Nucleoside analogs: Molecular mechanisms signaling cell death

Oncogene

Volumn 27, Issue 50, 2008, Pages 6522-6537

  Ewald, B ^a   Sampath, D ^a   Plunkett, W ^a  

^a UNIVERSITY OF TEXAS MD ANDERSON CANCER CENTER   (United States)

Author keywords

Checkpoints; DNA damage; DNA methylation; DNA repair; Sensors; Stalled replication forks

Indexed keywords

2' CYANO 2' DEOXY 1 BETA DEXTRO ARABINOPENTOFURANOSYLCYTOSINE; 2' CYANO 2',3' DIDEHYDRO 2 ,3' DIDEOXYCYTIDINE; 5 AZA 2' DEOXYCYTIDINE; 7 HYDROXYSTAUROSPORINE; APOPTOSOME; AZACITIDINE; CELL PROTEIN; CISPLATIN; CLADRIBINE; CLOFARABINE; CYTARABINE; DEOXYCYTIDINE; DNA POLYMERASE; FLUDARABINE; FLUOROURACIL; FORODESINE; GEMCITABINE; MICRORNA; NUCLEOSIDE DERIVATIVE; PENTOSTATIN; TOPOTECAN; TROXACITABINE; UNCLASSIFIED DRUG; ZEBULARINE;

ACUTE GRANULOCYTIC LEUKEMIA; ANTINEOPLASTIC ACTIVITY; APOPTOSIS; BREAST CANCER; CANCER RESISTANCE; CELL CYCLE ARREST; CELL DEATH; CLINICAL TRIAL; CPG ISLAND; DNA DAMAGE; DNA METHYLATION; DNA REPAIR; DNA REPLICATION; DNA STRAND BREAKAGE; DNA SYNTHESIS; DNA SYNTHESIS INHIBITION; DRUG STRUCTURE; DRUG TARGETING; EPIGENETICS; EXPERIMENTAL NEOPLASM; GENE SILENCING; HEMATOLOGIC MALIGNANCY; HUMAN; LOW DRUG DOSE; LUNG NON SMALL CELL CANCER; MYELODYSPLASTIC SYNDROME; NONHUMAN; OVARY CANCER; PANCREAS CANCER; PRIORITY JOURNAL; REVIEW; RNA REPAIR; SOLID TUMOR;

ANIMALS; APOPTOSIS; DNA DAMAGE; DNA METHYLATION; DNA REPAIR; DNA REPLICATION; HUMANS; NUCLEOSIDES; SIGNAL TRANSDUCTION;

EID: 54949098894     PISSN: 09509232     EISSN: 14765594     Source Type: Journal    
DOI: 10.1038/onc.2008.316     Document Type: Review

References (213)

1. Achanta G, Pelicano H, Feng L, Plunkett W, Huang P. (2001). Interaction of p53 and DNA-PK in response to nucleoside analogues: potential role as a sensor complex for DNA damage. Cancer Res 61: 8723-8729.
2. Agarwal RP. (1982). Inhibitors of adenosine deaminase. Pharmacol Ther 17: 399-429.
3. Ahluwalia A, Yan P, Hurteau JA, Bigsby RM, Jung SH, Huang TH et al. (2001). DNA methylation and ovarian cancer. I. Analysis of CpG island hypermethylation in human ovarian cancer using differential methylation hybridization. Gynecol Oncol 82: 261-268.
4. Azuma A, Huang P, Matsuda A, Plunkett W. (2001). 2′-C-cyano- 2′-deoxy-1-beta-D-arabino-pentofuranosylcytosine: a novel anticancer nucleoside analog that causes both DNA strand breaks and G(2) arrest. Mol Pharmacol 59: 725-731.
5. Baker CH, Banzon J, Bollinger JM, Stubbe J, Samano V, Robins MJ et al. (1991). 2′-Deoxy-2′-methylenecytidine and 2′-deoxy-2′, 2′-difluorocytidine 5′-diphosphates: potent mechanism-based inhibitors of ribonucleotide reductase. J Med Chem 34: 1879-1884.
6. Bakkenist CJ, Kastan MB. (2003). DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 421: 499-506.
7. Balakrishnan K, Nimmanapalli R, Ravandi F, Keating MJ, Gandhi V. (2006). Forodesine, an inhibitor of purine nucleoside phosphorylase, induces apoptosis in chronic lymphocytic leukemia cells. Blood 108: 2392-2398.
8. Bantia S, Ananth SL, Parker CD, Horn LL, Upshaw R. (2003). Mechanism of inhibition of T-acute lymphoblastic leukemia cells by PNP inhibitor-BCX-1777. Int Immunopharmacol 3: 879-887.
9. Bartek J, Lukas J. (2003). Chk1 and Chk2 kinases in checkpoint control and cancer. Cancer Cell 3: 421-429.
10. Belinsky SA, Nikula KJ, Palmisano WA, Michels R, Saccomanno G, Gabrielson E et al. (1998). Aberrant methylation of p16(INK4a) is an early event in lung cancer and a potential biomarker for early diagnosis. Proc Natl Acad Sci USA 95: 11891-11896.
11. Bellosillo B, Villamor N, Lopez-Guillermo A, Marce S, Bosch F, Campo E et al. (2002). Spontaneous and drug-induced apoptosis is mediated by conformational changes of Bax and Bak in B-cell chronic lymphocytic leukemia. Blood 100: 1810-1816.
12. Bianchi V, Pontis E, Reichard P. (1992). Dynamics of the dATP pool in cultured mammalian cells. Exp Cell Res 199: 120-128.
13. Brown EJ, Baltimore D. (2000). ATR disruption leads to chromosomal fragmentation and early embryonic lethality. Genes Dev 14: 397-402.
14. Brueckner B, Kuck D, Lyko F. (2007). DNA methyltransferase inhibitors for cancer therapy. Cancer J 13: 17-22.
15. Bueno MJ, Perez de Castro I, Gomez de Cedron M, Santos J, Calin GA, Cigudosa JC et al. (2008). Genetic and epigenetic silencing of microRNA-203 enhances ABL1 and BCR-ABL1 oncogene expression. Cancer Cell 13: 496-506.
16. Burma S, Chen DJ. (2004). Role of DNA-PK in the cellular response to DNA double-strand breaks. DNA Repair (Amst) 3: 909-918.
17. Buschfort C, Muller MR, Seeber S, Rajewsky MF, Thomale J. (1997). DNA excision repair profiles of normal and leukemic human lymphocytes: functional analysis at the single-cell level. Cancer Res 57: 651-658.
18. Busino L, Chiesa M, Draetta GF, Donzelli M. (2004). Cdc25A phosphatase: combinatorial phosphorylation, ubiquitylation and proteolysis. Oncogene 23: 2050-2056.
19. Calin GA, Croce CM. (2006). MicroRNA signatures in human cancers. Nat Rev Cancer 6: 857-866.
20. Carney JP, Maser RS, Olivares H, Davis EM, Le Beau M, Yates III JR et al. (1998). The hMre11/hRad50 protein complex and Nijmegen breakage syndrome: linkage of double-strand break repair to the cellular DNA damage response. Cell 93: 477-486.
21. Carson DA, Carrera CJ. (1990). Immunodeficiency secondary to adenosine deaminase deficiency and purine nucleoside phosphorylation deficiency. Semin Hematol 27: 260-269.
22. Carson DA, Seto S, Wasson DB, Carrera CJ. (1986). DNA strand breaks, NAD metabolism, and programmed cell death. Exp Cell Res 164: 273-281.
23. Carson DA, Wasson DB, Esparza LM, Carrera CJ, Kipps TJ, Cottam HB. (1992). Oral antilymphocyte activity and induction of apoptosis by 2-chloro-2′-arabino-fluoro-2′-deoxyadenosine. Proc Natl Acad Sci USA 89: 2970-2974.
24. Carson DA, Wasson DB, Taetle R, Yu A. (1983). Specific toxicity of 2-chlorodeoxyadenosine toward resting and proliferating human lymphocytes. Blood 62: 737-743.
25. Catovsky D, Richards S, Matutes E, Oscier D, Dyer MJ, Bezares RF et al. (2007). Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial. Lancet 370: 230-239.
26. Chaney SG, Sancar A. (1996). DNA repair: enzymatic mechanisms and relevance to drug response. J Natl Cancer Inst 88: 1346-1360.
27. Chang CN, Doong SL, Zhou JH, Beach JW, Jeong LS, Chu CK et al. (1992). Deoxycytidine deaminase-resistant stereoisomer is the active form of (+/-)-2′, 3′-dideoxy-3′-thiacytidine in the inhibition of hepatitis B virus replication. J Biol Chem 267: 13938-13942.
28. Chen R, Keating MJ, Gandhi V, Plunkett W. (2005). Transcription inhibition by flavopiridol: mechanism of chronic lymphocytic leukemia cell death. Blood 106: 2513-2519.
29. Chen Y, Sanchez Y. (2004). Chk1 in the DNA damage response: conserved roles from yeasts to mammals. DNA Repair (Amst) 3: 1025-1032.
30. Cheng JC, Matsen CB, Gonzales FA, Ye W, Greer S, Marquez VE et al. (2003). Inhibition of DNA methylation and reactivation of silenced genes by zebularine. J Natl Cancer Inst 95: 399-409.
31. Chini CC, Chen J. (2003). Human claspin is required for replication checkpoint control. J Biol Chem 278: 30057-30062.
32. Chou KM, Kukhanova M, Cheng YC. (2000). A novel action of human apurinic/apyrimidinic endonuclease: excision of L-configuration deoxyribonucleoside analogs from the 3′ termini of DNA. J Biol Chem 275: 31009-31015.
33. Cliby WA, Lewis KA, Lilly KK, Kaufmann SH. (2002). S phase and G2 arrests induced by topoisomerase I poisons are dependent on ATR kinase function. J Biol Chem 277: 1599-1606.
34. Cortez D, Guntuku S, Qin J, Elledge SJ. (2001). ATR and ATRIP: partners in checkpoint signaling. Science 294: 1713-1716.
35. Costanzo V, Robertson K, Bibikova M, Kim E, Grieco D, Gottesman M et al. (2001). Mre11 protein complex prevents double-strand break accumulation during chromosomal DNA replication. Mol Cell 8: 137-147.
36. Crews KR, Gandhi V, Srivastava DK, Razzouk BI, Tong X, Behm FG et al. (2002). Interim comparison of a continuous infusion versus a short daily infusion of cytarabine given in combination with cladribine for pediatric acute myeloid leukemia. J Clin Oncol 20: 4217-4224.
37. D'Amours D, Jackson SP. (2002). The Mre11 complex: at the crossroads of dna repair and checkpoint signalling. Nat Rev Mol Cell Biol 3: 317-327.
38. de Klein A, Muijtjens M, van Os R, Verhoeven Y, Smit B, Carr AM et al. (2000). Targeted disruption of the cell-cycle checkpoint gene ATR leads to early embryonic lethality in mice. Curr Biol 10: 479-482.
39. de Laat WL, Jaspers NG, Hoeijmakers JH. (1999). Molecular mechanism of nucleotide excision repair. Genes Dev 13: 768-785.
40. de Toledo SM, Azzam EI, Dahlberg WK, Gooding TB, Little JB. (2000). ATM complexes with HDM2 and promotes its rapid phosphorylation in a p53-independent manner in normal and tumor human cells exposed to ionizing radiation. Oncogene 19: 6185-6193.
41. Delacroix S, Wagner JM, Kobayashi M, Yamamoto K, Karnitz LM. (2007). The Rad9-Hus1-Rad1 (9-1-1) clamp activates checkpoint signaling via TopBP1. Genes Dev 21: 1472-1477.
42. Dewson G, Snowden RT, Almond JB, Dyer MJ, Cohen GM. (2003). Conformational change and mitochondrial translocation of Bax accompany proteasome inhibitor-induced apoptosis of chronic lymphocytic leukemic cells. Oncogene 22: 2643-2654.
43. Doench JG, Sharp PA. (2004). Specificity of microRNA target selection in translational repression. Genes Dev 18: 504-511.
44. Eastman A, Kohn EA, Brown MK, Rathman J, Livingstone M, Blank DH et al. (2002). A novel indolocarbazole, ICP-1, abrogates DNA damage-induced cell cycle arrest and enhances cytotoxicity: similarities and differences to the cell cycle checkpoint abrogator UCN-01. Mol Cancer Ther 1: 1067-1078.
45. Eichhorst BF, Busch R, Hopfinger G, Pasold R, Hensel M, Steinbrecher C et al. (2006). Fludarabine plus cyclophosphamide versus fludarabine alone in first-line therapy of younger patients with chronic lymphocytic leukemia. Blood 107: 885-891.
46. Ewald B, Sampath D, Plunkett W. (2007). H2AX phosphorylation marks gemcitabine-induced stalled replication forks and their collapse upon S-phase checkpoint abrogation. Mol Cancer Ther 6: 1239-1248.
47. Ewald B, Sampath D, Plunkett W. (2008). ATM and the Mre11-Rad50-Nbs1 complex respond to nucleoside analogue-induced stalled replication forks and contribute to drug resistance. Cancer Res (in press).
48. Flinn IW, Neuberg DS, Grever MR, Dewald GW, Bennett JM, Paietta EM et al. (2007). Phase III trial of fludarabine plus cyclophosphamide compared with fludarabine for patients with previously untreated chronic lymphocytic leukemia: US Intergroup Trial E2997. J Clin Oncol 25: 793-798.
49. Gandhi V, Balakrishnan K. (2007). Pharmacology and mechanism of action of forodesine, a T-cell targeted agent. Semin Oncol 34: S8-S12.
50. Geleziunas R, McQuillan A, Malapetsa A, Hutchinson M, Kopriva D, Wainberg MA et al. (1991). Increased DNA synthesis and repair-enzyme expression in lymphocytes from patients with chronic lymphocytic leukemia resistant to nitrogen mustards. J Natl Cancer Inst 83: 557-564.
51. Genini D, Adachi S, Chao Q, Rose DW, Carrera CJ, Cottam HB et al. (2000a). Deoxyadenosine analogs induce programmed cell death in chronic lymphocytic leukemia cells by damaging the DNA and by directly affecting the mitochondria. Blood 96: 3537-3543.
52. Genini D, Budihardjo I, Plunkett W, Wang X, Carrera CJ, Cottam HB et al. (2000b). Nucleotide requirements for the in vitro activation of the apoptosis protein-activating factor-1-mediated caspase pathway. J Biol Chem 275: 29-34.
53. Goodman GR, Burian C, Koziol JA, Saven A. (2003). Extended follow-up of patients with hairy cell leukemia after treatment with cladribine. J Clin Oncol 21: 891-896.
54. Gottifredi V, Shieh S, Taya Y, Prives C. (2001). p53 accumulates but is functionally impaired when DNA synthesis is blocked. Proc Natl Acad Sci USA 98: 1036-1041.
55. Gourdeau H, Bibeau L, Ouellet F, Custeau D, Bernier L, Bowlin T. (2001a). Comparative study of a novel nucleoside analogue (Troxatyl, troxacitabine, BCH-4556) and AraC against leukemic human tumor xenografts expressing high or low cytidine deaminase activity. Cancer Chemother Pharmacol 47: 236-240.
56. Gourdeau H, Clarke ML, Ouellet F, Mowles D, Selner M, Richard A et al. (2001b). Mechanisms of uptake and resistance to troxacitabine, a novel deoxycytidine nucleoside analogue, in human leukemic and solid tumor cell lines. Cancer Res 61: 7217-7224.
57. Grant S. (1998). Ara-C: cellular and molecular pharmacology. Adv Cancer Res 72: 197-233.
58. Griffith DA, Jarvis SM. (1996). Nucleoside and nucleobase transport systems of mammalian cells. Biochim Biophys Acta 1286: 153-181.
59. Grove KL, Cheng YC. (1996). Uptake and metabolism of the new anticancer compound beta-L-(-)-dioxolane-cytidine in human prostate carcinoma DU-145 cells. Cancer Res 56: 4187-4191.
60. Grove KL, Guo X, Liu SH, Gao Z, Chu CK, Cheng YC. (1995). Anticancer activity of beta-L-dioxolane-cytidine, a novel nucleoside analogue with the unnatural L configuration. Cancer Res 55: 3008-3011.
61. Han L, Witmer PD, Casey E, Valle D, Sukumar S. (2007). DNA methylation regulates MicroRNA expression. Cancer Biol Ther 6: 1284-1288.
62. Heffernan TP, Simpson DA, Frank AR, Heinloth AN, Paules RS, Cordeiro-Stone M et al. (2002). An ATR- and Chk1-dependent S checkpoint inhibits replicon initiation following UVC-induced DNA damage. Mol Cell Biol 22: 8552-8561.
63. Heinemann V, Hertel LW, Grindey GB, Plunkett W. (1988). Comparison of the cellular pharmacokinetics and toxicity of 2′, 2′- difluorodeoxycytidine and 1-beta-D-arabinofuranosylcytosine. Cancer Res 48: 4024-4031.
64. Heinemann V, Xu YZ, Chubb S, Sen A, Hertel LW, Grindey GB et al. (1990). Inhibition of ribonucleotide reduction in CCRF-CEM cells by 2′, 2′-difluorodeoxycytidine. Mol Pharmacol 38: 567-572.
65. Heinemann V, Xu YZ, Chubb S, Sen A, Hertel LW, Grindey GB et al. (1992). Cellular elimination of 2′, 2′-difluorodeoxycytidine 5′-triphosphate: a mechanism of self-potentiation. Cancer Res 52: 533-539.
66. Helleday T, Petermann E, Lundin C, Hodgson B, Sharma RA. (2008). DNA repair pathways as targets for cancer therapy. Nat Rev Cancer 8: 193-204.
67. Hentosh P, Koob R, Blakley RL. (1990). Incorporation of 2-halogeno-2′-deoxyadenosine 5-triphosphates into DNA during replication by human polymerases alpha and beta. J Biol Chem 265: 4033-4040.
68. Herman JG, Civin CI, Issa JP, Collector MI, Sharkis SJ, Baylin SB. (1997). Distinct patterns of inactivation of p15INK4B and p16INK4A characterize the major types of hematological malignancies. Cancer Res 57: 837-841.
69. Herman JG, Jen J, Merlo A, Baylin SB. (1996). Hypermethylation-associated inactivation indicates a tumor suppressor role for p15INK4B. Cancer Res 56: 722-727.
70. Hertel LW, Boder GB, Kroin JS, Rinzel SM, Poore GA, Todd GC et al. (1990). Evaluation of the antitumor activity of gemcitabine (2′, 2′-difluoro-2′-deoxycytidine). Cancer Res 50: 4417-4422.
71. Hickson I, Zhao Y, Richardson CJ, Green SJ, Martin NMB, Orr AI et al. (2004). Identification and characterization of a novel and specific inhibitor of the ataxia-telangiectasia mutated kinase ATM. Cancer Res 64: 9152-9159.
72. Hotte SJ, Oza A, Winquist EW, Moore M, Chen EX, Brown S et al. (2006). Phase I trial of UCN-01 in combination with topotecan in patients with advanced solid cancers: a Princess Margaret Hospital Phase II Consortium Study. Ann Oncol 17: 334-340.
73. Hsi LC, Xi X, Wu Y, Lippman SM. (2005). The methyltransferase inhibitor 5-aza-2-deoxycytidine induces apoptosis via induction of 15-lipoxygenase-1 in colorectal cancer cells. Mol Cancer Ther 4: 1740-1746.
74. Huang P, Chubb S, Hertel LW, Grindey GB, Plunkett W. (1991). Action of 2′, 2′-difluorodeoxycytidine on DNA synthesis. Cancer Res 51: 6110-6117.
75. Huang P, Chubb S, Plunkett W. (1990). Termination of DNA synthesis by 9-beta-D-arabinofuranosyl-2-fluoroadenine. A mechanism for cytotoxicity. J Biol Chem 265: 16617-16625.
76. Huang P, Plunkett W. (1991). Action of 9-beta-D-arabinofuranosyl-2- fluoroadenine on RNA metabolism. Mol Pharmacol 39: 449-455.
77. Huang P, Sandoval A, Van Den Neste E, Keating MJ, Plunkett W. (2000). Inhibition of RNA transcription: a biochemical mechanism of action against chronic lymphocytic leukemia cells by fludarabine. Leukemia 14: 1405-1413.
78. Jazayeri A, Falck J, Lukas C, Bartek J, Smith GC, Lukas J et al. (2006). ATM- and cell cycle-dependent regulation of ATR in response to DNA double-strand breaks. Nat Cell Biol 8: 37-45.
79. Jeong SY, Kumagai A, Lee J, Dunphy WG. (2003). Phosphorylated claspin interacts with a phosphate-binding site in the kinase domain of Chk1 during ATR-mediated activation. J Biol Chem 278: 46782-46788.
80. Jiemjit A, Fandy TE, Carraway H, Bailey KA, Baylin S, Herman JG et al. (2008). p21(WAF1/CIP1) induction by 5-azacytosine nucleosides requires DNA damage. Oncogene 27: 3615-3623.
81. Johnson SA. (2001). Nucleoside analogues in the treatment of haematological malignancies. Expert Opin Pharmacother 2: 929-943.
82. Jones PA, Baylin SB. (2007). The epigenomics of cancer. Cell 128: 683-692.
83. Jones PL, Wolffe AP. (1999). Relationships between chromatin organization and DNA methylation in determining gene expression. Semin Cancer Biol 9: 339-347.
84. Kamiya K, Huang P, Plunkett W. (1996). Inhibition of the 3′-5′ exonuclease of human DNA polymerase epsilon by fludarabine-terminated DNA. J Biol Chem 271: 19428-19435.
85. Kanda T, Tada M, Imazeki F, Yokosuka O, Nagao K, Saisho H. (2005). 5-aza-2′-deoxycytidine sensitizes hepatoma and pancreatic cancer cell lines. Oncol Rep 14: 975-979.
86. Kantarjian H, Garcia-Manero G, Faderl S, Cortes J, Estrov Z, Boone P et al. (2007a). Phase I study of sapacitabine, an oral nucleoside analogue, in patients with advanced leukemias or myelodysplastic syndromes (MDS). ASH Annu Meet Abstr 110: 884.
87. Kantarjian H, Oki Y, Garcia-Manero G, Huang X, O'Brien S, Cortes J et al. (2007b). Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood 109: 52-57.
88. Karnitz LM, Flatten KS, Wagner JM, Loegering D, Hackbarth JS, Arlander SJ et al. (2005). Gemcitabine-induced activation of checkpoint signaling pathways that affect tumor cell survival. Mol Pharmacol 68: 1636-1644.
89. Kawabe T. (2004). G2 checkpoint abrogators as anticancer drugs. Mol Cancer Ther 3: 513-519.
90. Kicska GA, Long L, Horig H, Fairchild C, Tyler PC, Furneaux RH et al. (2001). Immucillin H, a powerful transition-state analog inhibitor of purine nucleoside phosphorylase, selectively inhibits human T lymphocytes. Proc Natl Acad Sci USA 98: 4593-4598.
91. Kitada S, Andersen J, Akar S, Zapata JM, Takayama S, Krajewski S et al. (1998). Expression of apoptosis-regulating proteins in chronic lymphocytic leukemia: correlations with In vitro and In vivo chemoresponses. Blood 91: 3379-3389.
92. Kohn EA, Ruth ND, Brown MK, Livingstone M, Eastman A. (2002). Abrogation of the S phase DNA damage checkpoint results in S phase progression or premature mitosis depending on the concentration of 7-hydroxystaurosporine and the kinetics of Cdc25C activation. J Biol Chem 277: 26553-26564.
93. Konopleva M, Tari AM, Estrov Z, Harris D, Xie Z, Zhao S et al. (2000). Liposomal Bcl-2 antisense oligonucleotides enhance proliferation, sensitize acute myeloid leukemia to cytosine-arabinoside, and induce apoptosis independent of other antiapoptotic proteins. Blood 95: 3929-3938.
94. Kortmansky J, Shah MA, Kaubisch A, Weyerbacher A, Yi S, Tong W et al. (2005). Phase I trial of the cyclin-dependent kinase inhibitor and protein kinase C inhibitor 7-hydroxystaurosporine in combination with Fluorouracil in patients with advanced solid tumors. J Clin Oncol 23: 1875-1884.
95. Kozlov SV, Graham ME, Peng C, Chen P, Robinson PJ, Lavin MF. (2006). Involvement of novel autophosphorylation sites in ATM activation. EMBO J 25: 3504-3514.
96. Krenitsky TA. (1967). Purine nucleoside phosphorylase: kinetics, mechanism, and specificity. Mol Pharmacol 3: 526-536.
97. Krishnan P, Fu Q, Lam W, Liou JY, Dutschman G, Cheng YC. (2002). Phosphorylation of pyrimidine deoxynucleoside analog diphosphates: selective phosphorylation of L-nucleoside analog diphosphates by 3-phosphoglycerate kinase. J Biol Chem 277: 5453-5459.
98. Krishnan P, Gullen EA, Lam W, Dutschman GE, Grill SP, Cheng YC. (2003). Novel role of 3-phosphoglycerate kinase, a glycolytic enzyme, in the activation of L-nucleoside analogs, a new class of anticancer and antiviral agents. J Biol Chem 278: 36726-36732.
99. Kufe DW, Major PP, Egan EM, Beardsley GP. (1980). Correlation of cytotoxicity with incorporation of ara-C into DNA. J Biol Chem 255: 8997-9000.
100. Kufe DW, Weichselbaum R, Egan EM, Dahlberg W, Fram RJ. (1984). Lethal effects of 1-beta-D-arabinofuranosylcytosine incorporation into deoxyribonucleic acid during ultraviolet repair. Mol Pharmacol 25: 322-326.
101. Kukhanova M, Liu SH, Mozzherin D, Lin TS, Chu CK, Cheng YC. (1995). L- and D-enantiomers of 2′, 3′-dideoxycytidine 5′-triphosphate analogs as substrates for human DNA polymerases. Implications for the mechanism of toxicity. J Biol Chem 270: 23055-23059.
102. Kumagai A, Lee J, Yoo HY, Dunphy WG. (2006). TopBP1 activates the ATR-ATRIP complex. Cell 124: 943-955.
103. Kurz EU, Lees-Miller SP. (2004). DNA damage-induced activation of ATM and ATM-dependent signaling pathways. DNA Repair 3: 889-900.
104. Lara Jr PN, Mack PC, Synold T, Frankel P, Longmate J, Gumerlock PH et al. (2005). The cyclin-dependent kinase inhibitor UCN-01 plus cisplatin in advanced solid tumors: a California cancer consortium phase I pharmacokinetic and molecular correlative trial. Clin Cancer Res 11: 4444-4450.
105. Lee J, Kumagai A, Dunphy WG. (2007). The Rad9-Hus1-Rad1 checkpoint clamp regulates interaction of TopBP1 with ATR. J Biol Chem 282: 28036-28044.
106. Leoni LM, Chao Q, Cottam HB, Genini D, Rosenbach M, Carrera CJ et al. (1998). Induction of an apoptotic program in cell-free extracts by 2-chloro-2′-deoxyadenosine 5′-triphosphate and cytochrome c. Proc Natl Acad Sci USA 95: 9567-9571.
107. Li LH, Olin EJ, Buskirk HH, Reineke LM. (1970). Cytotoxicity and mode of action of 5-azacytidine on L1210 leukemia. Cancer Res 30: 2760-2769.
108. Liu X, Guo Y, Li Y, Jiang Y, Chubb S, Azuma A et al. (2005). Molecular basis for G2 arrest induced by 2′-C-cyano-2′-deoxy-1-beta- D-arabino-pentofuranosylcytosine and consequences of checkpoint abrogation. Cancer Res 65: 6874-6881.
109. Liu X, Matsuda A, Plunkett W. (2008). Ataxia-telangiectasia and Rad3-related and DNA-dependent protein kinase cooperate in G2 checkpoint activation by the DNA strand-breaking nucleoside analogue 2′-C-cyano- 2′-deoxy-1-beta-D-arabino-pentofuranosylcytosine. Mol Cancer Ther 7: 133-142.
110. Liu Z, Marcucci G, Byrd JC, Grever M, Xiao J, Chan KK. (2006). Characterization of decomposition products and preclinical and low dose clinical pharmacokinetics of decitabine (5-aza-2′-deoxycytidine) by a new liquid chromatography/tandem mass spectrometry quantification method. Rapid Commun Mass Spectrom 20: 1117-1126.
111. Lopes M, Cotta-Ramusino C, Pellicioli A, Liberi G, Plevani P, Muzi-Falconi M et al. (2001). The DNA replication checkpoint response stabilizes stalled replication forks. Nature 412: 557-561.
112. Luo G, Yao MS, Bender CF, Mills M, Bladl AR, Bradley A et al. (1999). Disruption of mRad50 causes embryonic stem cell lethality, abnormal embryonic development, and sensitivity to ionizing radiation. Proc Natl Acad Sci USA 96: 7376-7381.
113. Mailand N, Diffley JF. (2005). CDKs promote DNA replication origin licensing in human cells by protecting Cdc6 from APC/C-dependent proteolysis. Cell 122: 915-926.
114. Matsuda A, Nakajima Y, Azuma A, Tanaka M, Sasaki T. (1991). Nucleosides and nucleotides. 100. 2′-C-cyano-2′-deoxy-1-beta-D-arabinofuranosyl- cytosine (CNDAC): design of a potential mechanism-based DNA-strand-breaking antineoplastic nucleoside. J Med Chem 34: 2917-2919.
115. Matsuoka S, Ballif BA, Smogorzewska A, McDonald III ER, Hurov KE, Luo J et al. (2007). ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science 316: 1160-1166.
116. Matsuura S, Tauchi H, Nakamura A, Kondo N, Sakamoto S, Endo S et al. (1998). Positional cloning of the gene for Nijmegen breakage syndrome. Nat Genet 19: 179-181.
117. Matthews DJ, Yakes FM, Chen J, Tadano M, Bornheim L, Clary DO et al. (2007). Pharmacological abrogation of S-phase checkpoint enhances the anti-tumor activity of gemcitabine in vivo. Cell Cycle 6: 104-110.
118. McDermott KM, Zhang J, Holst CR, Kozakiewicz BK, Singla V, Tlsty TD. (2006). p16(INK4a) prevents centrosome dysfunction and genomic instability in primary cells. PLoS Biol 4: e51.
119. Mertens D, Wolf S, Tschuch C, Mund C, Kienle D, Ohl S et al. (2006). Allelic silencing at the tumor-suppressor locus 13q14.3 suggests an epigenetic tumor-suppressor mechanism. Proc Natl Acad Sci USA 103: 7741-7746.
120. Mirzoeva OK, Petrini JH. (2001). DNA damage-dependent nuclear dynamics of the Mre11 complex. Mol Cell Biol 21: 281-288.
121. Mirzoeva OK, Petrini JH. (2003). DNA replication-dependent nuclear dynamics of the Mre11 complex. Mol Cancer Res 1: 207-218.
122. Miyashita T, Reed JC. (1993). Bcl-2 oncoprotein blocks chemotherapy-induced apoptosis in a human leukemia cell line. Blood 81: 151-157.
123. Montgomery JA, Shortnacy-Fowler AT, Clayton SD, Riordan JM, Secrist 3rd JA. (1992). Synthesis and biologic activity of 2′-fluoro-2-halo derivatives of 9-beta-D-arabinofuranosyladenine. J Med Chem 35: 397-401.
124. Moreno-Herrero F, de Jager M, Dekker NH, Kanaar R, Wyman C, Dekker C. (2005). Mesoscale conformational changes in the DNA-repair complex Rad50/Mre11/Nbs1 upon binding DNA. Nature 437: 440-443.
125. Morita S, Iida S, Kato K, Takagi Y, Uetake H, Sugihara K. (2006). The synergistic effect of 5-aza-2′-deoxycytidine and 5-fluorouracil on drug-resistant tumors. Oncology 71: 437-445.
126. Moufarij MA, Sampath D, Keating MJ, Plunkett W. (2006). Fludarabine increases oxaliplatin cytotoxicity in normal and chronic lymphocytic leukemia lymphocytes by suppressing interstrand DNA crosslink removal. Blood 108: 4187-4193.
127. Myers JS, Cortez D. (2006). Rapid activation of ATR by ionizing radiation requires ATM and Mre11. J Biol Chem 281: 9346-9350.
128. Nakatsuka S, Takakuwa T, Tomita Y, Hoshida Y, Nishiu M, Yamaguchi M et al. (2003). Hypermethylation of death-associated protein (DAP) kinase CpG island is frequent not only in B-cell but also in T- and natural killer (NK)/T-cell malignancies. Cancer Sci 94: 87-91.
129. O'Driscoll M, Ruiz-Perez VL, Woods CG, Jeggo PA, Goodship JA. (2003). A splicing mutation affecting expression of ataxia-telangiectasia and Rad3-related protein (ATR) results in Seckel syndrome. Nat Genet 33: 497-501.
130. Ohno Y, Spriggs D, Matsukage A, Ohno T, Kufe D. (1988). Effects of 1-beta-D-arabinofuranosylcytosine incorporation on elongation of specific DNA sequences by DNA polymerase beta. Cancer Res 48: 1494-1498.
131. Oki Y, Issa JP. (2006). Review: recent clinical trials in epigenetic therapy. Rev Recent Clin Trials 1: 169-182.
132. Olson E, Nievera CJ, Liu E, Lee AY, Chen L, Wu X. (2007). The Mre11 complex mediates the S-phase checkpoint through an interaction with replication protein A. Mol Cell Biol 27: 6053-6067.
133. Palii SS, Van Emburgh BO, Sankpal UT, Brown KD, Robertson KD. (2008). DNA methylation inhibitor 5-Aza-2′-deoxycytidine induces reversible genome-wide DNA damage that is distinctly influenced by DNA methyltransferases 1 and 3B. Mol Cell Biol 28: 752-771.
134. Parker WB, Bapat AR, Shen JX, Townsend AJ, Cheng YC. (1988). Interaction of 2-halogenated dATP analogs (F, Cl, and Br) with human DNA polymerases, DNA primase, and ribonucleotide reductase. Mol Pharmacol 34: 485-491.
135. Parker WB, Shaddix SC, Chang CH, White EL, Rose LM, Brockman RW et al. (1991). Effects of 2-chloro-9-(2-deoxy-2-fluoro-beta-D-Responses arabinofuranosyl)adenine on K562 cellular metabolism and the inhibition of human ribonucleotide reductase and DNA polymerases by its 5′-triphosphate. Cancer Res 51: 2386-2394.
136. Paull TT, Gellert M. (1998). The 3′ to 5′ exonuclease activity of Mre 11 facilitates repair of DNA double-strand breaks. Mol Cell 1: 969-979.
137. Paulsen RD, Cimprich KA. (2007). The ATR pathway: fine-tuning the fork. DNA Repair (Amst) 6: 953-966.
138. Perez RP, Lewis LD, Beelen AP, Olszanski AJ, Johnston N, Rhodes CH et al. (2006). Modulation of cell cycle progression in human tumors: a pharmacokinetic and tumor molecular pharmacodynamic study of cisplatin plus the Chk1 inhibitor UCN-01 (NSC 638850). Clin Cancer Res 12: 7079-7085.
139. Pines J. (1999). Four-dimensional control of the cell cycle. Nat Cell Biol 1: E73-E79.
140. Plunkett W, Benjamin RS, Keating MJ, Freireich EJ. (1982). Modulation of 9-beta-D-arabinofuranosyladenine 5′-triphosphate and deoxyadenosine triphosphate in leukemic cells by 2′-deoxycoformycin during therapy with 9-beta-D-arabinofuranosyladenine. Cancer Res 42: 2092-2096.
141. Plunkett W, Gandhi V. (2001). Purine and pyrimidine nucleoside analogs. Cancer Chemother Biol Response Modif 19: 21-45.
142. Plunkett W, Huang P, Searcy CE, Gandhi V. (1996). Gemcitabine: preclinical pharmacology and mechanisms of action. Semin Oncol 23: 3-15.
143. Plunkett W, Huang P, Xu YZ, Heinemann V, Grunewald R, Gandhi V. (1995). Gemcitabine: metabolism, mechanisms of action, and self-potentiation. Semin Oncol 22: 3-10.
144. Pogribny IP, James SJ. (2002). Reduction of p53 gene expression in human primary hepatocellular carcinoma is associated with promoter region methylation without coding region mutation. Cancer Lett 176: 169-174.
145. Raj K, John A, Ho A, Chronis C, Khan S, Samuel J et al. (2007). CDKN2B methylation status and isolated chromosome 7 abnormalities predict responses to treatment with 5-azacytidine. Leukemia 21: 1937-1944.
146. Rao VA, Plunkett W. (2003). Activation of a p53-mediated apoptotic pathway in quiescent lymphocytes after the inhibition of DNA repair by fludarabine. Clin Cancer Res 9: 3204-3212.
147. Rice JC, Allis CD. (2001). Histone methylation versus histone acetylation: new insights into epigenetic regulation. Curr Opin Cell Biol 13: 263-273.
148. Richon VM, O'Brien JP. (2002). Histone deacetylase inhibitors: a new class of potential therapeutic agents for cancer treatment. Clin Cancer Res 8: 662-664.
149. Riedl SJ, Salvesen GS. (2007). The apoptosome: signalling platform of cell death. Nat Rev Mol Cell Biol 8: 405-413.
150. Robertson LE, Chubb S, Meyn RE, Story M, Ford R, Hittelman WN et al. (1993). Induction of apoptotic cell death in chronic lymphocytic leukemia by 2-chloro-2′-deoxyadenosine and 9-beta-D-arabinosyl-2- fluoroadenine. Blood 81: 143-150.
151. Robinson HMR, Jones R, Walker M, Zachos G, Brown R, Cassidy J et al. (2006). Chk1-dependent slowing of S-phase progression protects DT40 B-lymphoma cells against killing by the nucleoside analogue 5-fluorouracil. Oncogene 25: 5359-5369.
152. Robison JG, Elliott J, Dixon K, Oakley GG. (2004). Replication protein A and the Mre11.Rad50.Nbs1 complex co-localize and interact at sites of stalled replication forks. J Biol Chem 279: 34802-34810.
153. Robison JG, Lu L, Dixon K, Bissler JJ. (2005). DNA lesion-specific co-localization of the Mre11/Rad50/Nbs1 (MRN) complex and replication protein A (RPA) to repair foci. J Biol Chem 280: 12927-12934.
154. Ross DD, Chen SR, Cuddy DP. (1990). Effects of 1-beta-D- arabinofuranosylcytosine on DNA replication intermediates monitored by pH-step alkaline elution. Cancer Res 50: 2658-2666.
155. Saito Y, Liang G, Egger G, Friedman JM, Chuang JC, Coetzee GA et al. (2006). Specific activation of microRNA-127 with downregulation of the proto-oncogene BCL6 by chromatin-modifying drugs in human cancer cells. Cancer Cell 9: 435-443.
156. Sampath D, Cortes J, Estrov Z, Du M, Shi Z, Andreeff M et al. (2006). Pharmacodynamics of cytarabine alone and in combination with 7-hydroxystaurosporine (UCN-01) in AML blasts in vitro and during a clinical trial. Blood 107: 2517-2524.
157. Sampath D, Shi Z, Plunkett W. (2002). Inhibition of cyclin-dependent kinase 2 by the Chk1-Cdc25A pathway during the S-phase checkpoint activated by fludarabine: dysregulation by 7-hydroxystaurosporine. Mol Pharmacol 62: 680-688.
158. Sandoval A, Consoli U, Plunkett W. (1996). Fludarabine-mediated inhibition of nucleotide excision repair induces apoptosis in quiescent human lymphocytes. Clin Cancer Res 2: 1731-1741.
159. Schinazi RF, Chu CK, Peck A, McMillan A, Mathis R, Cannon D et al. (1992). Activities of the four optical isomers of 2′, 3′-dideoxy-3′-thiacytidine (BCH-189) against human immunodeficiency virus type 1 in human lymphocytes. Antimicrob Agents Chemother 36: 672-676.
160. Schmelz K, Wagner M, Dorken B, Tamm I. (2005). 5-Aza-2′- deoxycytidine induces p21WAF expression by demethylation of p73 leading to p53-independent apoptosis in myeloid leukemia. Int J Cancer 114: 683-695.
161. Seto S, Carrera CJ, Kubota M, Wasson DB, Carson DA. (1985). Mechanism of deoxyadenosine and 2-chlorodeoxyadenosine toxicity to nondividing human lymphocytes. J Clin Invest 75: 377-383.
162. Seto S, Carrera CJ, Wasson DB, Carson DA. (1986). Inhibition of DNA repair by deoxyadenosine in resting human lymphocytes. J Immunol 136: 2839-2843.
163. Shao RG, Cao CX, Shimizu T, O'Connor PM, Kohn KW, Pommier Y. (1997). 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.
164. Shen L, Toyota M, Kondo Y, Obata T, Daniel S, Pierce S et al. (2003). Aberrant DNA methylation of p57KIP2 identifies a cell-cycle regulatory pathway with prognostic impact in adult acute lymphocytic leukemia. Blood 101: 4131-4136.
165. Shi Z, Azuma A, Sampath D, Li YX, Huang P, Plunkett W. (2001). S-Phase arrest by nucleoside analogues and abrogation of survival without cell cycle progression by 7-hydroxystaurosporine. Cancer Res 61: 1065-1072.
166. Shieh SY, Ahn J, Tamai K, Taya Y, Prives C. (2000). The human homologs of checkpoint kinases Chk1 and Cds1 (Chk2) phosphorylate p53 at multiple DNA damage-inducible sites. Genes Dev 14: 289-300.
167. Shiloh Y. (2003). ATM and related protein kinases: safeguarding genome integrity. Nat Rev Cancer 3: 155-168.
168. Shiloh Y. (2006). The ATM-mediated DNA-damage response: taking shape. Trends Biochem Sci 31: 402-410.
169. Snyder RD, van Houten B, Regan JD. (1984). The inhibition of ultraviolet radiation-induced DNA repair in human diploid fibroblasts by arabinofuranosyl nucleosides. Chem Biol Interact 50: 1-14.
170. Stewart GS, Maser RS, Stankovic T, Bressan DA, Kaplan MI, Jaspers NG et al. (1999). The DNA double-strand break repair gene hMRE11 is mutated in individuals with an ataxia-telangiectasia-like disorder. Cell 99: 577-587.
171. Stracker TH, Theunissen JW, Morales M, Petrini JH. (2004). The Mre11 complex and the metabolism of chromosome breaks: the importance of communicating and holding things together. DNA Repair (Amst) 3: 845-854.
172. Stresemann C, Lyko F. (2008). Modes of action of the DNA methyltransferase inhibitors azacytidine and decitabine. Int J Cancer 123: 8-13.
173. Sugiyama K, Shimizu M, Akiyama T, Tamaoki T, Yamaguchi K, Takahashi R et al. (2000). UCN-01 selectively enhances mitomycin C cytotoxicity in p53 defective cells which is mediated through S and/or G(2) checkpoint abrogation. Int J Cancer 85: 703-709.
174. Sun Y, Xu Y, Roy K, Price BD. (2007). DNA damage-induced acetylation of lysine 3016 of ATM activates ATM kinase activity. Mol Cell Biol 27: 8502-8509.
175. Takai D, Jones PA. (2002). Comprehensive analysis of CpG islands in human chromosomes 21 and 22. Proc Natl Acad Sci USA 99: 3740-3745.
176. Tang X, Wu W, Sun SY, Wistuba II, Hong WK, Mao L. (2004). Hypermethylation of the death-associated protein kinase promoter attenuates the sensitivity to TRAIL-induced apoptosis in human non-small cell lung cancer cells. Mol Cancer Res 2: 685-691.
177. Tibbetts RS, Brumbaugh KM, Williams JM, Sarkaria JN, Cliby WA, Shieh SY et al. (1999). A role for ATR in the DNA damage-induced phosphorylation of p53. Genes Dev 13: 152-157.
178. Tili E, Michaille JJ, Gandhi V, Plunkett W, Sampath D, Calin GA. (2007). miRNAs and their potential for use against cancer and other diseases. Future Oncol 3: 521-537.
179. Townsend AJ, Cheng YC. (1987). Sequence-specific effects of ara-5-aza-CTP and ara-CTP on DNA synthesis by purified human DNA polymerases in vitro: visualization of chain elongation on a defined template. Mol Pharmacol 32: 330-339.
180. Toyooka S, Toyooka KO, Miyajima K, Reddy JL, Toyota M, Sathyanarayana UG et al. (2003). Epigenetic down-regulation of death-associated protein kinase in lung cancers. Clin Cancer Res 9: 3034-3041.
181. Trenz K, Smith E, Smith S, Costanzo V. (2006). ATM and ATR promote Mre11 dependent restart of collapsed replication forks and prevent accumulation of DNA breaks. EMBO J 25: 1764-1774.
182. Trujillo KM, Yuan SS, Lee EY, Sung P. (1998). Nuclease activities in a complex of human recombination and DNA repair factors Rad50, Mre11, and p95. J Biol Chem 273: 21447-21450.
183. Tse AN, Carvajal R, Schwartz GK. (2007). Targeting checkpoint kinase 1 in cancer therapeutics. Clin Cancer Res 13: 1955-1960.
184. Tseng WC, Derse D, Cheng YC, Brockman RW, Bennett Jr LL. (1982). In vitro biological activity of 9-beta-D-arabinofuranosyl-2-fluoroadenine and the biochemical actions of its triphosphate on DNA polymerases and ribonucleotide reductase from HeLa cells. Mol Pharmacol 21: 474-477.
185. Tsimberidou AM, Wierda WG, Plunkett W, Kurzrock R, O'Brien S, Wen S et al. (2008). Phase I-II study of oxaliplatin, fludarabine, cytarabine, and rituximab combination therapy in patients with Richter's syndrome or fludarabine-refractory chronic lymphocytic leukemia. J Clin Oncol 26: 196-203.
186. van den Bosch M, Bree RT, Lowndes NF. (2003). The MRN complex: coordinating and mediating the response to broken chromosomes. EMBO Rep 4: 844-849.
187. van der Donk WA, Yu G, Perez L, Sanchez RJ, Stubbe J, Samano V et al. (1998). Detection of a new substrate-derived radical during inactivation of ribonucleotide reductase from Escherichia coli by gemcitabine 5′-diphosphate. Biochemistry 37: 6419-6426.
188. Varon R, Vissinga C, Platzer M, Cerosaletti KM, Chrzanowska KH, Saar K et al. (1998). Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome. Cell 93: 467-476.
189. Vesely J, Cihak A. (1977). [Possibilities for the clinical use of 5-azacytidine]. Vopr Onkol 23: 65-73.
190. Villunger A, Michalak EM, Coultas L, Mullauer F, Bock G, Ausserlechner MJ et al. (2003). p53- and Drug-Induced Apoptotic Responses Mediated by BH3-Only Proteins Puma and Noxa. Science 302: 1036-1038.
191. Walton TJ, Li G, Seth R, McArdle SE, Bishop MC, Rees RC. (2008). DNA demethylation and histone deacetylation inhibition co-operate to re-express estrogen receptor beta and induce apoptosis in prostate cancer cell-lines. Prostate 68: 210-222.
192. Wang J, Lohman GJ, Stubbe J. (2007). Enhanced subunit interactions with gemcitabine-5′-diphosphate inhibit ribonucleotide reductases. Proc Natl Acad Sci USA 104: 14324-14329.
193. Wang JL, Wang X, Wang H, Iliakis G, Wang Y. (2002). CHK1-regulated S-phase checkpoint response reduces camptothecin cytotoxicity. Cell Cycle 1: 267-272.
194. Wang Y, Cortez D, Yazdi P, Neff N, Elledge SJ, Qin J. (2000). BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures. Genes Dev 14: 927-939.
195. Wang Y, Liu X, Matsuda A, Plunkett W. (2008). Repair of 2′-C-Cyano-2′-Deoxy-1-{beta}-D-arabino-Pentofuranosylcytosine- Induced DNA Single-Strand Breaks by Transcription-Coupled Nucleotide Excision Repair. Cancer Res 68: 3881-3889.
196. Welch S, Hirte HW, Carey MS, Hotte SJ, Tsao MS, Brown S et al. (2007). UCN-01 in combination with topotecan in patients with advanced recurrent ovarian cancer: a study of the Princess Margaret Hospital Phase II consortium. Gynecol Oncol 106: 305-310.
197. Wen Q, Scorah J, Phear G, Rodgers G, Rodgers S, Meuth M. (2008). A mutant allele of MRE11 found in mismatch repair-deficient tumor cells suppresses the cellular response to DNA replication fork stress in a dominant negative manner. Mol Biol Cell 19: 1693-1705.
198. Xiao Y, Weaver DT. (1997). Conditional gene targeted deletion by Cre recombinase demonstrates the requirement for the double-strand break repair Mre11 protein in murine embryonic stem cells. Nucleic Acids Res 25: 2985-2991.
199. Xiao Z, Xue J, Sowin TJ, Rosenberg SH, Zhang H. (2005). A novel mechanism of checkpoint abrogation conferred by Chk1 downregulation. Oncogene 24: 1403-1411.
200. Xie C, Plunkett W. (1995). Metabolism and actions of 2-chloro-9-(2-deoxy- 2-fluoro-beta-D- arabinofuranosyl)-adenine in human lymphoblastoid cells. Cancer Res 55: 2847-2852.
201. Xie KC, Plunkett W. (1996). Deoxynucleotide pool depletion and sustained inhibition of ribonucleotide reductase and DNA synthesis after treatment of human lymphoblastoid cells with 2-chloro-9-(2-deoxy-2-fluoro-beta-D- arabinofuranosyl) adenine. Cancer Res 56: 3030-3037.
202. Yamaguchi-Iwai Y, Sonoda E, Sasaki MS, Morrison C, Haraguchi T, Hiraoka Y et al. (1999). Mre11 is essential for the maintenance of chromosomal DNA in vertebrate cells. EMBO J 18: 6619-6629.
203. Yamauchi T, Nowak BJ, Keating MJ, Plunkett W. (2001). DNA repair initiated in chronic lymphocytic leukemia lymphocytes by 4- hydroperoxycyclophosphamide is inhibited by fludarabine and clofarabine. Clin Cancer Res 7: 3580-3589.
204. Yan PS, Chen CM, Shi H, Rahmatpanah F, Wei SH, Caldwell CW et al. (2001). Dissecting complex epigenetic alterations in breast cancer using CpG island microarrays. Cancer Res 61: 8375-8380.
205. Yang SW, Huang P, Plunkett W, Becker FF, Chan JY. (1992). Dual mode of inhibition of purified DNA ligase I from human cells by 9-beta-D- arabinofuranosyl-2-fluoroadenine triphosphate. J Biol Chem 267: 2345-2349.
206. Zhang L, Volinia S, Bonome T, Calin GA, Greshock J, Yang N et al. (2008). Genomic and epigenetic alterations deregulate microRNA expression in human epithelial ovarian cancer. Proc Natl Acad Sci USA 105: 7004-7009.
207. Zhang YW, Hunter T, Abraham RT. (2006). Turning the replication checkpoint on and off. Cell Cycle 5: 125-128.
208. Zhao H, Piwnica-Worms H. (2001). ATR-mediated checkpoint pathways regulate phosphorylation and activation of human Chk1. Mol Cell Biol 21: 4129-4139.
209. Zhao M, Rudek MA, He P, Hartke C, Gore S, Carducci MA et al. (2004). Quantification of 5-azacytidine in plasma by electrospray tandem mass spectrometry coupled with high-performance liquid chromatography. J Chromatogr B Analyt Technol Biomed Life Sci 813: 81-88.
210. Zhou B-BS, Bartek J. (2004). Targeting the checkpoint kinases: chemosensitization versus chemoprotection. Nat Rev Cancer 4: 216-225.
211. Zhu J, Petersen S, Tessarollo L, Nussenzweig A. (2001a). Targeted disruption of the Nijmegen breakage syndrome gene NBS1 leads to early embryonic lethality in mice. Curr Biol 11: 105-109.
212. Zhu WG, Lakshmanan RR, Beal MD, Otterson GA. (2001b). DNA methyltransferase inhibition enhances apoptosis induced by histone deacetylase inhibitors. Cancer Res 61: 1327-1333.
213. Zou L, Elledge SJ. (2003). Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes. Science 300: 1542-1548.