Flavopiridol, the first cyclin-dependent kinase inhibitor to enter the clinic: current status

Bibliography

• GARRETT MD, WORKMAN P: Discovering novel chemotherapeutic drugs for the third millennium. Eur. J. Cancer (1999) 35:2010–2030.
   PubMed Web of Science ®Google Scholar
• SENDEROWICZ AM, SAUSVILLE EA: Preclinical and clinical development of cyclin-dependent kinase modulators. J. Natl. Cancer Inst. (2000) 92:376–387.
   PubMed Web of Science ®Google Scholar
• SEDLACEK HH, CZECH J, NAIK R et al.: Flavopiridol (IS 6 8275; NSC 649890), a new kinase inhibitor for tumor therapy. Int. J. Oncol (1996) 9:1143–1168.
   PubMed Web of Science ®Google Scholar
• ••Comprehensive review of original preclinical studiesincluding cell-free enzyme inhibition, in vitro growth inhibi-tion, in vivo antitumour effects, rodent pharmacokinetics and toxicology.
   Google Scholar
• KAUR G, STETLER-STEVENSON M, SEBERS S etal.: Growth inhibition with reversible cell cycle arrest of carcinoma cells by flavone IS6-8275 .1 Natl. Cancer Inst. (1992) 84:1736–1740.
   Google Scholar
• KELLAND LR, ROGERS PM, PESTELL KE et al: Preclinical antitumor evaluation of cyclin-dependent kinase (cdk) inhibitors. Proc. AACR (1999) 40:125.
   Google Scholar
• DREES M, DENGLER WA, ROTH T et al: Flavopiridol (I86-8275): selective antitumour activity in vitro and activity in vivo for prostate carcinoma cells. Clin. Cancer Res. (1997) 3:273–279.
   PubMed Web of Science ®Google Scholar
• •Preclinical study showing promising in vivo antitumour activity in mice bearing human prostate carcinoma xenografts.
   Google Scholar
• LOSIEWICZ M, CARLSON B, KAUR G, SAUSVILLE EA, WORLAND PJ: Potent inhibition of cdc2 kinase activity by the flavonoid 1.86-8275. Biochem. Biophys. Res. Commun. (1994) 201:589–595.
   PubMed Web of Science ®Google Scholar
• CARLSON BA, DUBAY MM, SAUSVILLE EA, BRIZUELA L,WORLAND PJ: Flavopiridol induces Gi arrest with inhibition of cyclin-dependent kinase (cdk) 2 and cdk4 in human breast carcinoma cells. Cancer Res. (1996) 56:2973–2978.
   PubMed Web of Science ®Google Scholar
• CARLSON BA, PEARLSTEIN RA, NAIK RG, SEDLACEK H-H,SAUSVILLE EA, WORLAND PJ: Inhibition of cdk2, cdk4 and cdk7 by flavopiridol and structural analogs. Proc. AACR (1996) 37:424.
   Google Scholar
• DE AZEVEDO WF, JR., MUELLER-DIECKMANN H-J, SCHULZE-GAHMEN U, WORLAND PJ, SAUSVILLE E, SUNG-HOU K: 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.
   PubMed Web of Science ®Google Scholar
• •Co-crystallisation of flavopiridol with CDK2 showing structural features relevant for interaction within ATP-binding site.
   Google Scholar
• CARLSON B, LAHUSEN T, SINGH S et al.:Down-regulation of cyclin Di by transcriptional repression in MCF-7 human breast carcinoma cells induced by flavopiridol. Cancer Res. (1999) 59:4634–4641.
   PubMed Web of Science ®Google Scholar
• CHAO S-H, FUJINAGA K, MARION JE et al.: Flavopiridolinhibits P-1E113 and blocks 111V-1 replication. J. Biol. Chem. (2000) 275:28345–28348.
   PubMed Web of Science ®Google Scholar
• •Recent study showing potent inhibition (3 nM) against PTEFb and inhibition of transcription.
   Google Scholar
• ARGUELLO F, ALEXANDER M, STERRY JA 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.
   PubMed Web of Science ®Google Scholar
• •Preclinical in vivo study in mice bearing human leukaemia and lymphoma xenografts showing antitumour effects and induction of apoptosis in tumours and in resting lymphoid cells.
   Google Scholar
• BYRD JC, SHINN C, WASELENKO JK et al.: Flavopiridolinduces apoptosis in chronic lymphocytic leukemia cells via activation of caspase-3 without evidence of bc1-2 modulation or dependence on functional p53. Blood (1998) 92:3804–3816.
   PubMed Web of Science ®Google Scholar
• PARKER BW, KAUR G, NIEVES-NEIRA W et al.: Earlyinduction of apoptosis in hematopoietic cell lines after exposure to flavopiridol. Blood (1998) 91:458–465.
   PubMed Web of Science ®Google Scholar
• SCHRUMP DS, MATTHEWS W, CHEN GA, MIXON A, ALTORKI NK: Flavopiridol mediates cell cycle arrest and apoptosis in esophageal cancer cells. Clin. Cancer Res. (1998) 4:2885–2890.
   PubMed Web of Science ®Google Scholar
• SHAPIRO GI, KOESTNER DA, MATRANGA CB, ROLLINS BJ:Flavopiridol induces cell cycle arrest and p53-independent apoptosis in non-small cell lung cancer cell lines. Clin. Cancer Res. (1999) 5:2925–2938.
   PubMed Web of Science ®Google Scholar
• LI Y, BHUIYAN M, ALHASAN S, SENDEROWICZ AM, SARKAR FH: Induction of apoptosis and inhibition of c-erbB-2 in breast cancer cells by flavopiridol. Clin. Cancer Res. (2000) 5:223–229.
   Google Scholar
• ACHENBACH TV, MULLER R, SLATER EP: Bc1-2 independ-ence of flavopiridol-induced apoptosis. J. Biol. Chem. (2000) 275:32089–32097.
   PubMed Web of Science ®Google Scholar
• KITADA S, ZAPATA JM, ANDREEFF M, REED JC: Protein kinase inhibitors flavopiridol and 7-hydroxy-staurosporine down-regulate antiapoptosis proteins in B-cell chronic lymphocytic leukemia. Blood (2000) 96:393–397.
   PubMed Web of Science ®Google Scholar
• BIBLE KC, KAUFMANN SH: Flavopiridol: a cytotoxicflavone that induces cell death in noncycling A549 human lung carcinoma cells. Cancer Res. (1996) 56:4856–4861.
   PubMed Web of Science ®Google Scholar
• •Preclinical study showing that flavopiridol may also kill non-cycling cells.
   Google Scholar
• BRUSSELBACH S, NETTELBECK DM, SEDLACEK H-H, MULLER R: Cell cycle-independent induction of apoptosis by the anti-tumor drug flavopiridol in endothelial cells. Int. J. Cancer (1998) 77:146–152.
   PubMed Web of Science ®Google Scholar
• •Study using human endothelial cells indicating that flavopiridol may also possess anti-angiogenic properties.
   Google Scholar
• MOTVVANI 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.
   PubMed Web of Science ®Google Scholar
• SCHNIER JB, KAUR G, KAISER A et al.: Identification of cytosolic aldehyde dehyrogenase 1 from non-small cell lung carcinomas as a flavopiridol-binding protein. FEBS Lett. (1999) 454:100–104.
   PubMed Web of Science ®Google Scholar
• OIKONOMAKOS NG, SCHNIER JB, ZOGRAPHOS SE, SKAMNAKI VT, TSITSANOU KE, JOHNSON LN: Flavopiridol inhibits glycogen phosphorylase by binding at the inhibitor site. J. Biol. Chem. (2000) 275:34566–34573.
   PubMed Web of Science ®Google Scholar
• BIBLE KC, BIBLE JNR RH, KOTTKE TJ et al.: Flavopiridolbinds to duplex DNA. Cancer Res. (2000) 60:2419–2428.
   PubMed Web of Science ®Google Scholar
• •Studies indicating that the antitumour effects of flavopiridol may also be in part due to drug interaction with DNA.
   Google Scholar
• BIBLE KC, BOERNER SA, KIRKLAND K et al.: Characteriza- tion of an ovarian carcinoma cell line resistant to cisplatin and flavopiridol. Clin. Cancer Res. (2000) 6:661–670.
   PubMed Web of Science ®Google Scholar
• SMITH V, WORKMAN P, KELLAND LR: Drug r esistance to the cyclin-dependent kinase (CDK) inhibitor, flavopiridol. Proc. AACR (2000) 41:207.
   Google Scholar
• HOOIJBERG JH, BROXTERMAN HJ, SCHEFFER GL et al.: Potent interaction of flavopiridol with MRP1. Br. J. Cancer (1999) 81:269–276.
   PubMed Web of Science ®Google Scholar
• CZECH J, HOFFMANN D, NAIK R, SADLACEK HH: Antitu-moral activity of flavone IS6-8275. Int. J Oncol. (1995) 6:31–36.
   PubMed Web of Science ®Google Scholar
• PATEL V, SENDEROWICZ AM, PINTO D, JR. 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.
   Google Scholar
• JAGER W, ZEMBSCH B, WOLSCHANN PPE et al.: Metabo-lism of the anticancer drug flavopiridol, a new inhibitor of cyclin dependent kinases, in rat liver. Life Sci. (1998) 62:1861–1873.
   PubMed Web of Science ®Google Scholar
• INNOCENTI F, STADLER WM, IYER L, VOKES EE, RATAIN MJ: Flavopiridol metabolism in cancer patients is associated with the occurrence of diarrhea. Clin. Cancer Res. (2000) 6:3400–3405.
   PubMed Web of Science ®Google Scholar
• SENDEROWICZ AM, HEADLEE D, STINSON SF etal.: Phase I trial of continuous infusion flavopiridol, a novel cyclin-dependent kinase inhibitor, in patients with refractory neoplasms. J. Clin. °rico/. (1998) 16:2986–2999.
   Google Scholar
• ••Full report of initial Phase I study using 72 h continuousinfusion. Identification of Phase II dose and diarrhoea and hypotension as dose-limiting toxicities.
   Google Scholar
• STINSON SF, HILL K, SIFORD TJ, PHILIPS LR, DAW TW: Determination of flavopiridol (I86 8275; NSC 649890) in human plasma by reversed-phase liquid chroma-tography with electrochemical detection. Cancer Chemother. Pharmacol. (1998) 42:261–265.
   PubMed Web of Science ®Google Scholar
• THOMAS J, CLEARY J, TUTSCH K et al: Phase I clinical and pharmacokinetic trial of flavopiridol. Proc. AACR (1997) 38:222.
   Google Scholar
• SENDEROWICZ AM, MESSMAN R, ARBUCK SG et al.: A Phase I trial of 1 hour infusion of flavopiridol (FLA), a novel cyclin-dependent kinase inhibitor, in patients with advanced neoplasms. Proc. ASCO (2000) 19:796.
   Google Scholar
• BIBLE KC, KAUFMANN SH: Cytotoxic synergy between flavopiridol (NSC 649890, L86-8275) and various antineoplastic agents: the importance of sequence of administration. Cancer Res. (1997) 57:3375–3380.
   PubMed Web of Science ®Google Scholar
• •Preclinical studies showing synergistic growth inhibition with flavopiridol and cytotoxic drugs such as cisplatin and paclitaxel.
   Google Scholar
• MOTVVANI M, DELOHERY TM, SCHWARTZ GK: Sequen- tial dependent enhancement of caspase activation and apoptosis by flavopiridol on paclitaxel-treated human gastric and breast cancer cells. an. Cancer Res. (1999) 5:1876–1883.
   Web of Science ®Google Scholar
• •Preclinical studies showing sequence-dependent synergism between flavopiridol and paclitaxel.
   Google Scholar
• SCHWARTZ GK, FARSI K, MASTAK P, KELSEN DP, SPRIGGS D: Potentiation of ap op to sis by flavopiridol in mitomycin-C treated gastric and breast cancer cells. Clin. Cancer Res. (1997) 3:1467–1472.
   PubMed Web of Science ®Google Scholar
• SCHWARTZ GK, KAUBISCH A, SALTZ L et al.: Phase I trial of sequential paclitaxel and cisplatin in combination with the cyclin dependent kinase inhibitor flavopiridol (flavo) in patients with advanced solid tumors. Proc. AACR/NCl/EORTC (1999):26.
   Google Scholar
• BENNET P, MANI S, O'REILLY S et al: Phase II trial of flavopiridol in metastatic colorectal cancer: prelimi-nary results. Proc. ASCO (1999) 18:1065.
   Google Scholar
• SHAPIRO G, PATTERSON A, LYNCH C et al: A Phase II trial of flavopiridol in patients with stage IVnon-small cell lung cancer. Proc. ASCO (1999) 18:2013.
   Google Scholar
• WERNER JL, KELSEN DP, KARPEH M et al: The cyclin dependent kinase inhibitor flavopiridol is an active and unexpectedly toxic agent in advanced gastric cancer. Proc. ASCO (1998) 17:896.
   Google Scholar
• STADLER WM, VOGELZANG NJ, AMATO R et al.: Flavopiridol, a novel cyclin-dependent kinase inhibitor, in metastatic renal cancer: a University of Chicago Phase II Consortium Study. J. Clin. Oncol (2000) 18:371–375.
   PubMed Web of Science ®Google Scholar
• •First report of Phase II study: 6% objective response rate in metastatic renal cancer.
   Google Scholar
• CHEN Y-NP, 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.
   PubMed Web of Science ®Google Scholar
• •In vitro study describing the potential antitumour utility of selective CDK2 inhibitors.
   Google Scholar
• MEIJER L: Chemical inhibitors of cyclin-dependent kinases. Trends Cell Biol. (1996) 6:393–397.
   PubMed Web of Science ®Google Scholar
• FRY DW, GARRETT MD: Inhibitors of cyclin-dependent kinases as therapeutic agents for the treatment of cancer. Curr. Opin. Oncol. Endocr. Metab. Invest. Drugs (2000) 2:40–59.
   Google Scholar
• 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. Lloyd R Kelland
   Google Scholar