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Targeting the checkpoint kinases: chemosensitization versus chemoprotection

Key Points

  • DNA-damaging agents are among the most effective anticancer agents in clinical use; however, they have significant limitations. Many patients with cancer either do not respond, or develop resistance to them, they are also toxic, and have only a limited therapeutic window.

  • The DNA-damage-response network regulates not only cell-cycle checkpoints, but also DNA repair, genome maintenance, senescence and apoptosis. Modulation of the DNA-damage response, depending on where in the network this modulation occurs, could have different consequences including chemosensitization and chemoprotection.

  • CHK1 and CHK2 were originally discovered as checkpoint kinases. However, further studies have indicated that they are actually DNA-damage-response kinases, regulating more than just cell-cycle checkpoints.

  • CHK1 regulates numerous checkpoint pathways, including S-phase and G2–M checkpoints. Other potential CHK1 functions include replication, chromatin remodelling and DNA repair. CHK1 inhibition is expected to sensitize cells to a broad spectrum of DNA-damaging agents.

  • CHK2 might have a redundant and supportive role in checkpoints, but its role in ionizing-radiation-induced apoptosis is more prominent. However, its role in other DNA-damage-induced apoptosis mechanisms is less well established. CHK2 inhibition is expected to protect normal cells from the side effects of ionizing radiation, but its role in chemoprotection still needs to be clarified.

Abstract

An important part of the cellular response to DNA damage is checkpoint activation — checkpoint kinases CHK1 and CHK2 phosphorylate key proteins to elicit cell-cycle blocks. Inhibiting these kinases was believed to sensitize tumour cells to cancer treatments that damage DNA, because in the absence of checkpoints and efficient DNA repair, the response would switch to cell death or senescence. Recent discoveries have, however, highlighted different and expanded roles for CHK1 and CHK2, so should the therapeutic hypothesis that is concerned with targeting so-called checkpoint kinases be modified?

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Figure 1: Functions and regulations of CHK1 in the mammalian DNA-damage-response network.
Figure 2: Functions and regulations of CHK2 in the mammalian DNA-damage-response network.

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References

  1. Hurley, L. H. DNA and its associated processes as targets for cancer therapy. Nature Rev. Cancer 2, 188–200 (2002).

    Article  CAS  Google Scholar 

  2. Lea, D. E. Actions of Radiations on Living Cells (University Press, Cambridge, 1947).

    Google Scholar 

  3. Tobey, R. A. Different drugs arrest cells at a number of distinct stages in G2. Nature 254, 245–247 (1975).

    Article  CAS  PubMed  Google Scholar 

  4. Painter, R. B. & Young, B. R. Radiosensitivity in ataxia-telangiectasia: a new explanation. Proc. Natl Acad. Sci. USA 77, 7315–7317 (1980).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Weinert, T. A. & Hartwell, L. H. The RAD9 gene controls the cell cycle response to DNA damage in Saccharomyces cerevisiae. Science 241, 317–322 (1988).

    Article  CAS  PubMed  Google Scholar 

  6. Hartwell, L. H. & Weinert, T. A. Checkpoints: controls that ensure the order of cell cycle events. Science 246, 629–634 (1989).

    Article  CAS  PubMed  Google Scholar 

  7. Zhou, B. -B. & Elledge, S. J. The DNA damage response: putting checkpoints in perspective. Nature 408, 433–439 (2000).

    Article  CAS  PubMed  Google Scholar 

  8. Khanna, K. K. & Jackson, S. P. DNA double-strand breaks: signaling, repair and the cancer connection. Nature Genet. 27, 247–254 (2001).

    Article  CAS  PubMed  Google Scholar 

  9. Chang, B. D. et al. A senescence-like phenotype distinguishes tumor cells that undergo terminal proliferation arrest after exposure to anticancer agents. Cancer Res. 59, 3761–3767 (1999).

    CAS  PubMed  Google Scholar 

  10. Hartwell, L. H. & Kastan, M. B. Cell cycle control and cancer. Science 266, 1821–1828 (1994).

    Article  CAS  PubMed  Google Scholar 

  11. Shiloh, Y. ATM and related protein kinases: safeguarding genome integrity. Nature Rev. Cancer 3, 155–168 (2003).

    Article  CAS  Google Scholar 

  12. Abraham, R. T. Cell cycle checkpoint signaling through the ATM and ATR kinases. Genes Dev. 15, 2177–2196 (2001).

    Article  CAS  PubMed  Google Scholar 

  13. Kaneko, Y. et al. Cell cycle-dependent and ATM-independent expression of human Chk1 kinase. Oncogene 18, 3673–3681 (1999).

    Article  CAS  PubMed  Google Scholar 

  14. Lukas, C. et al. DNA damage-activated kinase Chk2 is independent of proliferation or differentiation yet correlates with tissue biology. Cancer Res. 61, 4990–4993 (2001).

    CAS  PubMed  Google Scholar 

  15. Sanchez, Y. et al. Conservation of the Chk1 checkpoint pathway in mammals: linkage of DNA damage to Cdk regulation through Cdc25. Science 277, 1497–1501 (1997). This paper describes the cloning, and preliminary biochemical characterization of CHK1, particularly its role in the G2–M transition

    Article  CAS  PubMed  Google Scholar 

  16. Liu, Q. et al. Chk1 is an essential kinase that is regulated by Atr and required for the G(2)/M DNA damage checkpoint. Genes Dev. 14, 1448–1459 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Zhao, H. & Piwnica-Worms, H. ATR-mediated checkpoint pathways regulate phosphorylation and activation of human Chk1. Mol. Cell. Biol. 21, 4129–4139 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Zhao, H., Watkins, J. L. & Piwnica-Worms, H. Disruption of the checkpoint kinase 1/cell division cycle 25A pathway abrogates ionizing radiation-induced S and G2 checkpoints. Proc. Natl Acad. Sci. USA 99, 14795–14800 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Sorensen, C. S. et al. Chk1 regulates the S phase checkpoint by coupling the physiological turnover and ionizing radiation-induced accelerated proteolysis of Cdc25A. Cancer Cell 3, 247–258 (2003).

    Article  CAS  PubMed  Google Scholar 

  20. Gatei, M. et al. Ataxia-telangiectasia-mutated (ATM) and NBS1-dependent phosphorylation of Chk1 on Ser-317 in response to ionizing radiation. J. Biol. Chem. 278, 14806–14811 (2003).

    Article  CAS  PubMed  Google Scholar 

  21. Xiao, Z. et al. Chk1 mediates S and G2 arrests through Cdc25A degradation in response to DNA-damaging agents. J. Biol. Chem. 278, 21767–21773 (2003).

    Article  CAS  PubMed  Google Scholar 

  22. Kumagai, A. & Dunphy, W. G. Claspin, a novel protein required for the activation of Chk1 during a DNA replication checkpoint response in Xenopus egg extracts. Mol. Cell 6, 839–849 (2000).

    Article  CAS  PubMed  Google Scholar 

  23. Chini, C. C. & Chen, J. Human claspin is required for replication checkpoint control. J. Biol. Chem. 278, 30057–30062. (2003).

    Article  CAS  PubMed  Google Scholar 

  24. Mailand, N. et al. Rapid destruction of human Cdc25A in response to DNA damage. Science 288, 1425–1429 (2000).

    Article  CAS  PubMed  Google Scholar 

  25. Mailand, N. et al. Regulation of G(2)/M events by Cdc25A through phosphorylation-dependent modulation of its stability. EMBO J. 21, 5911–5920 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Peng, C. Y. et al. Mitotic and G2 checkpoint control: regulation of 14-3-3 protein binding by phosphorylation of Cdc25C on serine-216. Science 277, 1501–1505 (1997).

    Article  CAS  PubMed  Google Scholar 

  27. Dalal, S. N., Schweitzer, C. M., Gan, J. & DeCaprio, J. A. Cytoplasmic localization of human cdc25C during interphase requires an intact 14-3-3 binding site. Mol. Cell. Biol. 19, 4465–4479 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Yang, J., Winkler, K., Yoshida, M. & Kornbluth, S. Maintenance of G2 arrest in the Xenopus oocyte: a role for 14-3-3-mediated inhibition of Cdc25 nuclear import. EMBO J. 18, 2174–2183 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Zachos, G., Rainey, M. D. & Gillespie, D. A. Chk1-deficient tumour cells are viable but exhibit multiple checkpoint and survival defects. EMBO J. 22, 713–723 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Akiyama, T. et al. G1 Phase accumulation induced by UCN-01 is associated with dephosphorylation of Rb and CDK2 proteins as well as induction of CDK inhibitor p21/Cip1/WAF1/sdil in p53-mutated human epidermoid carcinoma A431 cells. Cancer Res. 57, 1495–1501 (1997).

    CAS  PubMed  Google Scholar 

  31. Graves, P. R. et al. The Chk1 protein kinase and the Cdc25C regulatory pathways are targets of the anticancer agent UCN-01. J. Biol. Chem. 275, 5600–5605 (2000).

    Article  CAS  PubMed  Google Scholar 

  32. Busby, E. C., Leistritz, D. F., Abraham, R. T., Karnitz, L. M. & Sarkaria, J. N. The radiosensitizing agent 7-hydroxystaurosporine (UCN-01) inhibits the DNA damage checkpoint kinase hChk1. Cancer Res. 60, 2108–2112 (2000).

    CAS  PubMed  Google Scholar 

  33. Zhao, B. et al. Structural basis for Chk1 inhibition by UCN-01. J. Biol. Chem. 277, 46609–46615 (2002).

    Article  CAS  PubMed  Google Scholar 

  34. Sato, S., Fujita, N. & Tsuruo, T. Interference with PDK1–Akt survival signaling pathway by UCN-01 (7-hydroxystaurosporine). Oncogene 21, 1727–1738 (2002).

    Article  CAS  PubMed  Google Scholar 

  35. Brown, E. J. & Baltimore, D. ATR disruption leads to chromosomal fragmentation and early embryonic lethality. Genes Dev. 14, 397–402 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. de Klein, A. et al. Targeted disruption of the cell-cycle checkpoint gene ATR leads to early embryonic lethality in mice. Curr. Biol. 10, 479–482 (2000).

    Article  CAS  PubMed  Google Scholar 

  37. Takai, H. et al. Aberrant cell cycle checkpoint function and early embryonic death in Chk1(−/−) mice. Genes Dev. 14, 1439–1447 (2000). Work described in this reference and reference 16 indicates that Chk1 in mammals might have an essential role during the normal cell cycle.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Nghiem, P., Park, P. K., Kim, Y., Vaziri, C. & Schreiber, S. L. ATR inhibition selectively sensitizes G1 checkpoint-deficient cells to lethal premature chromatin condensation. Proc. Natl Acad. Sci. USA 98, 9092–9097 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Feijoo, C. et al. Activation of mammalian Chk1 during DNA replication arrest: a role for Chk1 in the intra-S phase checkpoint monitoring replication origin firing. J. Cell Biol. 154, 913–923 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Fogarty, P. et al. The Drosophila grapes gene is related to checkpoint gene chk1/rad27 and is required for late syncytial division fidelity. Curr. Biol. 7, 418–426 (1997).

    Article  CAS  PubMed  Google Scholar 

  41. Chen, Z. et al. Human Chk1 expression is dispensable for somatic cell death and critical for sustaining G2 DNA damage checkpoint. Mol. Cancer Ther. 2, 543–548 (2003).

    CAS  PubMed  Google Scholar 

  42. Koniaras, K., Cuddihy, A. R., Christopoulos, H., Hogg, A. & O'Connell, M. J. Inhibition of Chk1-dependent G2 DNA damage checkpoint radiosensitizes p53 mutant human cells. Oncogene 20, 7453–7463 (2001).

    Article  CAS  PubMed  Google Scholar 

  43. Wang, H. et al. Ku affects the ataxia and Rad 3-related/CHK1-dependent S phase checkpoint response after camptothecin treatment. Cancer Res. 62, 2483–2487 (2002).

    CAS  PubMed  Google Scholar 

  44. Akinaga, S., Nomura, K., Gomi, K., and Okabe, M. Enhancement of antitumor activity of mitomycin C in vitro and in vivo by UCN-01, a selective inhibitor of protein kinase C. Cancer Chemother. Pharmacol. 32, 183–189 (1993).

    Article  CAS  PubMed  Google Scholar 

  45. Hsueh, C., Kelsen, D., and Schwartz, G. K. UCN-01 suppresses thymidylate synthase gene expression and enhances 5-fluorouracil-induced apoptosis in sequence-dependent manner. Clin. Cancer Res. 4, 2201–2206 (1998).

    CAS  PubMed  Google Scholar 

  46. Bunch, R. T. & Eastman, A. Enhancement of cisplatin-induced cytotoxicity by 7-hydroxystaurosporine (ucn-01), a new G2-checkpoint inhibitor. Clin. Cancer Res. 2, 791–797 (1996).

    CAS  PubMed  Google Scholar 

  47. Shao, R. et al. Abrogation of an S-phase checkpoint and potentiation of camptothecin cytotoxicity by 7-hydroxystaurosporine (UCN–01) in human cancer cell lines, possibly influenced by p53 function. Cancer Res. 57, 4029–4035 (1997).

    CAS  PubMed  Google Scholar 

  48. Russell, K. J. et al. Abrogation of the G2 checkpoint results in differential radiosensitization of G1 checkpoint-deficient and G1 checkpoint-competent cells. Cancer Res. 55, 1639–1642 (1995).

    CAS  PubMed  Google Scholar 

  49. Wang, Q. et al. UCN-01: a potent abrogator of G2 checkpoint function in cancer cells with disrupted p53. J. Natl. Cancer Inst. 88, 956–965 (1996).

    Article  CAS  PubMed  Google Scholar 

  50. Jeggo, P. A., Carr, A. M. & Lehmann, A. R. Splitting the ATM: distinct repair and checkpoint defects in ataxia-telangiectasia. Trends Genet. 14, 312–316 (1998).

    Article  CAS  PubMed  Google Scholar 

  51. Xu, B., Kim, S. T., Lim, D. S. & Kastan, M. B. Two molecularly distinct G(2)/M checkpoints are induced by ionizing irradiation. Mol. Cell. Biol. 22, 1049–1059 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Lehmann, A. R. et al. A derivative of an ataxia-telangiectasia (A-T) cell line with normal radiosensitivity but A-T-like inhibition of DNA synthesis. Int. J. Radiat. Biol. Relat. Stud. Phys. Chem. Med. 49, 639–643 (1986).

    Article  CAS  PubMed  Google Scholar 

  53. Griffiths, D. J., Barbet, N. C., McCready, S., Lehmann, A. R. & Carr, A. M. Fission yeast rad17: a homologue of budding yeast RAD24 that shares regions of sequence similarity with DNA polymerase accessory proteins. EMBO J. 14, 5812–5823 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Kanter-Smoler, G., Knudsen, K. E., Jimenez, G., Sunnerhagen, P. & Subramani, S. Separation of phenotypes in mutant alleles of the Schizosaccharomyces pombe cell-cycle checkpoint gene rad1+. Mol. Biol. Cell 6, 793–805 (1995).

    Article  Google Scholar 

  55. al-Khodairy, F. et al. Identification and characterization of new elements involved in checkpoint and feedback controls in fission yeast. Mol. Biol. Cell 5, 147–160 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Groth, A. et al. Human Tousled like kinases are targeted by an ATM- and Chk1-dependent DNA damage checkpoint. EMBO J. 22, 1676–1687 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Krause, D. R. et al. Suppression of Tousled-like kinase activity after DNA damage or replication block requires ATM, NBS1 and Chk1. Oncogene 22, 5927–5937 (2003).

    Article  CAS  PubMed  Google Scholar 

  58. Sausville, E. A. et al. Phase I trial of 72-hour continuous infusion UCN-01 in patients with refractory neoplasms. J. Clin. Oncol. 19, 2319–2333 (2001).

    Article  CAS  PubMed  Google Scholar 

  59. Matsuoka, S., Huang, M. & Elledge, S. J. Linkage of ATM to cell cycle regulation by the Chk2 protein kinase. Science 282, 1893–1897 (1998). Work in this reference, and in references 60, 62 and 63, describes the cloning and preliminary biochemical characterization of CHK2.

    Article  CAS  PubMed  Google Scholar 

  60. Chaturvedi, P. et al. Mammalian Chk2 is a downstream effector of the ATM-dependent DNA damage checkpoint pathway. Oncogene 18, 4047–4054 (1999).

    Article  CAS  PubMed  Google Scholar 

  61. O'Neill, T. et al. Determination of substrate motifs for human Chk1 and hCds1/Chk2 by the oriented peptide library approach. J. Biol. Chem. 277, 16102–16115 (2002).

    Article  CAS  PubMed  Google Scholar 

  62. Blasina, A. et al. A human homologue of the checkpoint kinase Cds1 directly inhibits Cdc25 phosphatase. Curr. Biol. 9, 1–10 (1999).

    Article  CAS  PubMed  Google Scholar 

  63. Brown, A. L. et al. A human Cds1-related kinase that functions downstream of ATM protein in the cellular response to DNA damage. Proc. Natl Acad. Sci. USA 96, 3745–3750 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Chehab, N. H., Malikzay, A., Appel, M. & Halazonetis, T. D. Chk2/hCds1 functions as a DNA damage checkpoint in G(1) by stabilizing p53. Genes Dev. 14, 278–288 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Falck, J., Mailand, N., Syljuasen, R. G., Bartek, J. & Lukas, J. The ATM–Chk2–Cdc25A checkpoint pathway guards against radioresistant DNA synthesis. Nature 410, 842–847 (2001).

    Article  CAS  PubMed  Google Scholar 

  66. Falck, J., Petrini, J. H., Williams, B. R., Lukas, J. & Bartek, J. The DNA damage-dependent intra-S phase checkpoint is regulated by parallel pathways. Nature Genet. 30, 290–294 (2002). References 65 and 66 describe the first signalling and effector cascade that provided a mechanistic insight into the ionizing-radiation-induced intra-S-phase checkpoint in terms of its direct impact on cell-cycle machinery.

    Article  PubMed  Google Scholar 

  67. Hirao, A. et al. Chk2 is a tumor suppressor that regulates apoptosis in both an ATM-dependent and ATM-independent manner. Mol. Cell. Biol. 22, 6521–6532 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Takai, H. et al. Chk2-deficient mice exhibit radioresistance and defective p53-mediated transcription. EMBO J. 21, 5195–5205 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Jack, M. T. et al. Chk2 is dispensable for p53-mediated G1 arrest but is required for a latent p53-mediated apoptotic response. Proc. Natl Acad. Sci. USA 99, 9825–9829 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Bartek, J. & Lukas, J. Chk1 and Chk2 kinases in checkpoint control and cancer. Cancer Cell. 3, 421–429 (2003).

    Article  CAS  PubMed  Google Scholar 

  71. Hirao, A. et al. DNA damage-induced activation of p53 by the checkpoint kinase Chk2. Science 287, 1824–1827 (2000). Work described in this reference and references 67–69 show that CHK2 is crucial for IR-induced apoptosis and indicates that CHK2 could be a radioprotection target.

    Article  CAS  PubMed  Google Scholar 

  72. Chehab, N. H., Malikzay, A., Stavridi, E. S. & Halazonetis, T. D. Phosphorylation of Ser-20 mediates stabilization of human p53 in response to DNA damage. Proc. Natl Acad. Sci. USA 96, 13777–13782 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Shieh, S. Y., Ahn, J., Tamai, K., Taya, Y. & Prives, C. The human homologs of checkpoint kinases Chk1 and Cds1 (Chk2) phosphorylate p53 at multiple DNA damage-inducible sites. Genes Dev. 14, 289–300 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Craig, A. et al. Allosteric effects mediate CHK2 phosphorylation of the p53 transactivation domain. EMBO Rep. 4, 787–792 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Wu, Z. et al. Mutation of mouse p53 Ser23 and the response to DNA damage. Mol. Cell. Biol. 22, 2441–2449 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Ahn, J., Urist, M. & Prives, C. Questioning the role of checkpoint kinase 2 in the p53 DNA damage response. J. Biol. Chem. 278, 20480–20489 (2003).

    Article  CAS  PubMed  Google Scholar 

  77. Jallepalli, P. V., Lengauer, C., Vogelstein, B. & Bunz, F. The Chk2 tumor suppressor is not required for p53 responses in human cancer cells. J. Biol. Chem. 278, 20475–20479 (2003).

    Article  CAS  PubMed  Google Scholar 

  78. Brown, K. D. et al. The mismatch repair system is required for S-phase checkpoint activation. Nature Genet. 33, 80–84 (2003).

    Article  CAS  PubMed  Google Scholar 

  79. Giannini, G. et al. Human MRE11 is inactivated in mismatch repair-deficient cancers. EMBO Rep. 3, 248–254 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Keramaris, E., Hirao, A., Slack, R. S., Mak, T. W. & Park, D. S. ATM can regulate p53 and neuronal death independent of Chk2 in response to DNA damage. J. Biol. Chem. 278, 37782–37789 (2003).

    Article  CAS  PubMed  Google Scholar 

  81. Yang, S., Kuo, C., Bisi, J. E. & Kim, M. K. PML-dependent apoptosis after DNA damage is regulated by the checkpoint kinase hCds1/Chk2. Nature Cell Biol. 4, 865–870 (2002).

    Article  CAS  PubMed  Google Scholar 

  82. Stevens, C., Smith, L. & La Thangue, N. B. Chk2 activates E2F-1 in response to DNA damage. Nature Cell Biol. 5, 401–409 (2003).

    Article  CAS  PubMed  Google Scholar 

  83. Komarov, P. G. et al. A chemical inhibitor of p53 that protects mice from the side effects of cancer therapy. Science 285, 1733–1737 (1999). This reference describes the identification — by chemical library screening — and in vitro and in vivo testing of a p53 inhibitor, and indicates that inhibition of the p53 pathway could reduce IR-induced DNA damage and lead to radioprotection.

    Article  CAS  PubMed  Google Scholar 

  84. Gudkov, A. V. & Komarova, E. A. The role of p53 in determining sensitivity to radiotherapy. Nature Rev. Cancer. 3, 117–129 (2003).

    Article  CAS  Google Scholar 

  85. Botchkarev, V. A. et al. p53 is essential for chemotherapy-induced hair loss. Cancer Res. 60, 5002–5006 (2000).

    CAS  PubMed  Google Scholar 

  86. Davis, S. T. et al. Prevention of chemotherapy-induced alopecia in rats by CDK inhibitors. Science 291, 134–137 (2001).

    Article  CAS  PubMed  Google Scholar 

  87. Kim, S. T., Xu, B. & Kastan, M. B. Involvement of the cohesin protein, Smc1, in Atm-dependent and independent responses to DNA damage. Genes Dev. 16, 560–570 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Komarova, E. A., Christov, K., Faerman, A. I. & Gudkov, A. V. Different impact of p53 and p21 on the radiation response of mouse tissues. Oncogene 19, 3791–3798 (2000).

    Article  CAS  PubMed  Google Scholar 

  89. Lee, J. S., Collins, K. M., Brown, A. L., Lee, C. H. & Chung, J. H. hCds1-mediated phosphorylation of BRCA1 regulates the DNA damage response. Nature 404, 201–204 (2000).

    Article  CAS  PubMed  Google Scholar 

  90. Zhang, J. et al. Chk2 phosphorylation of BRCA1 regulates DNA double-strand break repair. Mol. Cell. Biol. 24, 708–718 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Zou, L. & Elledge, S. J. Sensing DNA damage through ATRIP recognition of RPA–ssDNA complexes. Science 300, 1542–1548 (2003).

    Article  CAS  PubMed  Google Scholar 

  92. Rouse, J. & Jackson, S. P. Interfaces between the detection, signaling, and repair of DNA damage. Science 297, 547–551 (2002).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  94. D'Amours, D. & Jackson, S. P. The Mre11 complex: at the crossroads of DNA repair and checkpoint signalling. Nature Rev. Mol. Cell Biol. 3, 317–327 (2002).

    Article  CAS  Google Scholar 

  95. Petrini, H. J. & Stracker, T. H. The cellular response to DNA double strand breaks: defining the sensors and mediators. Trends Cell Biol. 13, 458–462 (2003).

    Article  CAS  PubMed  Google Scholar 

  96. Pinedo, H. M. & Peters, G. F. Fluorouracil: biochemistry and pharmacology. J. Clin. Oncol. 6, 1653–1664 (1988).

    Article  CAS  PubMed  Google Scholar 

  97. Longley, D. B., Harkin, D. P. & Johnston, P. G. 5-fluorouracil: mechanisms of action and clinical strategies. Nature Rev. Cancer 3, 330–338 (2003).

    Article  CAS  Google Scholar 

  98. Advanced Colorectal Cancer Meta-Analysis Project. Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: evidence in terms of response rate. J. Clin. Oncol. 10, 896–903 (1992).

  99. Peters, G. J. & van der Vijgh, W. J. Protection of normal tissues from the cytotoxic effects of chemotherapy and radiation by amifostine (WR-2721): preclinical aspects. Eur. J. Cancer. 31A, S1–S7 (1995).

    Article  CAS  PubMed  Google Scholar 

  100. Capizzi, R. Amifostine: the preclinical basis for broad-spectrum selective cytoprotection of normal tissues from cytotoxic therapies. Semin. Oncol. 23, 2–17 (1996).

    CAS  PubMed  Google Scholar 

  101. Budd, G. T. et al. Randomized trial of carboplatin plus amifostine versus carboplatin alone in patients with advanced solid tumors. Cancer 80, 1134–1140 (1997).

    Article  CAS  PubMed  Google Scholar 

  102. Santini, V. & Giles, F. J. The potential of amifostine: from cytoprotectant to therapeutic agent. Haematologica 84, 1035–1042 (1999).

    CAS  PubMed  Google Scholar 

  103. Schiller, J. H. et al. Amifostine, cisplatin, and vinblastine in metastatic non-small-cell lung cancer: a report of high response rates and prolonged survival. J. Clin. Oncol. 14, 1913–1921 (1996).

    Article  CAS  PubMed  Google Scholar 

  104. Andreassen, C. N., Grau, C. & Lindegaard, J. C. Chemical radioprotection: a critical review of amifostine as a cytoprotector in radiotherapy. Semin. Radiat. Oncol. 13, 62–72 (2003).

    Article  PubMed  Google Scholar 

  105. Li, Y., Sun, X., LaMont, J. T., Pardee, A. B. & Li, C. J. Selective killing of cancer cells by β-lapachone: direct checkpoint activation as a strategy against cancer. Proc. Natl Acad. Sci. USA 100, 2674–2678 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

B.Z. would like to acknowledge helpful discussions with S. Davis and E. Rowinsky during the course of writing this review.

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Correspondence to Bin-Bing S. Zhou.

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DATABASES

Cancer.gov

non-Hodgkin's lymphoma

ovarian cancer

pancreatic cancer

LocusLink

ABL

AKT

ATM

ATR

BAX

BCR

BRCA1

CDC25A

CDC25C

CHK1

CHK2

claspin

E2F1

p53

PML

SMC1

Glossary

THERAPEUTIC WINDOW

The ratio between the toxic dose and the therapeutic dose of a drug, used as a measure of the relative safety of the drug for a particular treatment. Also called therapeutic index.

ATAXIA TELANGIECTASIA

(AT). AT belongs to a group of human diseases collectively known as 'genomic instability syndromes'. It is characterized by cerebellar degeneration — which leads to severe, progressive neuromotor dysfunction — immunodeficiency, genomic instability, thymic and gonadal atrophy, and a striking predisposition to lymphoreticular malignancies. It is associated with defects in the ATM gene, a member of the phosphatidylinositol 3-kinase superfamily.

CELL-CYCLE CHECKPOINTS

Regulatory mechanisms that do not allow the initiation of a new phase of the cell cycle before the previous one is completed, or temporarily arrest cell-cycle progression in response to stress. DNA damage activates specific checkpoints at the G1–S and G2–M boundaries, and in S phase, with each one based on a different mechanism.

MITOTIC CATASTROPHE

A series of cellular events that occur after premature and aberrant mitosis and that usually result in cell death. Such a mitosis does not produce proper chromosome segregation and cell division, but leads to the formation of large non-viable cells with several nuclei, which contain fractions of broken chromosomes.

RADIORESISTANT DNA SYNTHESIS

Characteristic inability to arrest DNA synthesis after irradiation, commonly seen in cells from patients with ataxia telangiectasia and those who are defective in other components of the intra-S-phase checkpoint.

XEROSTOMIA

Dryness of the mouth resulting from diminished or arrested salivary secretion

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Zhou, BB., Bartek, J. Targeting the checkpoint kinases: chemosensitization versus chemoprotection. Nat Rev Cancer 4, 216–225 (2004). https://doi.org/10.1038/nrc1296

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