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Review

Cyclin-dependent kinase inhibitors: novel anticancer agents

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Pages 1849-1870 | Published online: 24 Feb 2005

Bibliography

  • PESTELL RG, ALBANESE C, REUTENS AT et al: The cyclins and cyclin-dependent kinase inhibitors in hormonal regulation of proliferation and differentiation. Endocr. Rev. (1999) 20:501–534.
  • •An good overall review of cdk inhibitors during cell cycle progression.
  • JINNO S, SUTO K, NAGATA A et al.: Cdc25A is a novelphosphatase functioning early in the cell cycle. EMBO J. (1994) 13:1549–1556.
  • GALAKTIONOV K, LEE AK, ECKSTEIN J et al.: cDc25phosphatase as potential human oncogenes. Science (1995) 269:1575–1577.
  • SHERR CJ: Cancer cell cycles. Science (1996) 274:1672–1677.
  • ••This excellent article provides an up-to-date overview oncurrent thoughts on the cell cycle.
  • MORGAN DO, FISHER RP, ESPINOZA FH et al: Control ofeukaryotic cell cycle progression by phosphorylation of cyclin-dependent kin ase s. Cancer I ScL Am. (1998) 1:S77–83.
  • MACLACHLAN TK, SANG NGIORDANO A: Cyclins,cyclin-dependent kinases and cdk inhibitors: implica-tions in cell cycle control and cancer. Grit. Rev. Eukarimt. Gene Expr (1995) 5:127–156.
  • SHERR CJ, ROBERTS JM: CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev. (1999) 13:1501–1512.
  • LABAER J, GARRETT MD, STEVENSON LF et al: New functional activities for the p21 family of CDK inhibi-tors. Genes Dev. (1997) 11:847–862.
  • CHENG M, OLIVIER P, DIEHL JA et al.: The pn elm and p27KiP1 CDK 'inhibitors' are essential activators of cyclin D-dependent kinases in murine fibroblasts. EMBO J (1999) 18:1571–1583.
  • MOTOKURA T, BLOOM T, KIM HG et al: A novel cyclin encoded by a ben-linked candidate oncogene. Nature (1991) 3 5 0:512–515.
  • ARNOLD A, KIM HG, GAZ RD et al.: Molecular cloning and chromosomal mapping of DNA rearranged with the parathyroid hormone gene in a parathyroid adenoma. J Clin. Invest. (1989) 83:2034–2040.
  • XIONG Y, CONNOLLY T, FUTCHER B, BEACH D: Human D-type cyclin. Cell (1991) 65:691–699.
  • BALDIN V, LUKAS J, MARCOTE MJ et al.: Cyclin Di is a nuclear protein required for cell cycle progression in G1. Genes Dev. (1993) 7:812–821.
  • QUELLE DE, ASHMUN RA, SHURTLEFF SA et al.: Overex-pression of mouse D-type cyclins accelerates G1 phase in rodent fibroblasts. Genes Dev. (1993) 7:1559–1571.
  • RESNITZKY D, GOSSEN M, BUJARD H, REED SI: Accelera-tion of the G1/S phase transition by expression of cyclins Di and E with an inducible system. Mol. Biol. (1994) 14:1669–1679.
  • MUSGROVE EA, LEE CS, BUCKLEY MF, SUTHERLAND RL: Cyclin Di induction in breast cancer cells shortens G1 and is sufficient for cells arrested in G1 to complete the cell cycle. Proc. Natl. Acad. Sci. USA (1994) 91:8022–8026.
  • XIONG W, PESTELL RG, WATANABE G et al.: Cyclin Di is required for S-phase traversal in bovine tracheal myocytes. Am. J. Physiol (1997) 272:L1205–L1210.
  • LUKAS J, BARTKOVA J, BARTEK J: Convergence of mitogenic signalling cascades from diverse classes of receptors at the cyclin D-cyclin dependent kinase-pRb -controlled G1 checkpoint. Mol. Cell. Biol. (1996) 16:6917–6925.
  • LEE RJ, ALBANESE C, FU M et al.: Cyclin Di is required for transformation by activated Neu and is induced through an F2F-dependent signalling pathway. Mol. Cell. Biol. (2000) 20:672–683.
  • LEE RJ, ALBANESE C, STENGER RJ et al.: pp60v-"c induction of cyclin Di requires collaborative interac-tions between the ex tracellular signal-regulated kinase, p38 and Jun kinase pathways: A role for cAMP response element-binding protein and activating transcription factor-2 in pp6Ov're signalling in breast cancer cells. j Biol. Chem. (1999) 2 7 4:7341–7350.
  • ALBANESE C, JOHNSON J, WATANABE G et al.: Transforming p21.`" mutants and c-Ets-2 activate the cyclin Di promoter through distinguishable regions. J Biol. Chem. (1995) 270:23589–23597.
  • JOYCE D, BOUZAHZAH B, FU M et al.: Integration of Rac-dependent regulation of cyclin Di transcription through an NF-kB-dependent pathway. J. Biol. Chem. (1999) 274:25245–25249.
  • WATANABE G, HOWE A, LEE RJ et al: Induction of cyclin Di by simian virus 40 small tumor antigen. Proc. NatL Acad. Sci. USA (1996) 93:12861–12866.
  • SICINSKI P, DONAHER JL, PARKER SB et al.: Cyclin Di provides a link between development and oncogenesis in the retina and breast. Cell (1995) 82:621–630.
  • UTSUMI T, YOSHIMURA N, MARUTA M et al.: Correlationof cyclin Di mRNA levels with clinico-pathological parameters and clinical outcome in human breast carcinomas. Int. J. Cancer (2000) 89(1):39–43.
  • AMANATULLAH DF, REUTENS B, ZAFONTE B et al.: Cell-cycle dysregulation in prostate cancer. Cell-cycle Dysreg. Disease (2000) 1:372–390.
  • WANG TC, CARDIFF RD, ZUKERBERG L et al.: Mammary hyperplasia and carcinoma in MMTV-cyclin Di transgenic mice. Nature (1994) 3 6 9:669–671.
  • BODRUG SE, WARNER BJ, BATH ML et al.: Cyclin Di transgene impedes lymphocyte maturation and collaborates in lymphomagenesis with the myc gene. EMBO J (1994) 13:2124–2130.
  • PINES J: Regulation of the G2 to M transition. Results Probl. Cell Differ. (1998) 22:57–78.
  • PINES J: Four-dimensional control of the cell cycle. Nat. Cell Biol. (1999) 1:E73–E79.
  • •Another overview of the cell cycle with good references to other publications and work from the Pines Laboratory.
  • PARK M, CHAE HD, YUN J et al.: Constitutive activation of cyclin B1-associated cdc2 kinase overrides p53-mediated G2-M arrest. Cancer Res. (2 0 0 0) 60 (3):542–545.
  • PRINZ S, AMON A: Dual control of mitotic exit. Nature (1999) 402 (6758) :133–135.
  • ••This paper reviews control of entry and exit from mitotic celldivision.
  • BASTIANS H, TOPPER LM, GORBSKY GL, RUDERMAN JV:Cell cycle-regulated proteolysis of mitotic target proteins. Mol. Biol. Cell (1999) 10(1 0 :3927–3941.
  • LUKAS C, SORENSON CS, KRAMER E et al.: Accumulationof cyclin B1 requires F2F and cyclin-A-dependent rearrangement of the anaphase-promoting complex. Nature (1999) 401 (6755):815–818.
  • CHAN TA, HERMEKING H, LENGAUER C et al.: 14-3-3 Sigma is required to prevent mitotic catastrophe after DNA damage. Nature (1999) 401 (6753):616–620.
  • DALAL SN, SCHVVEITZER CM, GAN J, DECAPRIO JA: Cytoplasmic localization of human cdc25C during interphase requires an intact 14-3-3 binding site. Mol Cell. Biol. (1999) 1 9 (6):4465–4479.
  • CHAU AS, SHIBUYA EK: Mos-induced p42 mitogen-activated protein kinase activation stabilizes M-phase © Ashley Publications Ltd. All rights reserved.Exp. Opin. Invest. Drugs (2000) 9(8) in Xenopus egg extracts after cyclin destruction. Biol. Cell (1998) 90(8):565–572.
  • HARPER JW, ELLEDGE SJ, KEYOMARSKI K et al.: Inhibi- tion of cyclin-dependent kinases by p21. Mol. Biol. Cell (1995) 6:387–400.
  • COATS S, FLANAGAN WM, NOURSE J, ROBERTS JM: Requirement of p271(iP1 for restriction point control of the fibroblast cell cycle. Science (1996) 272:877–880.
  • RIVARD N, L'ALLEMAIN G, BARTEK J, POUYSSEGUR J:Abrogation of p271(iP1 by cDNA antisense suppresses quiescence (GO state) in fibroblasts. J. Biol. Chem. (1996) 271:18337–18341.
  • AGRAWAL D, DONG F, WANG YZ et al: Regulation of cyclin E and p271(iP1 during mitosis in Balb/c313 cells. Cell Growth Differ. (1995) 6:1199–1205.
  • REYNISDOTTIR I, MASSAGUE J: The subcellular locations of p151Ni41' and p27Ri1'i coordinate their inhibitory interactions with cdk4 and cdk2. Genes Dev. (1997) 11:492–503.
  • REYNISDOTTIR I, POLYAK K, IAVARONE A, MASSAGUE J: Kip /Cip and Ink4 Cdk inhibitors cooperate to induce cell cycle arrest in response to TGF-I3. Genes Dev. (1995) 9:1831–1845.
  • SOOS TJ, KIYOKAWA H, YAN JS et al: Formation ofp27-CDK complexes during the human mitotic cell cycle. Cell Growth Differ. (1996) 7:135–146.
  • KIM HS, PARK J, PARK JB, LEE JY: Mechanism for inacti-vation of the KIP family cyclin-dependent kinase inhibitor genes in gastric cancer cells. Cancer Res. (2000) 60:262–265.
  • QUELLE DE, ZINDY F, ASHMUN RA, SHERR CJ: Alterna-tive reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest. Cell (1995) 83:993–1000.
  • QUELLE DE, CHENG M, ASHMUN RA, SHERR CJ: Cancer-associated mutations at the INK4a locus cancel cell cycle arrest by p16INK4' but not by the alternative reading frame protein p19ARF. Proc. Natl. Acad. Sci. USA (1997) 94:669–673.
  • POMERANTZ J, SCHREIBER-AGUS N, LIEGEOIS NJ et al.:The Ink4a tumor suppressor gene product, p19ARF, interacts with MDM2 and neutralizes MDM2's inhibi-tion of p53. Cell (1998) 92:713–723.
  • KAMIJO T, ZINDY F, ROUSSEL MF et al.: Tumor suppres-sion at the mouse INK4a locus mediated by the alterna-tivep reading frame product9AR. Cell (1997)91:649–659.
  • ZHANG Y, XIONG Y, YARBROUGH WG: ARF promotesMDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways. Cell (1998) 92:725–734.
  • ASP J, SANGIORGI L, INEROT SE et al.: Changes of the p16gene but not the p53 gene in human chondrosarcoma tissues. Int. J. Cancer (2000) 85 (6):782–786.
  • SANCHEZ M., ESTELLER M, WU L et al.: Gene promoter hypermethylation in tumors and serum of head and neck cancer patients. Cancer Res. (2000) 60(4):892–895.
  • TSUJIE M, YAMAMOTO H, TOMITA N et al.: Expression of tumor suppressor gene p16(INK4) products in primary gastric cancer. Oncology (2000) 58(2):126–136.
  • TSUDA H, YAMAMOTO K, INOUE T et al.: The role of p 16 -cyclin d/CDK-p Rb pathway in the tum o r igen esis of endometrioid-type endometrial carcinoma. Br. J Cancer (2000) 82 (3):675–682.
  • KUSUME T, TSUDA H, KAWABATA M et al.: The p16 -cyclin Di /CDK4-pRb pathway and clinical outcome in epithelial ovarian cancer. Clin. Cancer Res. (1999) 5(12):4152–4157.
  • MIRACCA EC, KOWALSKI LP, NAGAI MA: High prevalence of p16 genetic alterations in head and neck tumours. Br. J. Cancer (1999) 81 (0677–683.
  • WISTUBA II, ALBORES-SAAVEDRA J: Genetic abnormali-ties involved in the pathogenesis of gallbladder carcinoma. J. Hepatobiliary PancreaL Surg. (1999) 6 (3):237–244.
  • REUTENS AT, PESTELL RG: Current views on regulationof the cell-cycle and tumor formation: New strategies for cancer therapy. Royal Australian College of Physicians. J. Fellowship Affairs, Continuing Education Series. (1997):4–13.
  • SENDEROWICZ AM, SAUSVILLE EA: Preclinical andclinical development of cyclin-dependent kinase modulators. J. Nati Cancer Inst. (2000) 92 (5):376–387.
  • •An excellent overview of the current status of cdk inhibitors with a focus on the development of flavopiridol and UCN-01.
  • KITAGAWA M, OKABE T, OGINO H et al.: Butyrolactone I, a selective inhibitor of cdk2 and cdc2 kinase. Oncogene (1993) 8(9):2425–2432.
  • KITAGAWA M, HIGASHI H, TAKAHASHI IS et al.: A cyclin-dependent kinase inhibitor, butyrolactone I, inhibits phosphorylation of RB protein and cell cycle progression. Oncogene (1994) 9(9):2549–2557.
  • NISHIO K, ISHIDA T, ARIOKA H et al: Antitumor effectsof butyrolactone I, a selective cdc2 kinase inhibitor, on human lung cancer cell lines. AntiCancer Res. (1996) 16 (6B):3387–3395.
  • MEIJER L, BORGNE A, MULNER 0 et al.: Biochemical and cellular effects of roscovitine, a potent and selective inhibitor of the cyclin-dependent kinases. Eur. Biochem. (1997) 243:527–536.
  • MEIJER L, KIM SH: Chemical inhibitors of cyclin-dependent kinases. Methods Enzymol. (1997) 283:113–128.
  • •An excellent overview of the chemical structures of cyclin-CDK inhibitors.
  • KAUR G, STETLER-STEVENSON M, SEBERS S et al.: Growth inhibition with reversible cell cycle arrest of carcinoma cells by flavone 186–8275. J. Natl. Cancer Inst. (1992) 84:1736-1740. © Ashley Publications Ltd. All rights reserved.Exp. Opin. Invest. Drugs (2000) 9(8)
  • LOSIEWICZ MD, CARLSON BA, KAUR G et al.: Potent inhibition of CDC2 kinase activity by the flavinoid L86-8275. Biochem. Biophys. Res. Commun. (1994) 21 0:589–595.
  • WORLAND PJ, KAUR G, STETLER-STEVENSON M et al: Alteration of the phosphorylation state of p34cdc2 kinase by the flavone 1S6-8275 in breast carcinoma cells. Correlation with decreased HI kinase activity. Biochem. Pharmacol. (1993) 46:1831–1840.
  • GRAY N, DETIVAUD L, DOERIG C, MEIJER L: ATP-site directed inhibitors of cyclin-dependent kinases. Curr. Med. Chem. (1999) 6(9):859–875.
  • DE AZEVEDO WFJ, MUELLER-DIECKMANN HJ, SCHULZE-GAHMEN U et al: Structural basis for specificity and potency of a flavonoid inhibitor of human CDK2, a cell cycle kinase. Proc. Natl. Acad. Sci. USA (1996) 93:2735–2740.
  • •An early paper describing specificity of inhibition of human CDK2 by flavopiridol.
  • CARLSON BA, DUBAY MM, SAUSVILLE EA et al.: Flavopiridol induces GI arrest with inhibition of cyclin-dependent kinase (CDK) 2 and CDK4 in human breast carcinoma cells. CancerRes. (1996) 56:2973–2978.
  • SEDLACEK HH, CZECH J, NAIK R et al: Flavopiridol (1S6-8275, NSC-649890), a new kinase inhibitor for tumor therapy. Int. J. Oncol. (1996) 9:1143–1168.
  • BIBLE KC, KAUFMANN SH: Flavopiridol: a cytotoxic flavone that induces cell death in noncycling A549 human lung carcinoma cells. Cancer Res. (1996) 56:4856–4861.
  • •Flavopiridol is shown to kill non-cycling cells implying that this drug may be cytotoxic to cells.
  • PARKER BW, KAUR G, NIEVES-NEIRA W et al.: Early induction of apoptosis in hematopoietic cell lines after exposure to flavopiridol. Blood (1998) 91:458–465.
  • ARGUELLO F, ALEXANDER M, STERRY J et al.: Flavopiridol induces apoptosis of normal lymphoid cells, causes immunosuppression and has potent antitumor activity in vivo against human leukemia and lymphoma xenografts. Blood (1998) 91:2482–2490.
  • PARK DS, FARINELLI SE, GREENE LA: Inhibitors of cyclin-dependent kinases promote survival of post-mitotic neuronally differentiated PC12 cells and sympathetic neurons. J. Biol. Chem. (1 9 9 6) 271:8161-8169.
  • PATEL V, SENDEROWICZ AM, DECIO P et al.:Flavopiridol, a novel cyclin-dependent kinase inhibitor, suppresses the growth of head and neck squamous cell carcinomas by inducing apoptosis. Clin. Invest. (1998) 102:1674–1681.
  • ALBANESE C, D'AMICO M, REUTENS AT et al.: Activation of the cyclin Di gene by the MA-associated protein p300 through AP-1 inhibits cellular apoptosis. J. Biol. Chem. (1999) 274:34186–34195.
  • CARLSON B, LAHUSEN T, SINGH S et al.: Downregulation of cyclin Di by transcriptional repression in MCF-7 human breast carcinoma cells induced by flavopiridol. Cancer Res. (1999) 59:4634–4641.
  • BIBLE KC, BIBLE RH JR, KOTTKE TJ et al: Flavopiridolbinds to duplex DNA. CancerRes. (2000) 60(9):2419–2428.
  • •This article demonstrates that flavopiridol has DNA binding properties.
  • BRUESSELBACH S, MOEHLE-STEINLEIN U, WANG Z-Q etal.: Cell proliferation and cell cycle progression are not impaired in fibroblasts and ES cells lacking c-Fos. Oncogene (1995) 10:79–86.
  • KERR JS, WEXLER RS, MOUSA SA et al.: Novel smallmolecule alpha v integrin antagonists: comparative anti-cancer efficacy with known angiogenesis AntiCancer Res. (1999) 19:959–968.
  • MELILLO G, SAUSVILLE EA, CLOUD K et al.: Flavopiridol,a novel protein kinase inhibitor, down regulates hypoxic induction of vascular endothelial growth factor expression in human monocytes. Cancer Res. (1999) 59:5433–5437.
  • •Flavopiridol is shown to regulate VEGF expression in human monocytes and may have a role as an antiangiogenic agent.
  • HOOIJBERG JH, BROXTERMAN HJ, SCHEFFER GL et al.:Potent interaction of flavopiridol with MRPI. Br. J Cancer (1999) 81:269–276.
  • CHIEN M, ASTUMIAN M, LIEBOWITZ D et al.: In vitroevaluation of flavopiridol, a novel cell cycle inhibitor, in bladder cancer. Cancer Chem other. Pharmacol. (1999) 44:81–87.
  • SENDEROWICZ AM, HEADLEE D, STINSON SF et al.: PhaseI trial of continuous infusion flavopiridol, a novel cyclin-dependent kinase inhibitor, in patients with refractory neoplasms. J. Clin. °rico/. (1998) 16:2986–2999.
  • •Early clinical trial with flavopiridol suggesting tolerability of this drug and defining toxicities and anti-tumour activity.
  • JAGER W, ZEMBSCH B, WOLSCHANN P et al.: Metabolismof the anticancer drug flavopiridol, a new inhibitor of cyclin dependent kinases, in rat liver. Life Sci. (1998) 62:1861–1873.
  • STADLER WM, VOGELZANG NJ, AMATO R et al.: Flavopiridol, a novel cyclin-dependant kinase inhibitor, in metastatic renal cell cancer: a University of Chicago Phase II Consortium Study. J. Clin. Onc. (2000) 18:371–375.
  • SCHWARTZ GK, FARSI K, MASLAK P et al: Potentiation ofapoptosis by flavopiridol in mitomycin-C-treated gastric and breast cancer cells. an. Cancer Res. (1997) 3:1467–1472.
  • BIBLE KC, KAUFMANN SH: Cyto toxic synergy betweenflavopiridol (NSC 649890, 1S6-8275) and various antineoplastic agents: the importance of sequence of administration. Cancer Res. (1997) 57:3375–3380.
  • •This paper examines the relationship of sequence of admini-stration of flavopiridol and other conventional cytotoxic agents for cancer therapy.
  • DICKER P, ROZENGURT E: Stimulation ofDNeksynthesis by tumour promoter and pure mitogenic factors. Nature (1978) 276:723-726. © Ashley Publications Ltd. All rights reserved.Exp. Opin. Invest. Drugs (2000) 9(8)
  • ROZENGURT E, RODRIGUEZ-PENA A, COOMBS M, SINNETT-SMITH J: Diacylglycerol stimulates DNA synthesis and cell division in mouse 3T3 cells: role of Ca2+-sensitive phospholipid-dependent protein kinase. Proc. Natl. Acad. Sci. USA (1984) 81:5748–5752.
  • ZHOU W, TAKUWA N, KUMADA M, TAKUWA Y: Protein kinase C-mediated bidirectional regulation of DNA synthesis, RB protein phosphorylation and cyclin-dependent kinases in human vascular endothelial cells. J Biol. Chem. (1993) 268:23041–23048.
  • HOUSEY GM, JOHNSON MD, HSIAO WL et al.: Overpro-duction of protein kinase C causes disordered growth control in rat fibroblasts. Cell (1988) 52:343–354.
  • CACACE AM, GUADAGNO SN, KRAUSS RS et al.: The epsilon isoform of protein kinase C is an oncogene when overexpressed in rat fibroblasts. Oncogene (1993) 8:2095–2104.
  • GRUBER JT, OHNO S, NILES RM: Increased expression of protein kinase C alpha plays a key role in retinoic acid-induced melanoma differentiation. j Biol. Chem. (1992) 267:13356–13360.
  • COPPOCK DL, TANSEY JB, NATHANSON L: 12-0-tetradecanoylphorbol-1 3-acetate induces transient cell cycle arrest in G1 and G2 in metastatic melanoma cells: inhibition of phosphorylation of p34cdc2. Cell. Growth Differ. (1992) 3:485–494.
  • FREY MR, SAXON ML, ZHAO X et al.: Protein kinase C isozyme-mediated cell cycle arrest involves induction of p21wafliciP1 and 2716P1 and hypophosphorylation of the retinoblastoma protein in intestinal epithelial cells. J Biol. Chem. (1997) 272:9424–9435.
  • LIVNEH E, SHIMON T, BECHOR E et al.: linking protein kinase C to the cell cycle: ectopic expression of PKC eta in NIH3T3 cells alters the expression of cyclins and CDK inhibitors and induces adipogenesis. Oncogene (1996) 12:1545–1555.
  • SASAGURI T, KOSAKA C, HIRATA M et al: Protein kinase C-mediated inhibition of vascular smooth muscle cell proliferation: the isoforms that may mediate G1 /S inhibition. Exp. Cell Res. (1993) 208:311–320.
  • HIRAI S, IZUMI Y, HIGA K et al.: Ras-dependent signal transduction is indispensable but not sufficient for the activation of AP1 /Jun by PKGS. EMBO J. (1994) 13:2331–2340.
  • WAYS DK, KUKOLY CA, DEVENTE J et al.: MCF-7 breast cancer cells transfected with protein kinase C-alpha exhibit altered expression of other protein kinase C isoforms and display a more aggressive neoplastic phenotype. J. Clin. Invest. (1995) 95:1906–1915.
  • WATANABE T, ONO Y, TANIYAMA Y et al.: Cell division arrest induced by phorbol ester in CHO cells overex-pressing protein kinase C-delta subspecies. Proc. Natl. Acad. Sci. USA (1992) 89:10159–10163.
  • TAMAOKI T: Use and specificity of staurosporine, UCN-01 and calphostin C as protein kinase inhibitors. Methods Enzymol. (1991) 201:340–347.
  • •This paper defines the use and specificity of staurosporine and its analogues as PKC inhibitors.
  • TAKAHASHI I, SAITOH Y, YOSHIDA M et al.: Purification, physico-chemical properties, structural determina-tion and biological activities. J Antibiot. (Tokyo) (1989) 42:571–576.
  • TAKAHASHI I, KOBAYASHI E, ASANO K et al.: UCN-01, a selective inhibitor of protein kinase C from Strepto-myces. j Antibiot. (Tokyo) (1987) 40:1782–1784.
  • SEYNAEVE CM, KAZANIETZ MG, BLUMBERG PM et al.: Differential inhibition of protein kinase Cisozymes by UCN-01, a staurosporine analogue. Mot. Pharmacol. (1994) 45:1207–1214.
  • AKIYAMA T, YOSHIDA T, TSUJITA T et al.: G1 phase accumulation induced by UCN-01 is associated with dephos-phorylation of Rb and CDK2 proteins as well as induction of CDK inhibitor p21/Cip1 /WAF1/Sdi1 in p53-mutated human epidermoid carcinoma A431 cells. Cancer Res. (1997) 57:1495–1501.
  • AKINAGA S, NOMURA K, GOMI K, OKABE M: 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 (1994) 33:273–280.
  • AKIYAMA T, SHIMIZU M, OKABE M et al.: Differential effects of UCN-01, staurosporine and CGP 41 251 on cell cycle progression and CDC2/cyclin B1 regulation in A431 cells synchronized at M phase by nocodazole. AntiCancer Drugs (1999) 10:67–78.
  • SEYNAEVE CM, STETLER-STEVENSON M, SEBERS S et al.: Cell cycle arrest and growth inhibition by the protein kinase antagonist UCN-01 in human breast carcinoma cells. Cancer Res. (1993) 53:2081–2086.
  • WANG Q, WORLAND PJ, CLARK JL et al.: Apoptosis in 7-hydroxystaurosporine-treated T lymphoblasts correlates with activation of cyclin-dependent kinases land 2. Cell Growth Differ. (1995) 6:927–936.
  • WANG Q, FAN S, EASTMAN A et al.: UCN-01: a potent abrogator of G2 checkpoint function in cancer cells with disrupted p53. J. NMI Cancer Inst. (1996) 88:956–965.
  • ••This paper defines UCN-01 as an effective abrogator of theG2 checkpoint in the majority of cancer cells that have disrupted p53 function. This paper also provides evidence of and rationale for synergy with the use of UCN-01 with DNA damaging agents.
  • YU L, ORLANDI L, WANG P et al.: 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. (1998) 273:33455–33464.
  • ••This paper defines the biochemical mechanism of the G2abrogating function of UCN–01.
  • SAUSVILLE EA, ZAHAREVITZ D, GUSSIO R et al.: Cyclin-dependent kinases: initial approaches to exploit a novel therapeutic target. Pharmacol. Ther. (1999) 82:285–292.
  • BUSBY EC, LEISTRITZ DF, ABRAHAM RT et al.: The radiosensitizing agent 7-hydroxystaurosporine © Ashley Publications Ltd. All rights reserved.Exp. Opin. Invest. Drugs (2000) 9(8) (UCN-01) inhibits the DNA damage checkpoint kinase hChk 1. Cancer Res. (2000) 15:2108–2112.
  • •This paper demonstrates UCN-01 as a radiosensitiser and provides a rationale for such an effect through inhibition of hChk 1.
  • HSUEH CT, KELSEN D, SCHWARTZ GK: UCN-01 suppresses thymidylate synthase gene expression and enhances 5-fluorouracil-induced apoptosis in a sequence-dependent manner. Clin. Cancer Res. (1998) 4:2201–2206.
  • BUNCH RT, EASTMAN A: Enhancement of cisplatin-induced cytotoxicity by 7-hydroxystaurosporine (UCN-01), a new G2-checkpoint inhibitor. Clin. Cancer Res. (1996) 2:791–797.
  • AKINAGA S, NOMURA K, GOMI K, OKABE M: Enhance-ment of antitumor activity of mitomycin C in vitro and in vivo by UCN-01, a selective inhibitor of protein kinase C. Cancer Chemother. Pharmacol. (1993) 32:183–189.
  • FUSE E, TANII H, KURATA N et al.: Unpredicted clinical pharmacology of UCN-01 caused by specific binding to human alpha1-acid glycoprotein. Cancer Res. (1998) 58:3248–3253.
  • PAULL KD, SHOEMAKER RH, HODES L et al: Display and analysis of patterns of differential activity of drugs against human tumor cell lines: development of mean graph and COMPARE algorithm. J. Natl. Cancer Inst. (1989) 81:1088–1092.
  • •This paper shows the usefulness of the NCI COMPARE algorithm for study of drug activity in cancer cell lines.
  • ZAHAREVITZ DW, GUSSIO R, LEOST M et al.: Discovery and initial characterization of the paullones, a novel class of small-molecule inhibitors of cyclin-dependent kinases. Cancer Res. (1999) 59:2566–2569.
  • KUNICK C, SCHULTZ C, LEMCKE T et al: 2-Substituted paullones: CDKI/cyclin B-inhibiting property and in vitro antiproliferative activity. Bioorg Med. Chem. Lett. (2000) 10:567–569.
  • MEIJER L, PONDAVEN P: Cyclic activation of histone HI kinase during sea urchin egg mitotic divisions. Exp. Cell Res. (1998) 1:116–129.
  • NEANT I, GUERRIER P: 6-Dimethylaminopurine blocks starfish oocyte maturation by inhibiting a relevant protein kinase activity. Exp. Cell Res. (1988) 176:68–79.
  • SCHULZE-GAHMEN U, BRANDSEN J, JONES HD et al.: Multiple modes of ligand recognition: crystal structures of cyclin-dependent protein kinase 2 in complex with ATP and two inhibitors, olomoucine and isopentenyladenine. Proteins (1995) 22:378–391.
  • LAWRIE AM, NOBLE ME, TUNNAH P et al: Protein kinase inhibition by staurosporine revealed in details of the molecular interaction with CDK2. Nature Struct. (1997) 4:769–801.
  • DE AZEVEDO WF, LECLERC S, MEIJER L et al: Inhibition of cyclin-dependent kinases by purine analogues: crystal structure of human cdk2 complexed with roscovitine. Eur. j Biochem. (1997) 243:518–526.
  • GRAY NS, WODICKA L, THUNNISSEN AM et al.: Exploiting chemical libraries, structure and genomics in the search for kinase inhibitors. Science (1998) 281 (5376):533–538.
  • •This paper reviews the use of chemical libraries in the study of putative CDK inhibitors.
  • BROOKS EE, GRAY NS, JOLY A et al.: CVT-313, a specific and potent inhibitor of CDK2 that prevents neointimal proliferation. J. Biol. Chem. (1997) 272:29207–29211.
  • MEIJER L, THUNNISSEN AM, WHITE AW et al.: Inhibition of cyclin-dependant kinases, GSK-3beta and KKI by hymenialdysine, a marine sponge constituent. Chem. Biol. (2000) 7:51–63.
  • BYEON I-JL, LI J, ERICSON K et al.: Tumor suppressor p161N1(4A: Determination of solution structure and analyses of its interaction with cyclin-dependent kinase 4. Mol. Cell (1998) 1:421–431.
  • CHEN YN, SHARMA SK, RAMSEY TM et al.: Selective killing of transformed cells by cyclin/cyclin-dependent kinase 2 antagonists. Proc. Natl. Acad. Sci. USA (1999) 96:4325–4329.
  • •Provides evidence for a selective CDK2 antagonist as a potential anticancer agent.
  • SCHWARZE SR, HO A, VOCERO-AKBANI A, DOWDY SF: In vivo protein transduction: delivery of a biologically active protein into the mouse. Science (1999) 285:1569–1572.
  • ALBANESE C, REUTENS A, D'AMICO M et al.: Sustained Mammary gland directed Ponasterone A-inducible expression in transgenic mice. FASEB J (2000) (In Press).
  • STEPANOVA L, LENG X, PARKER SB, HARPER JW: Mammalian p50Cdc37 is a protein kinase-targeting subunit of Hsp 90 that binds and stabilizes Cdk4. Genes Dev. (1996) 10:1491–1502.
  • STEBBINS CE, RUSSO AA, SCHNEIDER C et al.: Crystal structure of an Hsp90-geldanamycin complex: targeting of a protein chaperone by an antitumor agent. Cell (1997) 89:239–250.
  • •Provides the crystal structure of heat shock protein (HSP 90)-geldanamycin complex which would allow for synthesis of other novel compounds that bind to chaperone proteins such as Hsp–90.
  • ZHENG FF, KUDUK SD, CHIOSIS G etal.: Identification of a geldanamycin dimer that induces the selective degradation of HER-family tyrosine kinase. Cancer Res. (2000) 60:2090–2094.
  • NECKERS L, SCHULTE TVV, MIMNAUGH E: Geldanamycin as a potential anti-cancer agent: its molecular target and biochemical activity. Invest. New Drugs. (1999) 17 :361–373.
  • GOROSPE M, SHACKS, GUYTON KZ et al.: Up-regulation and functional role of p21w'fliciP1 during growth arrest of human breast carcinoma MCF-7 cells by phenylacetate. Cell Growth Differ. (1996) 7:1609–1615.
  • LAVELLE D, CHEN YH, HANKEWYCH M, DESIMONE J: Inhibition of myeloma cell growth by all-trans retinoic acid is associated with upreg-ulation of p21wAF1 and © Ashley Publications Ltd. All rights reserved.Exp. Opin. Invest. Drugs (2000) 9(8) dephosphorylation of the retinoblastoma protein. Leuk. Lymphoma. (1999) 35:261–268.
  • MUTO A, KIZAKI M, YAMATO K et al.: 1,25-Dihydroxy vitamin D3 induces differentiation of a retinoic acid-resistant acute promyelocytic leukemia cell line (UF-1) associated with expression of p21(WAFI/CIP1) and p27(KIP1). Blood (1999) 7:2225–2233.
  • JANKNECHT T, HUNTER T: A growing coactivator network. Nature (1996) 383:22–23.
  • MARTINEZ-BALBAS MA, BANNISTER AJ, MARTIN K et al.: The acetyltransferase activity of CBP stimulates transcription. EMBO J (1998) 17(102886–2893.
  • BANNISTER AJ, KOUZARIDES T: The CBP co activator is a histone acetyltransferase. Nature (1996) 384:641–643.
  • OGRYZKO VV, SCHILTZ RL, RUSSANOVA V et al.: The transcriptional coactivators p300 and CBP are histone acetyltransferases. Cell (1996) 87:953–959.
  • WOLFFE AP: Histone deacetylase: a regulator of transcription. Science (1997) 272:371–372.
  • •Reviews histone deacetylase function in detail as a regulator of DNA transcription.
  • STRUHL K: Ilistone acetylation and transcriptional regulatory mechanisms. Genes Dev. (1998) 12:599–606.
  • PAZIN MJ, KADONAGA JT: What's up and down with histone deacetylation and transcription? Cell (1997) 89 :325–328.
  • LIU L, SCOLNICK DM, TRIEVEL RC et al.: p53 sites acetylated in vitro by PCAF and p300 are acetylated in vivo in response to DNA damage. Mol Cell Biol. (1999) 19:1202–1209.
  • ZHANG W, BIEKER JJ: Acetylation and modulation of erythroid Kruppel-like factor (EKLF) activity by interaction with histone acetyltransferases. Proc. Natl. Acad. Sci. USA (1998) 95:9855–9860.
  • HUNG HL, LAU J, KIM AY et al.: CREB-bin ding protein acetylates hematopoietic transcription factor GATA-1 at functionally important sites. Mol Cell Biol. (1999) 19:3496–3505.
  • FU M, WANG C, REUTENS AT et al.: p300 and P/CAF Acetylate the Androgen Receptor at sites governing hormone-dependent transactivation. J Biol. Chem. (2000) (In Press).
  • CHEN H, LIN RJ, XIE W et al.: Regulation of hormone-induced histone hyperacetylation and gene activation via acetylation of an acetylase. Cell (1999) 98:675–686.
  • BERGER SL: Gene activation by histone and factor acetyltransferases. CUIT. Opin. Cell Biol. (1999) 11:336–341.
  • YOSHIDA M, HORINOUCHI SB, EPPU T: Trichostatin A and trapoxin: novel chemical probes for the role of histone acetylation in chromatin structure and function. BioEssays (1995) 17:23–43.
  • RICHON VM, EMILIANI S, VERDIN E et al.: A class of hybrid polar inducers of transformed cell differentiation inhibits histone deacetylases. Proc. Natl. Acad. Sci. USA (1998) 95:3003–3007.
  • DARKIN-RATTRAY SJ, GURNETT AM, MYERS RW et al: Apicidin: a novel antiprotozoal agent that inhibits parasite histone deacetylase. Proc. Nati Acad. Sci. USA (1996) 93:13143–13147.
  • NAKAJIMA H, KIM YB, TERANO H et al.: FR901228, a potent antitumor antibiotic, is a novel histone deacety-lase inhibitor. Exp. Cell Res. (1998) 241:126–133.
  • SAITO A, YAMASHITA T, MARIKO YEA: A synthetic inhibitor of histone deacetylase, MS-27-275, with marked in vivo antitumor activity against human tumors. Proc. Natl. Acad. Sci. USA (1999) 96:4592–4597.
  • QIU L, KELSO MJ, HANSEN C et al.: Anti-tumour activity in vitro and in vivo of selective differentiating agents containing hydroxamate. Br. J. Cancer (1999) 80:1252–1258.
  • SAUNDERS NA, POPA C, SEREWKO MM et al.: Ilistone deacetylase inhibitors: novel anticancer agents. Exp. Opin. Invest. Drugs (1999) 8:1611–1621.
  • •Up-to-date review on novel HDAC inhibitors as anticancer agents.
  • CAMERON EE, BACHMAN KE, MYOHANEN S et al.: Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nature Genet. (1999) 21:103–107.
  • FUKS F, BURGERS WA, BREHM A et al.: DNA methyltr an s-ferase Dnmt1 associates with histone deacetylase activity. Nature Genet. (2000) 24:88–91.
  • MAYER TU, KAPOOR TM, HAGGARTY SJ et al.: Small molecule inhibitor of mitotic spindle bipolarity identi-fied in a phenotype-based screen. Science (1999) 286:971–974.
  • •Novel phenotype based assay for identification of new microtubule binding agents.
  • KOMAROV PG, KOMAROVA EA, KONDRATOV RV et al.: A chemical inhibitor of p53 that protects mice from the side effects of cancer therapy. Science (1999) 285: 1733-1737.
  • ••Describes a combined approach of using p53 transcriptionalreporter and apoptosis assays to screen for agents that interact with p53 and induce cellular apoptosis.
  • DOGLIONI C, MAURI FA, FERRERO S et al.: Heteroge-neous expression of cyclin D3 in breast carcinoma:absence of prognostic significance in a series of 92 cases with long follow-up. Patho/ogka (1999) 91 :410–411.
  • SUZUKI M, HOSAKA Y, MATSUSHIMA H et al.: Butyr olac-tone I induces cyclin B1 and causes G2/M arrest and skipping of mitosis in human prostate cell lines. Cancer Lett. (1999) 138 (1-2):121–130.
  • MOTWANI M, LI X, SCHWARTZ GK: Flavopiridol, a cyclin-dependent kinase inhibitor, prevents spindle inhibitor-induced endoreduplication in human cancer cells. Clin. Cancer Res. (2000) 6:924–932.
  • LEVKAU B, KOYAMA H, RAINES EW et al.: Cleavage of and p27Ki1'1 mediates apoptosis in endothelial cells through activation of cdk2: Role of a caspase cascade. Mol Cells (1998) 1:553–563.
  • CHEN J, SAHA P, KORNBLUTH S et al.: Cyclin-binding p. motifs are essential for the function of n CIP1 Cell. Biol. (1996) 16:4673–4682.
  • MATSUOKA M, KATO J-Y, FISHER RP et al.: Activation of cyclin-dependent kinase-4 (cdk4) by mouse M015-associated kinase. Mol. Cell. Biol. (1994) 14:7265–7275.
  • TOYOSHIMA H, HUNTER T: p27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21. Cell (1994) 78:67–74.

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