biological Chemistry, 276, 38224–38230.PubMedGoogle Scholar
  32. 32.
    Bassing, C. H., & Alt, F. W. (2004). The cellular response to general and programmed DNA double strand breaks. DNA Repair (Amst), 3, 781–796.CrossRefGoogle Scholar
  33. 33.
    Sabharwal, A., & Middleton, M. R. (2006). Exploiting the role of O6-methylguanine-DNA-methyltransferase (MGMT) in cancer therapy. Current Opinion in Pharmacology, 6, 355–363.CrossRefPubMedGoogle Scholar
  34. 34.
    Gerson, S. L. (2004). MGMT: Its role in cancer aetiology and cancer therapeutics. Nature Reviews Cancer, 4, 296–307.CrossRefPubMedGoogle Scholar
  35. 35.
    Esteller, M., Hamilton, S. R., Burger, P. C., Baylin, S. B., & Herman, J. G. (1999). Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia. Cancer Research, 59, 793–797.PubMedGoogle Scholar
  36. 36.
    Esteller, M., Garcia-Foncillas, J., Andion, E., Goodman, S. N., Hidalgo, O. F., Vanaclocha, V., et al. (2000). Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. The New England Journal of Medicine, 343, 1350–1354.CrossRefPubMedGoogle Scholar
  37. 37.
    Jaeckle, K. A., Eyre, H. J., Townsend, J. J., Schulman, S., Knudson, H. M., Belanich, M., et al. (1998). Correlation of tumor O6 methylguanine-DNA methyltransferase levels with survival of malignant astrocytoma patients treated with bis-chloroethylnitrosourea: A Southwest Oncology Group study. Journal of Clinical Oncology, 16, 3310–3315.PubMedGoogle Scholar
  38. 38.
    Hegi, M. E., Diserens, A. C., Godard, S., Dietrich, P. Y., Regli, L., Ostermann, S., et al. (2004). Clinical trial substantiates the predictive value of O-6-methylguanine-DNA methyltransferase promoter methylation in glioblastoma patients treated with temozolomide. Clinical Cancer Research, 10, 1871–1874.CrossRefPubMedGoogle Scholar
  39. 39.
    Paz, M. F., Yaya-Tur, R., Rojas-Marcos, I., Reynes, G., Pollan, M., Guirre-Cruz, L., et al. (2004). CpG island hypermethylation of the DNA repair enzyme methyltransferase predicts response to temozolomide in primary gliomas. Clinical Cancer Research, 10, 4933–4938.CrossRefPubMedGoogle Scholar
  40. 40.
    van den Bent, M. J., Dubbink, H. J., Sanson, M., van der Lee-Haarloo, C. R., Hegi, M., Jeuken, J. W., et al. (2009). MGMT promoter methylation is prognostic but not predictive for outcome to adjuvant PCV chemotherapy in anaplastic oligodendroglial tumors: A report from EORTC Brain Tumor Group Study 26951. Journal of Clinical Oncology, 27, 5881–5886.CrossRefPubMedGoogle Scholar
  41. 41.
    Simon, G. R., Sharma, S., Cantor, A., Smith, P., & Bepler, G. (2005). ERCC1 expression is a predictor of survival in resected patients with non-small cell lung cancer. Chest, 127, 978–983.CrossRefPubMedGoogle Scholar
  42. 42.
    Lord, R. V., Brabender, J., Gandara, D., Alberola, V., Camps, C., Domine, M., et al. (2002). Low ERCC1 expression correlates with prolonged survival after cisplatin plus gemcitabine chemotherapy in non-small cell lung cancer. Clinical Cancer Research, 8, 2286–2291.PubMedGoogle Scholar
  43. 43.
    Shirota, Y., Stoehlmacher, J., Brabender, J., Xiong, Y. P., Uetake, H., Danenberg, K. D., et al. (2001). ERCC1 and thymidylate synthase mRNA levels predict survival for colorectal cancer patients receiving combination oxaliplatin and fluorouracil chemotherapy. Journal of Clinical Oncology, 19, 4298–4304.PubMedGoogle Scholar
  44. 44.
    Dabholkar, M., Vionnet, J., Bostick-Bruton, F., Yu, J. J., & Reed, E. (1994). Messenger RNA levels of XPAC and ERCC1 in ovarian cancer tissue correlate with response to platinum-based chemotherapy. The Journal of Clinical Investigation, 94, 703–708.CrossRefPubMedGoogle Scholar
  45. 45.
    Metzger, R., Leichman, C. G., Danenberg, K. D., Danenberg, P. V., Lenz, H. J., Hayashi, K., et al. (1998). ERCC1 mRNA levels complement thymidylate synthase mRNA levels in predicting response and survival for gastric cancer patients receiving combination cisplatin and fluorouracil chemotherapy. Journal of Clinical Oncology, 16, 309–316.PubMedGoogle Scholar
  46. 46.
    Welsh, C., Day, R., McGurk, C., Masters, J. R., Wood, R. D., & Koberle, B. (2004). Reduced levels of XPA, ERCC1 and XPF DNA repair proteins in testis tumor cell lines. International Journal of Cancer, 110, 352–361.CrossRefGoogle Scholar
  47. 47.
    Stevens, E. V., Raffeld, M., Espina, V., Kristensen, G. B., Trope’, C. G., Kohn, E. C., et al. (2005). Expression of xeroderma pigmentosum A protein predicts improved outcome in metastatic ovarian carcinoma. Cancer, 103, 2313–2319.CrossRefPubMedGoogle Scholar
  48. 48.
    Starostik, P., Manshouri, T., O’Brien, S., Freireich, E., Kantarjian, H., Haidar, M., et al. (1998). Deficiency of the ATM protein expression defines an aggressive subgroup of B-cell chronic lymphocytic leukemia. Cancer Research, 58, 4552–4557.PubMedGoogle Scholar
  49. 49.
    Korabiowska, M., Tscherny, M., Grohmann, U., Honig, J. F., Bartkowski, S. B., Cordon-Cardo, C., et al. (2002). Decreased expression of Ku70/Ku80 proteins in malignant melanomas of the oral cavity. Anticancer Research, 22, 193–196.PubMedGoogle Scholar
  50. 50.
    Komuro, Y., Watanabe, T., Hosoi, Y., Matsumoto, Y., Nakagawa, K., Tsuno, N., et al. (2002). The expression pattern of Ku correlates with tumor radiosensitivity and disease free survival in patients with rectal carcinoma. Cancer, 95, 1199–1205.CrossRefPubMedGoogle Scholar
  51. 51.
    Komuro, Y., Watanabe, T., Hosoi, Y., Matsumoto, Y., Nakagawa, K., Saito, S., et al. (2003). Prediction of tumor radiosensitivity in rectal carcinoma based on p53 and Ku70 expression. Journal of Experimental & Clinical Cancer Research, 22, 223–228.Google Scholar
  52. 52.
    Komuro, Y., Watanabe, T., Hosoi, Y., Matsumoto, Y., Nakagawa, K., Suzuki, N., et al. (2005). Prognostic significance of Ku70 protein expression in patients with advanced colorectal cancer. Hepatogastroenterology, 52, 995–998.PubMedGoogle Scholar
  53. 53.
    Brooks, K. R., To, K., Joshi, M. B., Conlon, D. H., Herndon, J. E., D’Amico, T. A., et al. (2003). Measurement of chemoresistance markers in patients with stage III non-small cell lung cancer: A novel approach for patient selection. The Annals of Thoracic Surgery, 76, 187–193.CrossRefPubMedGoogle Scholar
  54. 54.
    Taubert, H. W., Bartel, F., Kappler, M., Schuster, K., Meye, A., Lautenschlager, C., et al. (2003). Reduced expression of hMSH2 protein is correlated to poor survival for soft tissue sarcoma patients. Cancer, 97, 2273–2278.CrossRefPubMedGoogle Scholar
  55. 55.
    Nakata, B., Wang, Y. Q., Yashiro, M., Ohira, M., Ishikawa, T., Nishino, H., et al. (2003). Negative hMSH2 protein expression in pancreatic carcinoma may predict a better prognosis of patients. Oncology Reports, 10, 997–1000.PubMedGoogle Scholar
  56. 56.
    Catto, J. W., Xinarianos, G., Burton, J. L., Meuth, M., & Hamdy, F. C. (2003). Differential expression of hMLH1 and hMSH2 is related to bladder cancer grade, stage and prognosis but not microsatellite instability. International Journal of Cancer, 105, 484–490.CrossRefGoogle Scholar
  57. 57.
    Son, B. H., Ahn, S. H., Ko, C. D., Ka, I. W., Gong, G. Y., & Kim, J. C. (2004). Significance of mismatch repair protein expression in the chemotherapeutic response of sporadic invasive ductal carcinoma of the breast. The Breast Journal, 10, 20–26.CrossRefPubMedGoogle Scholar
  58. 58.
    Arabi, H., Guan, H., Kumar, S., Cote, M., Bandyopadhyay, S., Bryant, C., et al. (2009). Impact of microsatellite instability (MSI) on survival in high grade endometrial carcinoma. Gynecological Oncology, 113, 153–158.CrossRefGoogle Scholar
  59. 59.
    Bilbao, C., Lara, P. C., Ramirez, R., Henriquez-Hernandez, L. A., Rodriguez, G., Falcon, O., et al. (2010). Microsatellite instability predicts clinical outcome in radiation-treated endometrioid endometrial cancer. International Journal of Radiation Oncology, Biology, Physics, 76, 9–13.PubMedGoogle Scholar
  60. 60.
    Des, G. G., Schischmanoff, O., Nicolas, P., Perret, G. Y., Morere, J. F., & Uzzan, B. (2009). Does microsatellite instability predict the efficacy of adjuvant chemotherapy in colorectal cancer? A systematic review with meta-analysis. European Journal of Cancer, 45, 1890–1896.CrossRefGoogle Scholar
  61. 61.
    Benatti, P., Gafa, R., Barana, D., Marino, M., Scarselli, A., Pedroni, M., et al. (2005). Microsatellite instability and colorectal cancer prognosis. Clinical Cancer Research, 11, 8332–8340.CrossRefPubMedGoogle Scholar
  62. 62.
    Kim, S. T., Lee, J., Park, S. H., Park, J. O., Lim, H. Y., Kang, W. K., et al. (2010). Clinical impact of microsatellite instability in colon cancer following adjuvant FOLFOX therapy. Cancer Chemotherapy and Pharmacology, 66, 659–667.CrossRefPubMedGoogle Scholar
  63. 63.
    Des, G. G., Uzzan, B., Nicolas, P., Schischmanoff, O., Perret, G. Y., & Morere, J. F. (2009). Microsatellite instability does not predict the efficacy of chemotherapy in metastatic colorectal cancer. A systematic review and meta-analysis. Anticancer Research, 29, 1615–1620.Google Scholar
  64. 64.
    Pegg, A. E. (1990). Mammalian O6-alkylguanine-DNA alkyltransferase: Regulation and importance in response to alkylating carcinogenic and therapeutic agents. Cancer Research, 50, 6119–6129.PubMedGoogle Scholar
  65. 65.
    Gander, M., Leyvraz, S., Decosterd, L., Bonfanti, M., Marzolini, C., Shen, F., et al. (1999). Sequential administration of temozolomide and fotemustine: Depletion of O6-alkyl guanine-DNA transferase in blood lymphocytes and in tumours. Annals of Oncology, 10, 831–838.CrossRefPubMedGoogle Scholar
  66. 66.
    Gerard, B., Aamdal, S., Lee, S. M., Leyvraz, S., Lucas, C., D’Incalci, M., et al. (1993). Activity and unexpected lung toxicity of the sequential administration of two alkylating agents—dacarbazine and fotemustine—in patients with melanoma. European Journal of Cancer, 29A, 711–719.CrossRefPubMedGoogle Scholar
  67. 67.
    Quinn, J. A., Desjardins, A., Weingart, J., Brem, H., Dolan, M. E., Delaney, S. M., et al. (2005). Phase I trial of temozolomide plus O6-benzylguanine for patients with recurrent or progressive malignant glioma. Journal of Clinical Oncology, 23, 7178–7187.CrossRefPubMedGoogle Scholar
  68. 68.
    Ryan, C. W., Dolan, M. E., Brockstein, B. B., McLendon, R., Delaney, S. M., Samuels, B. L., et al. (2006). A phase II trial of O6-benzylguanine and carmustine in patients with advanced soft tissue sarcoma. Cancer Chemotherapy and Pharmacology, 58, 634–639.CrossRefPubMedGoogle Scholar
  69. 69.
    Batts, E. D., Maisel, C., Kane, D., Liu, L., Fu, P., O’Brien, T., et al. (2007). O6-benzylguanine and BCNU in multiple myeloma: A phase II trial. Cancer Chemotherapy and Pharmacology, 60, 415–421.CrossRefPubMedGoogle Scholar
  70. 70.
    Sabharwal, A., Corrie, P. G., Midgley, R. S., Palmer, C., Brady, J., Mortimer, P., et al. (2010). A phase I trial of lomeguatrib and irinotecan in metastatic colorectal cancer. Cancer Chemotherapy and Pharmacology, 66, 829–835.CrossRefPubMedGoogle Scholar
  71. 71.
    Khan, O. A., Ranson, M., Michael, M., Olver, I., Levitt, N. C., Mortimer, P., et al. (2008). A phase II trial of lomeguatrib and temozolomide in metastatic colorectal cancer. British Journal of Cancer, 98, 1614–1618.CrossRefPubMedGoogle Scholar
  72. 72.
    Watson, A. J., Middleton, M. R., McGown, G., Thorncroft, M., Ranson, M., Hersey, P., et al. (2009). O(6)-methylguanine-DNA methyltransferase depletion and DNA damage in patients with melanoma treated with temozolomide alone or with lomeguatrib. British Journal of Cancer, 100, 1250–1256.CrossRefPubMedGoogle Scholar
  73. 73.
    Kefford, R. F., Thomas, N. P., Corrie, P. G., Palmer, C., Abdi, E., Kotasek, D., et al. (2009). A phase I study of extended dosing with lomeguatrib with temozolomide in patients with advanced melanoma. British Journal of Cancer, 100, 1245–1249.CrossRefPubMedGoogle Scholar
  74. 74.
    Ranson, M., Hersey, P., Thompson, D., Beith, J., McArthur, G. A., Haydon, A., et al. (2007). Randomized trial of the combination of lomeguatrib and temozolomide compared with temozolomide alone in chemotherapy naive patients with metastatic cutaneous melanoma. Journal of Clinical Oncology, 25, 2540–2545.CrossRefPubMedGoogle Scholar
  75. 75.
    Liu, L., Nakatsuru, Y., & Gerson, S. L. (2002). Base excision repair as a therapeutic target in colon cancer. Clinical Cancer Research, 8, 2985–2991.PubMedGoogle Scholar
  76. 76.
    Zhu, Y., Hu, J., Hu, Y., & Liu, W. (2009). Targeting DNA repair pathways: A novel approach to reduce cancer therapeutic resistance. Cancer Treatment Reviews, 35, 590–596.CrossRefPubMedGoogle Scholar
  77. 77.
    Haince, J. F., Rouleau, M., Hendzel, M. J., Masson, J. Y., & Poirier, G. G. (2005). Targeting poly(ADP-ribosyl)ation: A promising approach in cancer therapy. Trends in Molecular Medicine, 11, 456–463.CrossRefPubMedGoogle Scholar
  78. 78.
    Drew, Y., & Plummer, R. (2009). PARP inhibitors in cancer therapy: Two modes of attack on the cancer cell widening the clinical applications. Drug Resistance Updates, 12, 153–156.CrossRefPubMedGoogle Scholar
  79. 79.
    Farmer, H., McCabe, N., Lord, C. J., Tutt, A. N., Johnson, D. A., Richardson, T. B., et al. (2005). Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature, 434, 917–921.CrossRefPubMedGoogle Scholar
  80. 80.
    Fong, P. C., Boss, D. S., Carden, C. P., Roelvink, M., DeGreve, J., Gourley, C. M., et al. (2008). AZD2281 (KU-0059436), a PARP (poly ADP-ribose polymerase) inhibitor with single agent anticancer activity in patients with BRCA deficient ovarian cancer: Results from a phase I study. Journal of Clinical Oncology, 26, abstr 5510.Google Scholar
  81. 81.
    Audeh, M. W., Penson, R. T., Friedlander, M., Powell, B., Bell-McGuinn, K. M., Scott, C., et al. (2009). Phase II trial of the oral PARP inhibitor olaparib (AZD2281) in BRCA-deficient advanced ovarian cancer. Journal of Clinical Oncology, 27, abstr 5500.Google Scholar
  82. 82.
    Tutt, A., Robson, M., Garber, E., Domchek, S., Audeh, M. W., Weitzel, J. N., et al. (2009). Phase II trial of the oral PARP inhibitor olaparib in BRCA-deficient advanced breast cancer. Journal of Clinical Oncology, 27, abstr CRA501.Google Scholar
  83. 83.
    Plummer, R., Lorigan, P., Evans, J., Steven, N., Middleton, M., Wilson, R., 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). Journal of Clinical Oncology, 24, abstr 8013.Google Scholar
  84. 84.
    Bedikian, A. Y., Papadopoulos, N. E., Kim, K. B., Hwu, W. J., Homsi, J., Glass, M. R., et al. (2009). A phase IB trial of intravenous INO-1001 plus oral temozolomide in subjects with unresectable stage-III or IV melanoma. Cancer Investigation, 27, 756–763.CrossRefPubMedGoogle Scholar
  85. 85.
    Kummar, S., Kinders, R., Gutierrez, M. E., Rubinstein, L., Parchment, R. E., Phillips, L. R., et al. (2009). Phase 0 clinical trial of the poly (ADP-ribose) polymerase inhibitor ABT-888 in patients with advanced malignancies. Journal of Clinical Oncology, 27, 2705–2711.CrossRefPubMedGoogle Scholar
  86. 86.
    Plummer, R., Jones, C., Middleton, M., Wilson, R., Evans, J., Olsen, A., et al. (2008). Phase I study of the poly(ADP-ribose) polymerase inhibitor, AG014699, in combination with temozolomide in patients with advanced solid tumors. Clinical Cancer Research, 14, 7917–7923.CrossRefPubMedGoogle Scholar
  87. 87.
    Fong, P. C., Boss, D. S., Yap, T. A., Tutt, A., Wu, P., Mergui-Roelvink, M., et al. (2009). Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. The New England Journal of Medicine, 361, 123–134.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Athanasios G. Pallis
    • 1
  • Michalis V. Karamouzis
    • 2
  1. 1.Department of Medical OncologyUniversity General Hospital of HeraklionHeraklionGreece
  2. 2.Department of Biological Chemistry, School of MedicineUniversity of AthensAthensGreece

Personalised recommendations