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Inhibitors of cyclin-dependent kinase modulators for cancer therapy

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Advances in Targeted Cancer Therapy

Part of the book series: Progress in Drug Research ((PDR,volume 63))

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References

  1. Paulovich A, Toczyski D, Hartwell L (1997) When checkpoints fail. Cell 88: 315–321

    Article  CAS  PubMed  Google Scholar 

  2. Morgan DO (1997) Cyclin-dependent kinases: engines, clocks, and microprocessors. Annu Rev Cell Dev Biol 13: 261–291

    Article  CAS  PubMed  Google Scholar 

  3. Senderowicz AM (2003) Small-molecule cyclin-dependent kinase modulators. Oncogene 22: 6609–6620

    Article  CAS  PubMed  Google Scholar 

  4. Senderowicz AM (2003) Novel small molecule cyclin-dependent kinases modulators in human clinical trials. Cancer Biol Ther 2: S84–95

    CAS  PubMed  Google Scholar 

  5. Bharadwaj R, Yu H (2004) The spindle checkpoint, aneuploidy, and cancer. Oncogene 23: 2016–2027

    Article  CAS  PubMed  Google Scholar 

  6. Lew DJ, Burke DJ (2003) The spindle assembly and spindle position checkpoints. Annu Rev Genet 37: 251–282

    Article  CAS  PubMed  Google Scholar 

  7. Chan GK, Yen TJ (2003) The mitotic checkpoint: a signaling pathway that allows a single unattached kinetochore to inhibit mitotic exit. Prog Cell Cycle Res 5: 431–439

    PubMed  Google Scholar 

  8. Kops GJPL, Foltz DR, Cleveland DW (2004) Lethality to human cancer cells through massive chromosome loss by inhibition of the mitotic checkpoint. Proc Natl Acad Sci USA 101: 8699–8704

    Article  CAS  PubMed  Google Scholar 

  9. Meraldi P, Honda R, Nigg EA (2004) Aurora kinases link chromosome segregation and cell division to cancer susceptibility. Curr Opin Genet Dev 14: 29–36

    Article  CAS  PubMed  Google Scholar 

  10. Jiang Y, Zhang Y, Lees E, Seghezzi W (2003) AuroraA overexpression overrides the mitotic spindle checkpoint triggered by nocodazole, a microtubule destabilizer. Oncogene 22: 8293–8301

    CAS  PubMed  Google Scholar 

  11. Harrington EA, Bebbington D, Moore J, Rasmussen RK, Ajose-Adeogun AO, Nakayama T, Graham JA, Demur C, Hercend T, Diu-Hercend A et al (2004) VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo. Nat Med 10: 262–267

    Article  CAS  PubMed  Google Scholar 

  12. Hauf S, Cole RW, LaTerra S, Zimmer C, Schnapp G, Walter R, Heckel A, van Meel J, Rieder CL, Peters JM (2003) The small molecule Hesperadin reveals a role for Aurora B in correcting kinetochore-microtubule attachment and in maintaining the spindle assembly checkpoint. J Cell Biol 161: 281–294

    Article  CAS  PubMed  Google Scholar 

  13. Ditchfield C, Johnson VL, Tighe A, Ellston R, Haworth C, Johnson T, Mortlock A, Keen N, Taylor SS (2003) Aurora B couples chromosome alignment with anaphase by targeting BubR1, Mad2, and Cenp-E to kinetochores. J Cell Biol 161: 267–280

    Article  CAS  PubMed  Google Scholar 

  14. Sillje HH, Nigg EA (2003) Signal transduction. Capturing polo kinase. Science 299: 1190–1191

    CAS  PubMed  Google Scholar 

  15. Vousden KH, Lu X (2002) Live or let die: the cell’s response to p53. Nat Rev Cancer 2: 594–604

    Article  CAS  PubMed  Google Scholar 

  16. Kawabe T (2004) G2 checkpoint abrogators as anticancer drugs. Mol Cancer Ther 3: 513–519

    CAS  PubMed  Google Scholar 

  17. Senderowicz AM (2004) Targeting cell cycle and apoptosis for the treatment of human malignancies. Curr Opin Cell Biol 16: 670–678

    Article  CAS  PubMed  Google Scholar 

  18. Motokura T, Bloom T, Kim HG, Juppner H, Ruderman JV, Kronenberg HM, Arnold A (1991) A novel cyclin encoded by a bcl1-linked candidate oncogene. Nature 350: 512–515

    Article  CAS  PubMed  Google Scholar 

  19. Weinberg RA (1992) The integration of molecular genetics into cancer management. Cancer 70: 1653–1658

    CAS  PubMed  Google Scholar 

  20. Weinberg RA (1996) The molecular basis of carcinogenesis: understanding the cell cycle clock. Cytokines Mol Ther 2: 105–110

    CAS  PubMed  Google Scholar 

  21. Hatakeyama M, Brill JA, Fink GR, Weinberg RA (1994) Collaboration of G1 cyclins in the functional inactivation of the retinoblastoma protein. Genes Dev 8: 1759–1771

    CAS  PubMed  Google Scholar 

  22. Pines J (1995) Cyclins and cyclin-dependent kinases: a biochemical view. Biochem J 308: 697–711

    CAS  PubMed  Google Scholar 

  23. Bartek J, Staskova Z, Draetta G, Lukas J (1993) Molecular pathology of the cell cycle in human cancer cells. Stem Cells 11Suppl 1: 51–58

    CAS  PubMed  Google Scholar 

  24. Lukas J, Aagaard L, Strauss M, Bartek J (1995) Oncogenic aberrations of p16INK4/CDKN2 and cyclin D1 cooperate to deregulate G1 control. Cancer Res 55: 4818–4823

    CAS  PubMed  Google Scholar 

  25. Bartek J, Bartkova J, Lukas J (1996) The retinoblastoma protein pathway and the restriction point. Curr Opin Cell Biol 8: 805–814

    Article  CAS  PubMed  Google Scholar 

  26. Aagaard L, Lukas J, Bartkova J, Kjerulff AA, Strauss M, Bartek J (1995) Aberrations of p16Ink4 and retinoblastoma tumour-suppressor genes occur in distinct sub-sets of human cancer cell lines. Int J Cancer 61: 115–120

    CAS  PubMed  Google Scholar 

  27. Lukas J, Bartkova J, Bartek J (1996) Convergence of mitogenic signalling cascades from diverse classes of receptors at the cyclin D-cyclin-dependent kinase-pRb-controlled G1 checkpoint. Mol Cell Biol 16: 6917–6925

    CAS  PubMed  Google Scholar 

  28. Sherr C J (2000) Cell cycle control and cancer. Harvey Lect 96: 73–92

    CAS  PubMed  Google Scholar 

  29. Sonoda Y, Yoshimoto T, Sekiya T (1995) Homozygous deletion of the MTS1/p16 and MTS2/p15 genes and amplification of the CDK4 gene in glioma. Oncogene 11: 2145–2149

    CAS  PubMed  Google Scholar 

  30. Wolfel T, Hauer M, Schneider J, Serrano M, Wolfel C, Klehmann-Hieb E, De Plaen E, Hankeln T, Meyer zum Buschenfelde KH, Beach D (1995) A p16INK4a-insensitive CDK4 mutant targeted by cytolytic T lymphocytes in a human melanoma. Science 269: 1281–1284

    CAS  PubMed  Google Scholar 

  31. An HX, Beckmann MW, Reifenberger G, Bender HG, Niederacher D (1999) Gene amplification and overexpression of CDK4 in sporadic breast carcinomas is associated with high tumor cell proliferation. Am J Pathol 154: 113–118

    CAS  PubMed  Google Scholar 

  32. Masciullo V, Scambia G, Marone M, Giannitelli C, Ferrandina G, Bellacosa A, Benedetti Panici P, Mancuso S (1997) Altered expression of cyclin D1 and CDK4 genes in ovarian carcinomas. Int J Cancer 74: 390–395

    Article  CAS  PubMed  Google Scholar 

  33. Kanoe H, Nakayama T, Murakami H, Hosaka T, Yamamoto H, Nakashima Y, Tsuboyama T, Nakamura T, Sasaki MS, Toguchida J (1998) Amplification of the CDK4 gene in sarcomas: tumor specificity and relationship with the RB gene mutation. Anticancer Res 18: 2317–2321

    CAS  PubMed  Google Scholar 

  34. Meijer L (2000) Cyclin-dependent kinases inhibitors as potential anticancer, anti-neurodegenerative, antiviral and antiparasitic agents. Drug Resist Updat 3: 83–88

    CAS  PubMed  Google Scholar 

  35. Senderowicz AM, Sausville EA (2000) Preclinical and clinical development of cyclindependent kinase modulators. J Natl Cancer Inst 92: 376–387

    CAS  PubMed  Google Scholar 

  36. Zaharevitz DW, Gussio R, Leost M, Senderowicz AM, Lahusen T, Kunick C, Meijer L, Sausville EA (1999) Discovery and initial characterization of the paullones, a novel class of small-molecule inhibitors of cyclin-dependent kinases. Cancer Res 59: 2566–2569

    CAS  PubMed  Google Scholar 

  37. De Azevedo WF, Leclerc S, Meijer L, Havlicek L, Strnad M, Kim SH (1997) Inhibition of cyclin-dependent kinases by purine analogues: crystal structure of human cdk2 complexed with roscovitine. Eur J Biochem 243: 518–526

    Article  PubMed  Google Scholar 

  38. Meijer L, Borgne A, Mulner O, Chong JP, Blow JJ, Inagaki N, Inagaki M, Delcros JG, Moulinoux JP (1997) Biochemical and cellular effects of roscovitine, a potent and selective inhibitor of the cyclin-dependent kinases cdc2, cdk2 and cdk5. Eur J Biochem 243: 527–536

    Article  CAS  PubMed  Google Scholar 

  39. Misra RN, Xiao HY, Kim KS, Lu S, Han WC, Barbosa SA, Hunt JT, Rawlins DB, Shan W, Ahmed SZ et al (2004) N-(cycloalkylamino)acyl-2-aminothiazole inhibitors of cyclin-dependent kinase 2. N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide (BMS-387032), a highly efficacious and selective antitumor agent. J Med Chem 47: 1719–1728

    Article  CAS  PubMed  Google Scholar 

  40. Mettey Y, Gompel M, Thomas V, Garnier M, Leost M, Ceballos-Picot I, Noble M, Endicott J, Vierfond JM, Meijer L (2003) Aloisines, a new family of CDK/GSK-3 inhibitors. SAR study, crystal structure in complex with CDK2, enzyme selectivity, and cellular effects. J Med Chem 46: 222–236

    Article  CAS  PubMed  Google Scholar 

  41. Ortega MA, Montoya ME, Zarranz B, Jaso A, Aldana I, Leclerc S, Meijer L, Monge A (2002) Pyrazolo[3, 4-b]quinoxalines. A new class of cyclin-dependent kinases inhibitors. Bioorg Med Chem 10: 2177–2184

    CAS  PubMed  Google Scholar 

  42. Worland PJ, Kaur G, Stetler-Stevenson M, Sebers S, Sartor O, Sausville EA (1993) Alteration of the phosphorylation state of p34cdc2 kinase by the flavone L86-8275 in breast carcinoma cells. Correlation with decreased H1 kinase activity. Biochem Pharmacol 46: 1831–1840

    Article  CAS  PubMed  Google Scholar 

  43. Kaur G, Stetler-Stevenson M, Sebers S, Worland P, Sedlacek H, Myers C, Czech J, Naik R, Sausville E (1992) Growth inhibition with reversible cell cycle arrest of carcinoma cells by flavone L86-8275. J Natl Cancer Inst 84: 1736–1740

    CAS  PubMed  Google Scholar 

  44. Carlson BA, Dubay MM, Sausville EA, Brizuela L, Worland PJ (1996) Flavopiridol induces G1 arrest with inhibition of cyclin-dependent kinase (CDK) 2 and CDK4 in human breast carcinoma cells. Cancer Res 56: 2973–2978

    CAS  PubMed  Google Scholar 

  45. De Azevedo WF Jr, Mueller-Dieckmann HJ, Schulze-Gahmen U, Worland PJ, Sausville E, Kim SH (1996) Structural basis for specificity and potency of a flavonoid inhibitor of human CDK2, a cell cycle kinase. Proc Natl Acad Sci USA 93: 2735–2740

    PubMed  Google Scholar 

  46. Losiewicz MD, Carlson BA, Kaur G, Sausville EA, Worland PJ (1994) Potent inhibition of CDC2 kinase activity by the flavonoid L86-8275. Biochem Biophys Res Commun 201: 589–595

    Article  CAS  PubMed  Google Scholar 

  47. Carlson B, Pearlstein R, Naik R, Sedlacek H, Sausville E, Worland P (1996) Inhibition of CDK2, CDK4 and CDK7 by flavopiridol and structural analogs. Proc Am Assoc Cancer Res 1996: 424

    Google Scholar 

  48. Fredersdorf S, Burns J, Milne AM, Packham G, Fallis L, Gillett CE, Royds JA, Peston D, Hall PA, Hanby AM et al (1997) High level expression of p27(kip1) and cyclin D1 in some human breast cancer cells: inverse correlation between the expression of p27(kip1) and degree of malignancy in human breast and colorectal cancers. Proc Natl Acad Sci USA 94: 6380–6385

    Article  CAS  PubMed  Google Scholar 

  49. Carlson B, Lahusen T, Singh S, Loaiza-Perez A, Worland PJ, Pestell R, Albanese C, Sausville EA, Senderowicz AM (1999) Down-regulation of cyclin D1 by transcriptional repression in MCF-7 human breast carcinoma cells induced by flavopiridol. Cancer Res 59: 4634–4641

    CAS  PubMed  Google Scholar 

  50. Gray NS, Wodicka L, Thunnissen AM, Norman TC, Kwon S, Espinoza FH, Morgan DO, Barnes G, LeClerc S, Meijer L et al (1998) Exploiting chemical libraries, structure, and genomics in the search for kinase inhibitors. Science 281: 533–538

    Article  CAS  PubMed  Google Scholar 

  51. Chao SH, Fujinaga K, Marion JE, Taube R, Sausville EA, Senderowicz AM, Peterlin BM, Price DH (2000) Flavopiridol inhibits P-TEFb and blocks HIV-1_replication. J Biol Chem 275: 28345–28348

    Article  CAS  PubMed  Google Scholar 

  52. Wright J, Blatner GL, Cheson BD (1998) Clinical trials referral resource. Clinical trials of flavopiridol. Oncology (Huntingt) 12: 1014–1023

    Google Scholar 

  53. Arguello F, Alexander M, Sterry J, Tudor G, Smith E, Kalavar N, Greene J, Koss W, Morgan D, Stinson S et al (1998) Flavopiridol induces apoptosis of normal lymphoid cells, causes immunosuppresion, and has potent antitumor activity in vivo against human and leukemia xenografts. Blood 91: 2482–2490

    CAS  PubMed  Google Scholar 

  54. Byrd JC, Shinn C, Waselenko JK, Fuchs EJ, Lehman TA, Nguyen PL, Flinn IW, Diehl LF, Sausville E, Grever MR (1998) Flavopiridol induces apoptosis in chronic lymphocytic leukemia cells via activation of caspase-3 without evidence of bcl-2 modulation or dependence on functional p53. Blood 92: 3804–3816

    CAS  PubMed  Google Scholar 

  55. Konig A, Schwartz GK, Mohammad RM, Al-Katib A, Gabrilove JL (1997) The novel cyclin-dependent kinase inhibitor flavopiridol downregulates Bcl-2 and induces growth arrest and apoptosis in chronic B-cell leukemia lines. Blood 90: 4307–4312

    CAS  PubMed  Google Scholar 

  56. Parker B, Kaur G, Nieves-Neira W, Taimi M, Kolhagen G, Shimizu T, Pommier Y, Sausville E, Senderowicz AM (1998) Early induction of Apoptosis in hematopoietic cell lines after exposure to flavopiridol. Blood 91: 458–465

    CAS  PubMed  Google Scholar 

  57. Decker RH, Dai Y, Grant S (2001) The cyclin-dependent kinase inhibitor flavopiridol induces apoptosis in human leukemia cells (U937) through the mitochondrial rather than the receptor-mediated pathway. Cell Death Differ 8: 715–724

    Article  CAS  PubMed  Google Scholar 

  58. Parker BW, Kaur G, Nieves-Neira W, Taimi M, Kohlhagen G, Shimizu T, Losiewicz MD, Pommier Y, Sausville EA, Senderowicz AM (1998) Early induction of apoptosis in hematopoietic cell lines after exposure to flavopiridol. Blood 91: 458–465

    CAS  PubMed  Google Scholar 

  59. Kitada S, Zapata JM, Andreeff M, Reed JC (2000) Protein kinase inhibitors flavopiridol and 7-hydroxy-staurosporine down-regulate antiapoptosis proteins in B-cell chronic lymphocytic leukemia. Blood 96: 393–397

    CAS  PubMed  Google Scholar 

  60. Patel V, Senderowicz AM, Pinto D, Igishi T, Raffeld M, Quintanilla-Martinez L, Ensley JF, Sausville EA, Gutkind JS (1998) Flavopiridol, a novel cyclin-dependent kinase inhibitor, suppresses the growth of head and neck squamous cell carcinomas by inducing apoptosis. J Clin Invest 102: 1674–1681

    CAS  PubMed  Google Scholar 

  61. Guedez L, Quintanilla-Martinez L, Lahusen T, Davies T, Singh SS, Barotto N, Vistica D, Raffeld M, Sausville EA, Senderowicz AM (1999) Flavopiridol-induced apoptosis is associated with a decrease in cyclin D1 in mantle lymphoma cell lines. Proc Am Assoc Cancer Res 1999: 3413

    Google Scholar 

  62. Schrump DS, Matthews W, Chen GA, Mixon A, Altorki NK (1998) Flavopiridol mediates cell cycle arrest and apoptosis in esophageal cancer cells. Clin Cancer Res 4: 2885–2890

    CAS  PubMed  Google Scholar 

  63. Wu K, Wang C, D’Amico M, Lee RJ, Albanese C, Pestell RG, Mani S (2002) Flavopiridol and trastuzumab synergistically inhibit proliferation of breast cancer cells: association with selective cooperative inhibition of cyclin D1-dependent kinase and Akt signaling pathways. Mol Cancer Ther 1: 695–706

    CAS  PubMed  Google Scholar 

  64. Brusselbach S, Nettelbeck DM, Sedlacek HH, Muller R (1998) Cell cycle-independent induction of apoptosis by the anti-tumor drug Flavopiridol in endothelial cells. Int J Cancer 77: 146–152

    CAS  PubMed  Google Scholar 

  65. Kerr JS, Wexler RS, Mousa SA, Robinson CS, Wexler EJ, Mohamed S, Voss ME, Devenny JJ, Czerniak PM, Gudzelak A Jr, Slee AM (1999) Novel small molecule alpha v integrin antagonists: comparative anti-cancer efficacy with known angiogenesis inhibitors. Anticancer Res 19: 959–968

    CAS  PubMed  Google Scholar 

  66. Melillo G, Sausville EA, Cloud K, Lahusen T, Varesio L, Senderowicz AM (1999) Flavopiridol, a protein kinase inhibitor, down-regulates hypoxic induction of vascular endothelial growth factor expression in human monocytes. Cancer Res 59: 5433–5437

    CAS  PubMed  Google Scholar 

  67. Parng C, Seng WL, Semino C, McGrath P (2002) Zebrafish: a preclinical model for drug screening. Assay Drug Dev Technol 1: 41–48

    Article  CAS  PubMed  Google Scholar 

  68. Lee HR, Chang TH, Tebalt MJ 3rd, Senderowicz AM, Szabo E (1999) Induction of differentiation accompanies inhibition of Cdk2 in a non-small cell lung cancer cell line. Int J Oncol 15: 161–166

    CAS  PubMed  Google Scholar 

  69. Schwartz G, Farsi K, Maslak P, Kelsen D, Spriggs D (1997) Potentiation of apoptosis by flavopiridol in mitomycin-C-treated gastric and breast cancer cells. Clin Cancer Res 3: 1467–1472

    CAS  PubMed  Google Scholar 

  70. Bible KC, Kaufmann SH (1997) Cytotoxic synergy between flavopiridol (NSC 649890, L86-8275) and various antineoplastic agents: the importance of sequence of administration. Cancer Res 57: 3375–3380

    CAS  PubMed  Google Scholar 

  71. Yu C, Krystal G, Dent P, Grant S (2002) Flavopiridol potentiates STI571-induced mitochondrial damage and apoptosis in BCR-ABL-positive human leukemia cells. Clin Cancer Res 8: 2976–2984

    CAS  PubMed  Google Scholar 

  72. Dai Y, Rahmani M, Pei XY, Dent P, Grant S (2004) Bortezomib and Flavopiridol interact synergistically to induce apoptosis in chronic myeloid leukemia cells resistant to imatinib mesylate through both Bcr/Abl-dependent and-independent mechanisms. Blood 104: 509–518

    Article  CAS  PubMed  Google Scholar 

  73. Chien M, Astumian M, Liebowitz D, Rinker-Schaeffer C, Stadler WM (1999) In vitro evaluation of flavopiridol, a novel cell cycle inhibitor, in bladder cancer. Cancer Chemother Pharmacol 44: 81–87

    Article  CAS  PubMed  Google Scholar 

  74. Sedlacek HH, Czech J, Naik R, Kaur G, Worland P, Losiewicz M, Parker B, Carlson B, Smith A, Senderowicz A, Sausville E (1996) Flavopiridol (L86-8275, NSC-649890), a new kinase inhibitor for tumor therapy. Int J Oncol 9: 1143–1168

    CAS  Google Scholar 

  75. Drees M, Dengler W, Roth T, Labonte H, Mayo J, Malspeis L, Grever M, Sausville E, Fiebig H (1997) Flavopiridol (L86-8275): Selective antitumor activity in vitro and activity in vivo for prostate carcinoma cells. Clin Cancer Res 32: 273–279

    Google Scholar 

  76. Senderowicz AM, Headlee D, Stinson SF, Lush RM, Kalil N, Villalba L, Hill K, Steinberg SM, Figg WD, Tompkins A, Arbuck SG, Sausville EA (1998) Phase I trial of continuous infusion flavopiridol, a novel cyclin-dependent kinase inhibitor, in patients with refractory neoplasms. J Clin Oncol 16: 2986–2999

    CAS  PubMed  Google Scholar 

  77. Tan AR, Headlee D, Messmann R, Sausville EA, Arbuck SG, Murgo AJ, Melillo G, Zhai S, Figg WD, Swain SM et al (2002) Phase I clinical and pharmacokinetic study of flavopiridol administered as a daily 1-hour infusion in patients with advanced neoplasms. J Clin Oncol 20: 4074–4082

    Article  CAS  PubMed  Google Scholar 

  78. Messmann RA, Ullmann CD, Lahusen T, Kalehua A, Wasfy J, Melillo G, Ding I, Headlee D, Figg WD, Sausville EA et al (2003) Flavopiridol-related proinflammatory syndrome is associated with induction of interleukin-6. Clin Cancer Res 9: 562–570

    CAS  PubMed  Google Scholar 

  79. Thomas JP, Tutsch KD, Cleary JF, Bailey HH, Arzoomanian R, Alberti D, Simon K, Feierabend C, Binger K, Marnocha R et al (2002) Phase I clinical and pharmacokinetic trial of the cyclin-dependent kinase inhibitor flavopiridol. Cancer Chemother Pharmacol 50: 465–472

    Article  CAS  PubMed  Google Scholar 

  80. Stadler WM, Vogelzang NJ, Amato R, Sosman J, Taber D, Liebowitz D, Vokes EE (2000) Flavopiridol, a novel cyclin-dependent kinase inhibitor, in metastatic renal cancer: a University of Chicago Phase II Consortium study. J Clin Oncol 18: 371–375

    CAS  PubMed  Google Scholar 

  81. Schwartz GK, Ilson D, Saltz L, O’Reilly E, Tong W, Maslak P, Werner J, Perkins P, Stoltz M, Kelsen D (2001) Phase II study of the cyclin-dependent kinase inhibitor flavopiridol administered to patients with advanced gastric carcinoma. J Clin Oncol 19: 1985–1992

    CAS  PubMed  Google Scholar 

  82. Shapiro GI, Supko JG, Patterson A, Lynch C, Lucca J, Zacarola PF, Muzikansky A, Wright JJ, Lynch TJ Jr, Rollins BJ (2001) A phase ii trial of the cyclin-dependent kinase inhibitor flavopiridol in patients with previously untreated stage IV non-small cell lung cancer. Clin Cancer Res 7: 1590–1599

    CAS  PubMed  Google Scholar 

  83. Aklilu M, Kindler HL, Donehower RC, Mani S, Vokes EE (2003) Phase II study of flavopiridol in patients with advanced colorectal cancer. Ann Oncol 14: 1270–1273

    Article  CAS  PubMed  Google Scholar 

  84. Liu G, Gandara DR, Lara PN Jr, Raghavan D, Doroshow JH, Twardowski P, Kantoff P, Oh W, Kim K, Wilding G (2004) A Phase II trial of flavopiridol (NSC #649890) in patients with previously untreated metastatic androgen-independent prostate cancer. Clin Cancer Res 10: 924–928

    CAS  PubMed  Google Scholar 

  85. Bible K, Lensing J, Nelson S, Atherton P, Sloan J, Erlichman C (2003) A phase 1 trial of flavopiridol combined with 5-fluorouracil (5-FU) and leucovorin (CF) in patients with advanced malignancies. Proc Am Soc Clin Oncol 2003: 129

    Google Scholar 

  86. Schwartz GK, O’Reilly E, Ilson D, Saltz L, Sharma S, Tong W, Maslak P, Stoltz M, Eden L, Perkins P et al (2002) Phase I study of the cyclin-dependent kinase inhibitor flavopiridol in combination with paclitaxel in patients with advanced solid tumors. J Clin Oncol 20: 2157–2170

    CAS  PubMed  Google Scholar 

  87. Gries J, Kasimis B, Schwarzenberger P, Shapiro G, Fidias P, Rodrigues L, Cogswell J, Bukowski R (2002) Phase I study of flavopiridol (HMR1275) in combination with paclitaxel and carboplatin in non-small cell lung cancer (NCSLC) patients. Eur J Cancer 38: S49–S50

    Google Scholar 

  88. Tan AR, Yang X, Berman A, Zhai S, Sparreboom A, Parr AL, Chow C, Brahim JS, Steinberg SM, Figg WD et al (2004) Phase I trial of the cyclin-dependent kinase inhibitor flavopiridol in combination with docetaxel in patients with metastatic breast cancer. Clin Cancer Res 10: 5038–5047

    CAS  PubMed  Google Scholar 

  89. Tamaoki T (1991) Use and specificity of staurosporine, UCN-01, and calphostin C as protein kinase inhibitors. Methods Enzymol 201: 340–347

    CAS  PubMed  Google Scholar 

  90. Takahashi I, Kobayashi E, Asano K, Yoshida M, Nakano H (1987) UCN-01, a selective inhibitor of protein kinase C from Streptomyces. J Antibiot (Tokyo) 40: 1782–1784

    CAS  Google Scholar 

  91. Seynaeve CM, Stetler-Stevenson M, Sebers S, Kaur G, Sausville EA, Worland PJ (1993) Cell cycle arrest and growth inhibition by the protein kinase antagonist UCN-01 in human breast carcinoma cells. Cancer Res 53: 2081–2086

    CAS  PubMed  Google Scholar 

  92. Akinaga S, Gomi K, Morimoto M, Tamaoki T, Okabe M (1991) Antitumor activity of UCN-01, a selective inhibitor of protein kinase C, in murine and human tumor models. Cancer Res 51: 4888–4892

    CAS  PubMed  Google Scholar 

  93. Wang Q, Fan S, Eastman A, Worland PJ, Sausville EA, O’Connor P (1996) UCN-01: a potent abrogator of G2 checkpoint function in cancer cells with disrupted p53. J Natl Cancer Inst 88: 956–965

    CAS  PubMed  Google Scholar 

  94. Wang Q, Worland PJ, Clark JL, Carlson BA, Sausville EA (1995) Apoptosis in 7-hydroxystaurosporine-treated T lymphoblasts correlates with activation of cyclin-dependent kinases 1 and 2. Cell Growth Differ 6: 927–936

    CAS  PubMed  Google Scholar 

  95. Yu L, Orlandi L, Wang P, Orr MS, Senderowicz AM, Sausville EA, Silvestrini R, Watanabe N, Piwnica-Worms H, O’Connor PM (1998) UCN-01 abrogates G2 arrest through a Cdc2-dependent pathway that is associated with inactivation of the Wee1Hu kinase and activation of the Cdc25C phosphatase. J Biol Chem 273: 33455–33464

    CAS  PubMed  Google Scholar 

  96. Sarkaria JN, Busby EC, Tibbetts RS, Roos P, Taya Y, Karnitz LM, Abraham RT (1999) Inhibition of ATM and ATR kinase activities by the radiosensitizing agent, caffeine. Cancer Res 59: 4375–4382

    CAS  PubMed  Google Scholar 

  97. Graves PR, Yu L, Schwarz JK, Gales J, Sausville EA, O’Connor PM, Piwnica-Worms H (2000) The Chk1 protein kinase and the Cdc25C regulatory pathways are targets of the anticancer agent UCN-01. J Biol Chem 275: 5600–5605

    Article  CAS  PubMed  Google Scholar 

  98. Busby EC, Leistritz DF, Abraham RT, Karnitz LM, Sarkaria JN (2000) The radiosensitizing agent 7-hydroxystaurosporine (UCN-01) inhibits the DNA damage checkpoint kinase hChk1. Cancer Res 60: 2108–2112

    CAS  PubMed  Google Scholar 

  99. 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

    CAS  PubMed  Google Scholar 

  100. Bunch RT, Eastman A (1996) Enhancement of cisplatin-induced cytotoxicity by 7-hydroxystaurosporine (UCN-01), a new G2-checkpoint inhibitor. Clin Cancer Res 2: 791–797

    CAS  PubMed  Google Scholar 

  101. Akinaga S, Nomura K, Gomi K, Okabe M (1994) Effect of UCN-01, a selective inhibitor of protein kinase C, on the cell-cycle distribution of human epidermoid carcinoma, A431 cells. Cancer Chemother Pharmacol 33: 273–280

    CAS  PubMed  Google Scholar 

  102. Akiyama T, Sugiyama K, Shimizu M, Tamaoki T, Akinaga S (1999) G1-checkpoint function including a cyclin-dependent kinase 2 regulatory pathway as potential determinant of 7-hydroxystaurosporine (UCN-01)-induced apoptosis and G1-phase accumulation. Jpn J Cancer Res 90: 1364–1372

    CAS  PubMed  Google Scholar 

  103. Chen X, Lowe M, Keyomarsi, K (1999) UCN-01-mediated G1 arrest in normal but not tumor breast cells is pRb-dependent and p53-independent. Oncogene 18: 5691–5702

    CAS  Google Scholar 

  104. Facchinetti MM, De Siervi A, Toskos D, Senderowicz AM (2004) UCN-01-induced cell cycle arrest requires the transcriptional induction of p21(waf1/cip1) by activation of mitogen-activated protein/extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase pathway. Cancer Res 64: 3629–3637

    Article  CAS  PubMed  Google Scholar 

  105. Kawakami K, Futami H, Takahara J, Yamaguchi K (1996) UCN-01, 7-hydroxyl-staurosporine, inhibits kinase activity of cyclin-dependent kinases and reduces the phosphorylation of the retinoblastoma susceptibility gene product in A549 human lung cancer cell line. Biochem Biophys Res Commun 219: 778–783

    Article  CAS  PubMed  Google Scholar 

  106. Patel V, Lahusen T, Leethanakul C, Igishi T, Kremer M, Quintanilla-Martinez L, Ensley JF, Sausville EA, Gutkind JS, Senderowicz AM (2002) Antitumor activity of UCN-01 in carcinomas of the head and neck is associated with altered expression of cyclin D3 and p27(KIP1). Clin Cancer Res 8: 3549–3560

    CAS  PubMed  Google Scholar 

  107. Shimizu E, Zhao MR, Nakanishi H, Yamamoto A, Yoshida S, Takada M, Ogura T, Sone S (1996) Differing effects of staurosporine and UCN-01 on RB protein phosphorylation and expression of lung cancer cell lines. Oncology 53: 494–504

    CAS  PubMed  Google Scholar 

  108. Usuda J, Saijo N, Fukuoka K, Fukumoto H, Kuh HJ, Nakamura T, Koh Y, Suzuki T, Koizumi F, Tamura T, Kato H, Nishio K (2000) Molecular determinants of UCN-01-induced growth inhibition in human lung cancer cells. Int J Cancer 85: 275–280

    CAS  PubMed  Google Scholar 

  109. Marchetti A, Buttitta F, Merlo G, Diella F, Pellegrini S, Pepe S, Macchiarini P, Chella A, Angeletti CA, Callahan R et al (1993) p53 alterations in non-small cell lung cancers correlate with metastatic involvement of hilar and mediastinal lymph nodes. Cancer Res 53: 2846–2851

    CAS  PubMed  Google Scholar 

  110. Lowe SW, Bodis S, Bardeesy N, McClatchey A, Remington L, Ruley HE, Fisher DE, Jacks T, Pelletier J, Housman DE (1994) Apoptosis and the prognostic significance of p53 mutation. Cold Spring Harb Symp Quant Biol 59: 419–426

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  112. Tsuchida E, Tsuchida M, Urano M (1997) Synergistic cytotoxicity between a protein kinase C inhibitor, UCN-01, and monoclonal antibody to the epidermal growth factor receptor on MDA-468 cells. Cancer Biother Radiopharm 12: 117–121

    CAS  PubMed  Google Scholar 

  113. Sugiyama K, Shimizu M, Akiyama T, Tamaoki T, Yamaguchi K, Takahashi R, Eastman A, Akinaga S (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

    Article  CAS  PubMed  Google Scholar 

  114. Pollack IF, Kawecki S, Lazo JS (1996) Blocking of glioma proliferation in vitro and in vivo and potentiating the effects of BCNU and cisplatin: UCN-01, a selective protein kinase C inhibitor. J Neurosurg 84: 1024–1032

    CAS  PubMed  Google Scholar 

  115. Jones CB, Clements MK, Redkar A, Daoud SS (2000) UCN-01 and camptothecin induce DNA double-strand breaks in p53 mutant tumor cells, but not in normal or p53 negative epithelial cells. Int J Oncol 17: 1043–1051

    CAS  PubMed  Google Scholar 

  116. Husain A, Yan XJ, Rosales N, Aghajanian C, Schwartz GK, Spriggs DR (1997) UCN-01 in ovary cancer cells: effective as a single agent and in combination with cis-diamminedichloroplatinum( II)independent of p53 status. Clin Cancer Res 3: 2089–2097

    CAS  PubMed  Google Scholar 

  117. Hsueh CT, Kelsen D, Schwartz GK (1998) UCN-01 suppresses thymidylate synthase gene expression and enhances 5-fluorouracil-induced apoptosis in a sequence-dependent manner. Clin Cancer Res 4: 2201–2206

    CAS  PubMed  Google Scholar 

  118. Akinaga S, Nomura K, Gomi K, Okabe M (1993) 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

    Article  CAS  PubMed  Google Scholar 

  119. Hahn M, Li W, Yu C, Rahmani M, Dent P, Grant S (2005) Rapamycin and UCN-01 synergistically induce apoptosis in human leukemia cells through a process that is regulated by the Raf-1/MEK/ERK, Akt, and JNK signal transduction pathways. Mol Cancer Ther 4: 457–470

    CAS  PubMed  Google Scholar 

  120. Dasmahapatra GP, Didolkar P, Alley MC, Ghosh S, Sausville EA, Roy KK (2004) In vitro combination treatment with perifosine and UCN-01 demonstrates synergism against prostate (PC-3) and lung (A549) epithelial adenocarcinoma cell lines. Clin Cancer Res 10: 5242–5252

    CAS  PubMed  Google Scholar 

  121. Tsuchida E, Urano M (1997) The effect of UCN-01 (7-hydroxystaurosporine), a potent inhibitor of protein kinase C, on fractionated radiotherapy or daily chemotherapy of a murine fibrosarcoma. Int J Radiat Oncol Biol Phys 39: 1153–1161

    Article  CAS  PubMed  Google Scholar 

  122. Senderowicz AM, Headlee D, Lush R, Bauer K, Figg W, Murgo AS, Arbuck S, Inoue K, Kobashi S, Kuwabara T, Sausville E (1999) Phase I trial of infusional UCN-01, a novel protein kinase inhibitor, in patients with refractory neoplasms. Proc Am Soc Clin Oncol 1999: 3111

    Google Scholar 

  123. Sausville EA, Arbuck SG, Messmann R, Headlee D, Bauer KS, Lush RM, Murgo A, Figg WD, Lahusen T, Jaken S et al (2001) Phase I trial of 72-hour continuous infusion UCN-01 in patients with refractory neoplasms. J Clin Oncol 19: 2319–2333

    CAS  PubMed  Google Scholar 

  124. Fuse E, Tanii H, Kurata N, Kobayashi H, Shimada Y, Tamura T, Sasaki Y, Tanigawara Y, Lush RD, Headlee D et al (1998) Unpredicted clinical pharmacology of UCN-01 caused by specific binding to human alpha1-acid glycoprotein. Cancer Res 58: 3248–3253

    CAS  PubMed  Google Scholar 

  125. Sparreboom A, Chen H, Acharya MR, Senderowicz AM, Messmann RA, Kuwabara T, Venzon DJ, Murgo AJ, Headlee D, Sausville EA et al (2004) Effects of alpha1-acid glycoprotein on the clinical pharmacokinetics of 7-hydroxystaurosporine. Clin Cancer Res 10: 6840–6846

    CAS  PubMed  Google Scholar 

  126. Wilson WH, Sorbara L, Figg WD, Mont EK, Sausville E, Warren KE, Balis FM, Bauer K, Raffeld M, Senderowicz AM et al (2000) Modulation of clinical drug resistance in a B cell lymphoma patient by the protein kinase inhibitor 7-hydroxystaurosporine: presentation of a novel therapeutic paradigm. Clin Cancer Res 6: 415–421

    CAS  PubMed  Google Scholar 

  127. Tamura T, Sasaki Y, Minami H, Fujii H, Ito K, Igarashi T, Kamiya Y, Kurata T, Ohtsu T, Onozawa Y et al (1999) Phase I study of UCN-01 by 3-hour infusion. Proc Am Soc Clin Oncol 1999: 159

    Google Scholar 

  128. Dees EC, Baker SD, O’Reilly S, Rudek MA, Davidson SB, Aylesworth C, Elza-Brown K, Carducci MA, Donehower RC (2005) A phase I and pharmacokinetic study of short infusions of UCN-01 in patients with refractory solid tumors. Clin Cancer Res 11: 664–671

    CAS  PubMed  Google Scholar 

  129. Simon R, Freidlin B, Rubinstein L, Arbuck SG, Collins J, Christian MC (1997) Accelerated titration designs for phase I clinical trials in oncology. J Natl Cancer Inst 89: 1138–1147

    Article  CAS  PubMed  Google Scholar 

  130. Kortmansky J, Shah MA, Kaubisch A, Weyerbacher A, Yi S, Tong W, Sowers R, Gonen M, O’Reilly E, Kemeny N, Ilson DI 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

    Article  CAS  PubMed  Google Scholar 

  131. Rini BI, Weinberg V, Shaw V, Scott J, Bok R, Park JW, Small EJ (2004) Time to disease progression to evaluate a novel protein kinase C inhibitor, UCN-01, in renal cell carcinoma. Cancer 101: 90–95

    Article  CAS  PubMed  Google Scholar 

  132. Mendez J (2003) Cell proliferation without cyclin E-CDK2. Cell 114: 398–399

    Article  CAS  PubMed  Google Scholar 

  133. Geng Y, Yu Q, Sicinska E, Das M, Schneider JE, Bhattacharya S, Rideout WM, Bronson RT, Gardner H, Sicinski P (2003) Cyclin E ablation in the mouse. Cell 114: 431–443

    Article  CAS  PubMed  Google Scholar 

  134. Ortega S, Prieto I, Odajima J, Martin A, Dubus P, Sotillo R, Barbero JL, Malumbres M, Barbacid M (2003) Cyclin-dependent kinase 2 is essential for meiosis but not for mitotic cell division in mice. Nat Genet 35: 25–31

    Article  CAS  PubMed  Google Scholar 

  135. Lents NH, Baldassare JJ (2004) CDK2 and cyclin E knockout mice: lessons from breast cancer. Trends Endocrinol Metab 15: 1–3

    CAS  PubMed  Google Scholar 

  136. Tetsu O, McCormick F (2003) Proliferation of cancer cells despite CDK2 inhibition. Cancer Cell 3: 233–245

    Article  CAS  PubMed  Google Scholar 

  137. Sherr CJ, Roberts JM (2004) Living with or without cyclins and cyclin-dependent kinases. Genes Dev 18: 2699–2711

    Article  CAS  PubMed  Google Scholar 

  138. Berthet C, Aleem E, Coppola V, Tessarollo L, Kaldis P (2003) Cdk2 knockout mice are viable. Curr Biol 13: 1775–1785

    Article  CAS  PubMed  Google Scholar 

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  1. Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bldg. 10, Room B3-B6, Bethesda, MD, 20892, USA

    Adrian M. Senderowicz

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  1. Novartis International AG, CH-4002, Basel, Switzerland

    Paul L. Herrling

  2. Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, Singapore, 138670, Singapore

    Alex Matter M.D. (Director) (Director)

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    Richard M. Schultz

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Senderowicz, A.M. (2005). Inhibitors of cyclin-dependent kinase modulators for cancer therapy. In: Herrling, P.L., Matter, A., Schultz, R.M. (eds) Advances in Targeted Cancer Therapy. Progress in Drug Research, vol 63. Birkhäuser Basel. https://doi.org/10.1007/3-7643-7414-4_8

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