Radioprotection by hymenialdisine-derived checkpoint kinase 2 inhibitors

ACS Chemical Biology

Volumn 7, Issue 1, 2012, Pages 172-184

  Nguyen, Thu N T ^a   Saleem, Rahman S Z ^a   Luderer, Micah J ^a   Hovde, Stacy ^b   Henry, R William ^b   Tepe, Jetze J ^a  

^a MICHIGAN STATE UNIVERSITY   (United States)

^b Michigan State University   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 ARYLBENZIMIDAZOLE; ANTINEOPLASTIC AGENT; CCT 241533; CHECKPOINT KINASE 1; CHECKPOINT KINASE 2; ENZYME INHIBITOR; HYMENIALDISINE; INDOLOAZEPINE; NATURAL PRODUCT; PROTEIN P53; PV 1019; SERINE; UNCLASSIFIED DRUG; VRX 0466617;

ARTICLE; AUTOPHOSPHORYLATION; CELL CYCLE ARREST; CELL MUTANT; CELL SURVIVAL; CONTROLLED STUDY; DNA REPAIR; DRUG EFFICACY; ENZYME INHIBITION; HUMAN; HUMAN CELL; IONIZING RADIATION; PRIORITY JOURNAL; RADIATION PROTECTION; SIGNAL TRANSDUCTION; T LYMPHOCYTE; WILD TYPE;

APOPTOSIS; AZEPINES; CELL CYCLE; CELL LINE; CELL SURVIVAL; DNA DAMAGE; DNA REPAIR; DOSE-RESPONSE RELATIONSHIP, DRUG; HUMANS; MODELS, MOLECULAR; MUTATION; PHOSPHORYLATION; PROTEIN KINASE INHIBITORS; PROTEIN-SERINE-THREONINE KINASES; PYRROLES; RADIATION, IONIZING; RADIATION-PROTECTIVE AGENTS; SERINE; SIGNAL TRANSDUCTION; TUMOR SUPPRESSOR PROTEIN P53;

ATAXIA TELANGIECTASIA;

EID: 84856132809     PISSN: 15548929     EISSN: 15548937     Source Type: Journal    
DOI: 10.1021/cb200320c     Document Type: Article

References (80)

1. Kastan, M. B. and Bartek, J. (2004) Cell-cycle checkpoints and cancer Nature 432, 316-323 (Pubitemid 39551659)
2. Lengauer, C., Kinzler, K. W., and Vogelstein, B. (1998) Genetic instabilities in human cancers Nature 396, 643-649 (Pubitemid 29003936)
3. Bartek, J., Falck, J., and Lukas, J. (2001) CHK2 kinase? - ?a busy messenger Nat. Rev. Mol. Cell Biol. 2, 877-886
4. Bartek, J. and Lukas, J. (2003) Chk1 and Chk2 kinases in checkpoint control and cancer Cancer Cell 3, 421-429 (Pubitemid 38340288)
5. Pommier, Y., Weinstein, J. N., Aladjem, M. I., and Kohn, K. W. (2006) Chk2 molecuar interaction map and rationale for Chk2 inhibitors Clin. Cancer Res. 12, 2657-2661
6. Choudhury, A., Cuddihy, A., and Bristow, R. G. (2006) Radiation and new molecular agents part I: targeting ATM-ATR checkpoints, DNA repair, and the proteasome Semin. Radiat. Oncol. 16, 51-58 (Pubitemid 41832316)
7. Dart, D. A., Adams, K. E., Akerman, I., and Lakin, N. D. (2004) Recruitment of the cell cycle checkpoint kinase ATR to chromatin during S-phase J. Biol. Chem. 279, 16433-16440 (Pubitemid 38509341)
8. Lupardus, P. J., Byun, T., Yee, M. C., Hekmat-Nejad, M., and Cimprich, K. A. (2002) A requirement for replication in activation of the ATR-dependent DNA damage checkpoint Genes Dev. 16, 2327-2332 (Pubitemid 35034401)
9. Zou, L. and Elledge, S. J. (2003) Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes Science 300, 1542-1548 (Pubitemid 36682880)
10. Lee, J. H. and Paull, T. T. (2005) ATM activation by DNA double-strand breaks through the Mre11-Rad50-Nbs1 complex Science 308, 551-554 (Pubitemid 40570585)
11. Poehlmann, A. and Roessner, A. (2010) Importance of DNA damage checkpoints in the pathogenesis of human cancers Pathol. Res. Pract. 206, 591-601
12. Abraham, R. T. (2001) Cell cycle checkpoint signaling through the ATM and ATR kinases Genes Dev. 15, 2177-2196 (Pubitemid 32843830)
13. Smith, J., Mun Tho, L., Xu, N., A. Gillespie, D., George, F. V. W., and George, K. (2010) The ATM-Chk2 and ATR-Chk1 pathways in DNA damage signaling and cancer Adv. Cancer Res. 108, 73-112
14. Byun, T. S., Pacek, M., Yee, M. C., Walter, J. C., and Cimprich, K. A. (2005) Functional uncoupling of MCM helicase and DNA polymerase activities activates the ATR-dependent checkpoint Genes Dev. 19, 1040-1052 (Pubitemid 40632450)
15. Matsuoka, S., Rotman, G., Ogawa, A., Shiloh, Y., Tamai, K., and Elledge, S. J. (2000) Ataxia telangiectasia-mutated phosphorylates Chk2 in vivo and in vitro Proc. Natl. Acad. Sci. U.S.A. 97, 10389-10394
16. Bakkenist, C. J. and Kastan, M. B. (2003) DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation Nature 421, 499-506 (Pubitemid 36168436)
17. Pellegrini, M., Celeste, A., Difilippantonio, S., Guo, R., Wang, W. D., Feigenbaum, L., and Nussenzweig, A. (2006) Autophosphorylation at serine 1987 is dispensable for murine Atm activation in vivo Nature 443, 222-225 (Pubitemid 44387611)
18. Lee, J. H. and Paull, T. T. (2007) Activation and regulation of ATM kinase activity in response to DNA double-strand breaks Oncogene 26, 7741-7748 (Pubitemid 350242454)
19. Zhou, B. B. and Sausville, E. A. (2003) Drug discovery targeting Chk1 and Chk2 kinases Prog. Cell Cycle Res. 5, 413-421
20. Niida, H. and Nakanishi, M. (2006) DNA damage checkpoints in mammals Mutagenesis 21, 3-9 (Pubitemid 43288730)
21. Zhou, B. B. and Elledge, S. J. (2000) The DNA damage response: putting checkpoints in perspective Nature 408, 433-439
22. Khanna, K. K., Lavin, M. F., Jackson, S. P., and Mulhern, T. D. (2001) ATM, a central controller of cellular responses to DNA damage Cell Death Differ. 8, 1052-1065 (Pubitemid 33061823)
23. Chang, B. D., Broude, E. V., Dokmanovic, M., Zhu, H., Ruth, A., Xuan, Y., Kandel, E. S., Lausch, E., Christov, K., and Roninson, I. B. (1999) A senescence-like phenotype distinguishes tumor cells that undergo terminal proliferation arrest after exposure to anticancer agents Cancer Res. 59, 3761-3767 (Pubitemid 29381884)
24. Sancar, A., Lindsey-Boltz, L. A., Unsal-Kacmaz, K., and Linn, S. (2004) Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints Annu. Rev. Biochem. 73, 39-85 (Pubitemid 39050363)
25. Liu, Q. H., Guntuku, S., Cui, X. S., Matsuoka, S., Cortez, D., Tamai, K., Luo, G. B., Carattini-Rivera, S., DeMayo, F., Bradley, A., Donehower, L. A., and Elledge, S. J. (2000) 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 (Pubitemid 30421838)
26. Zhao, H. and Piwnica-Worms, H. (2001) ATR-mediated checkpoint pathways regulate phosphorylation and activation of human Chk1 Mol. Cell. Biol. 21, 4129-4139 (Pubitemid 32565295)
27. Niida, H., Katsuno, Y., Banerjee, B., Hande, M. P., and Nakanishi, M. (2007) Specific role of Chk1 phosphorylations in cell survival and checkpoint activation Mol. Cell. Biol. 27, 2572-2581 (Pubitemid 46581348)
28. Gatei, M., Sloper, K., Sorensen, C., Syljuasen, R., Falck, J., Hobson, K., Savage, K., Lukas, J., Zhou, B. B., Bartek, J., and Khanna, K. K. (2003) Ataxia-telangiectasia-mutated (ATM) and NBS1-dependent phosphorylation of Chk1 on Ser-317 in response to ionizing radiation J. Biol. Chem. 278, 14806-14811 (Pubitemid 36799806)
29. Sorensen, C. S., Syljuasen, R. G., Falck, J., Schroeder, T., Ronnstrand, L., Khanna, K. K., Zhou, B. B., Bartek, J., and Lukas, J. (2003) Chk1 regulates the S phase checkpoint by coupling the physiological turnover and ionizing radiation-induced accelerated proteolysis of Cdc25A Cancer Cell 3, 247-258 (Pubitemid 37443880)
30. Zaugg, K., Su, Y. W., Reilly, P. T., Moolani, Y., Cheung, C. C., Hakem, R., Hirao, A., Elledge, S. J., and Mak, T. W. (2007) Cross-talk between Chk1 and Chk2 in double-mutant thymocytes Proc. Natl. Acad. Sci. U.S.A. 104, 3805-3810 (Pubitemid 47181535)
31. Larson, G., Yan, S., Chen, H., Rong, F., Hong, Z., and Wu, J. Z. (2007) Identification of novel, selective and potent Chk2 inhibitors Bioorg. Med. Chem. Lett. 17, 172-175 (Pubitemid 44959967)
32. Antoni, L., Sodha, N., Collins, I., and Garrett, M. D. (2007) CHK2 kinase: cancer susceptibility and cancer therapy - two sides of the same coin? Nat. Rev. Cancer 7, 925-936 (Pubitemid 350165855)
33. Hirao, A., Kong, Y. Y., Matsuoka, S., Wakeham, A., Ruland, J., Yoshida, H., Liu, D., Elledge, S. J., and Mak, T. W. (2000) DNA damage-induced activation of p53 by the checkpoint kinase Chk2 Science 287, 1824-1827 (Pubitemid 30143967)
34. Bartkova, J., Horejsi, Z., Koed, K., Kramer, A., Tort, F., Zieger K., Guldberg, P., Sehested, M., Nesland, J. M., Lukas, C., Orntoft, T., Lukas, J., and Bartek, J. (2005) DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis Nature 434, 864-870 (Pubitemid 40558993)
35. Gorgoulis, V. G., Vassiliou, L. V. F., Karakaidos, P., Zacharatos, P., Kotsinas, A., Liloglou, T., Venere, M., DiTullio, R. A., Kastrinakis, N. G., Levy, B., Kletsas, D., Yoneta, A., Herlyn, M., Kittas, C., and Halazonetis, T. D. (2005) Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions Nature 434, 907-913 (Pubitemid 40559004)
36. Ahn, J. Y., Schwarz, J. K., Piwnica-Worms, H., and Canman, C. E. (2000) Threonine 68 phosphorylation by ataxia telangiectasia mutated is required for efficient activation of Chk2 in response to ionizing radiation Cancer Res. 60, 5934-5936
37. Ahn, J. Y., Li, X., Davis, H. L., and Canman, C. E. (2002) Phosphorylation of threonine 68 promotes oligomerization and autophosphorylation of the Chk2 protein kinase via the forkhead-associated domain J. Biol. Chem. 277, 19389-19395 (Pubitemid 34967446)
38. Oliver, A. W., Paul, A., Boxall, K. J., Barrie, S. E., Aherne, G. W., Garrett, M. D., Mittnacht, S., and Pearl, L. H. (2006) Trans-activation of the DNA-damage signalling protein kinase Chk2 by T-loop exchange EMBO J. 25, 3179-3190 (Pubitemid 44106768)
39. Wu, X. and Chen, J. (2003) Autophosphorylation of checkpoint kinase 2 at serine 516 is required for radiation-induced apoptosis J. Biol. Chem. 278, 36163-36168 (Pubitemid 37139938)
40. Schwarz, J. K., Lovly, C. M., and Piwnica-Worms, H. (2003) Regulation of the Chk2 protein kinase by oligomerization-mediated cis- and trans-phosphorylation Mol. Cancer Res. 1, 598-609 (Pubitemid 36706347)
41. Clarke, D. J. and Gimenez-Abian, J. F. (2000) Checkpoints controlling mitosis BioEssays 22, 351-363 (Pubitemid 30213497)
42. Maity, A., McKenna, W. G., and Muschel, R. J. (1994) The molecular-basis for cell-cycle delays following ionizing-radiation - A review Radiother. Oncol. 31, 1-13 (Pubitemid 24167585)
43. Iliakis, G., Wang, Y., Guan, J., and Wang, H. C. (2003) DNA damage checkpoint control in cells exposed to ionizing radiation Oncogene 22, 5834-5847 (Pubitemid 37176704)
44. Bernhard, E. J., Maity, A., Muschel, R. J., and McKenna, W. G. (1995) Effects of ionizing-radiation on cell-cycle progression - A review Radiat. Environ. Biophys. 34, 79-83
45. Iliakis, G. (1997) Cell cycle regulation in irradiated and nonirradiated cells Semin. Oncol. 24, 602-615 (Pubitemid 28035877)
46. Lowndes, N. F. and Murguia, J. R. (2000) Sensing and responding to DNA damage Curr. Opin. Genet. Dev. 10, 17-25 (Pubitemid 30113701)
47. Pommier, Y., Sordet, O., Rao, V. A., Zhang, H. L., and Kohn, K. W. (2005) Targeting Chk2 kinase: Molecular interaction maps and therapeutic rationale Curr. Pharm. Des. 11, 2855-2872 (Pubitemid 41051871)
48. Warshawsky, D. and Landolph, J. R. J., Eds. (2006) Molecular Carcinogenesis and the Molecular Biology of Human Cancer, CRC Taylor & Francis Group, LLC, Boca Raton.
49. Levesque, A. A. and Eastman, A. (2007) p53-based cancer therapies: is defective p53 the Achilles heel of the tumor? Carcinogenesis 28, 13-20 (Pubitemid 44942622)
50. Kruse, J. P. and Gu, W. (2009) Modes of p53 Regulation Cell 137, 609-622
51. Takai, H., Naka, K., Okada, Y., Watanabe, M., Harada, N., Saito, S., Anderson, C. W., Appella, E., Nakanishi, M., Suzuki, H., Nagashima, K., Sawa, H., Ikeda, K., and Motoyama, N. (2002) Chk2-deficient mice exhibit radioresistance and defective p53-mediated transcription EMBO J. 21, 5195-5205
52. Carlessi, L., Buscemi, G., Larson, G., Hong, Z., Wu, J. Z., and Delia, D. (2007) Biochemical and cellular characterization of VRX0466617, a novel and selective inhibitor for the checkpoint kinase Chk2 Mol. Cancer Ther. 6, 935-944 (Pubitemid 46554563)
53. Arienti, K. L., Brunmark, A., Axe, F. U., McClure, K., Lee, A., Blevitt, J., Neff, D. K., Huang, L., Crawford, S., Pandit, C. R., Karlsson, L., and Breitenbucher, J. G. (2005) Chekpoint kinase inhibitors: SAR and radioprotective properties of a series of 2-arylbenzimidazoles J. Med. Chem. 48, 1873-1885 (Pubitemid 40396318)
54. McClure, K. J., Huang, L. M., Arienti, K. L., Axe, F. U., Brunmark, A., Blevitt, J., and Breitenbucher, J. G. (2006) Novel non-benzimidazole chk2 kinase inhibitors Bioorg. Med. Chem. Lett. 16, 1924-1928 (Pubitemid 43267378)
55. Jobson, A. G., Cardellina, J. H., Scudiero, D., Kondapaka, S., Zhang, H., Kim, H., Shoemaker, R., and Pommier, Y. (2007) Identification of a bis-guanylhydrazone [4,4 '-diacetyldiphenylurea-bis(guanylhydrazone); NSC 109555] as a novel chemotype for inhibition of Chk2 kinase Mol. Pharmacol. 72, 876-884 (Pubitemid 47481411)
56. Hilton, S., Naud, S., Caldwell, J. J., Boxall, K., Burns, S., Anderson, V. E., Antoni, L., Allen, C. E., Pearl, L. H., Oliver, A. W., Wynne Aherne, G., Garrett, M. D., and Collins, I. (2010) Identification and characterisation of 2-aminopyridine inhibitors of checkpoint kinase 2 Bioorg. Med. Chem. 18, 707-718
57. Jobson, A. G., Lountos, G. T., Lorenzi, P. L., Llamas, J., Connelly, J., Cerna, D., Tropea, J. E., Onda, A., Zoppoli, G., Kondapaka, S., Zhang, G. T., Caplen, N. J., Cardellina, J. H., Yoo, S. S., Monks, A., Self, C., Waugh, D. S., Shoemaker, R. H., and Pommier, Y. (2009) Cellular inhibition of checkpoint kinase 2 (Chk2) and potentiation of camptothecins and radiation by the novel Chk2 inhibitor PV1019 [7-nitro-1 H -indole-2-carboxylic acid {4-[1-(guanidinohydrazone)-ethyl]-phenyl}-amide] J. Pharmacol. Exp. Ther. 331, 816-826
58. Yu, Q., La Rose, J. H., Zhang, H. L., and Pommier, Y. (2001) Antisense inhibition of Chk2/hCds1 expression attenuates DNA damage-induced S and G2 checkpoints and enhances apoptotic activity in HEK-293 cells FEBS Lett. 505, 7-12 (Pubitemid 32831020)
59. Ghosh, J. C., Dohi, T., Raskett, C. M., Kowalik, T. F., and Altieri, D. C. (2006) Activated checkpoint kinase 2 provides a survival signal for tumor cells Cancer Res. 66, 11576-11579 (Pubitemid 46094165)
60. Chabalier-Taste, C., Racca, C., Dozier, C., and Larminat, F. (2008) BRCA1 is regulated by Chk2 in response to spindle damage Biochim. Biophys. Acta, Mol. Cell Res. 1783, 2223-2233
61. Ahn, J., Urist, M., and Prives, C. (2003) Questioning the role of checkpoint kinase 2 in the p53 DNA damage response J. Biol. Chem. 278, 20480-20489 (Pubitemid 36806344)
62. Castedo, M., Perfettini, J. L., Roumier, T., Valent, A., Raslova, H., Yakushijin, K., Horne, D., Feunteun, J., Lenoir, G., Medema, R., Vainchenker, W., and Kroemer, G. (2004) Mitotic catastrophe constitutes a special case of apoptosis whose suppression entails aneuploidy Oncogene 23, 4362-4370 (Pubitemid 38850415)
63. Vakifahmetoglu, H., Olsson, M., Tamm, C., Heidari, N., Orrenius, S., and Zhivotovsky, B. (2008) DNA damage induces two distinct modes of cell death in ovarian carcinomas Cell Death Differ. 15, 555-566 (Pubitemid 351267306)
64. Anderson, V. E., Walton, M. I., Eve, P. D., Boxall, K. J., Antoni, L., Caldwell, J. J., Aherne, W., Pearl, L. H., Oliver, A. W., Collins, I., and Garrett, M. D. (2011) CCT241533 is a potent and selective inhibitor of CHK2 that potentiates the cytotoxicity of PARP inhibitors Cancer Res. 71, 463-472
65. Caldwell, J. J., Welsh, E. J., Matijssen, C., Anderson, V. E., Antoni, L., Boxall, K., Urban, F., Hayes, A., Raynaud, F. I., Rigoreau, L. J., Raynham, T., Aherne, G. W., Pearl, L. H., Oliver, A. W., Garrett, M. D., and Collins, I. (2011) Structure-based design of potent and selective 2-(quinazolin-2-yl)phenol inhibitors of checkpoint kinase 2 J. Med. Chem. 54, 580-590
66. Sharma, V. and Tepe, J. J. (2004) Potent inhibition of checkpoint kinase activity by a hymenialdisine-derived indoloazepine Bioorg. Med. Chem. Lett. 14, 4319-4321 (Pubitemid 38922849)
67. Sharma, V., Lansdell, T. A., Jin, G., and Tepe, J. J. (2004) Inhibition of cytokine production by hymenialdisine derivatives J. Med. Chem. 47, 3700-3703 (Pubitemid 38822032)
68. Johnson, T. B. and Nicolet, B. H. (1915) Researches on hydantoins XXXV. A new method of synthesizing glycocyamidine compounds, and the conversion of glycocyamidine into isomers of creatinine J. Am. Chem. Soc. 37, 2416-2426
69. Venuti, M. C., Jones, G. H., Alvarez, R., and Bruno, J. J. (1987) Inhibitors of cyclic-AMP phosphodiesterase. 2. Structural variations of N -cyclohexyl- N -methyl-4-[(1,2,3,5-tetrahydro-2-oxoimidazo[2,1- b ]quinazolin-7-yl)-oxy]butyramide (RS-82856) J. Med. Chem. 30, 303-318 (Pubitemid 17003802)
70. Lempert, K. and Doleschall, G. (1962) The condensation of anthranilic acid with S -methyl-2-thiohydantoin Experientia 18, 401-402
71. Papeo, G., Posteri, H., Borghi, D., and Varasi, M. (2005) A new glycociamidine ring precursor: Syntheses of (Z)-hymenialdisine, (Z)-2-debromohymenialdisine, and (±)- endo -2-debromohymenialdisine Org. Lett. 7, 5641-5644 (Pubitemid 43010818)
72. He, Q., Chen, W., and Qin, Y. (2007) Synthesis of 2-substituted endo-hymenialdisine derivatives Tetrahedron Lett. 48, 1899-1901
73. Meijer, L., Thunnissen, A. M. W. H., White, A. W., Garnier, M., Nikolic, M., Tsai, L. H., Walter, J., Cleverley, K. E., Salinas, P. C., Wu, Y. Z., Biernat, J., Mandelkow, E. M., Kim, S. H., and Pettit, G. R. (2000) Inhibition of cyclin-dependent kinases, GSK-3 beta and CK1 by hymenialdisine, a marine sponge constituent Chem. Biol. 7, 51-63 (Pubitemid 30141925)
74. Wan, Y., Hur, W., Cho, C. Y., Liu, Y., Adrian, F. J., Lozach, O., Bach, S., Mayer, T., Fabbro, D., Meijer, L., and Gray, N. S. (2004) Synthesis and target identification of hymenialdisine analogs Chem. Biol. 11, 247-259 (Pubitemid 38305843)
75. Carlessi, L., Buscemi, G., Larson, G., Hong, Z., Wu, J. Z., and Delia, D. (2007) Biochemical and cellular characterization of VRX0466617, a novel and selective inhibitor for the checkpoint kinase Chk2 Mol. Cancer Ther. 6, 935-944 (Pubitemid 46554563)
76. Kim, W. J., Vo, Q. N., Shrivastav, M., Lataxes, T. A., and Brown, K. D. (2002) Aberrant methylation of the ATM promoter correlates with increased radiosensitivity in a human colorectal tumor cell line Oncogene 21, 3864-3871 (Pubitemid 34620854)
77. Takemura, H., Rao, V. A., Sordet, O., Furuta, T., Miao, Z. H., Meng, L., Zhang, H., and Pommier, Y. (2006) Defective Mre11-dependent activation of Chk2 by ataxia telangiectasia mutated in colorectal carcinoma cells in response to replication-dependent DNA double strand breaks J. Biol. Chem. 281, 30814-30823 (Pubitemid 44582136)
78. Charrier, J. D., Durrant, S. J., Golec, J. M., Kay, D. P., Knegtel, R. M., MacCormick, S., Mortimore, M., O'Donnell, M. E., Pinder, J. L., Reaper, P. M., Rutherford, A. P., Wang, P. S., Young, S. C., and Pollard, J. R. (2011) Discovery of potent and selective inhibitors of ataxia telangiectasia mutated and Rad3 related (ATR) protein kinase as potential anticancer agents J. Med. Chem. 54, 2320-2330
79. Yang, J., Yu, Y. N., Hamrick, H. E., and Duerksen-Hughes, P. J. (2003) ATM, ATR and DNA-PK: initiators of the cellular genotoxic stress responses Carcinogenesis 24, 1571-1580 (Pubitemid 37304662)
80. Bernhard, E. J., McKenna, W. G., and Muschel, R. J. (1999) Radiosensitivity and the cell cycle Cancer J. Sci. Am. 5, 194-204 (Pubitemid 29528744)