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Flavopiridol: the First Cyclin-Dependent Kinase Inhibitor in Human Clinical Trials

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Abstract

The discovery and cloning of the cyclin-dependent kinases (cdks), main regulators of cell cycle progression, allowed several investigators to design novel modulators of cdk activity. Flavopiridol (HMR 1275, L86-8275), a flavonoid derived from an indigenous plant from India, demonstrated potent and specific in vitro inhibition of all cdks tested (cdks 1, 2, 4 and 7) with clear block in cell cycle progression at the G1/S and G2/M boundaries. Moreover, preclinical studies demonstrated the capacity of flavopiridol to induce programmed cell death, promote differentiation, inhibit angiogenic processes and modulate transcriptional events. The relationship between the latter effects and cdk inhibition is still unclear. Initial testing in early clinical human trials with infusional flavopiridol showed activity in some patients with non-Hodgkin's lymphoma, renal, prostate, colon and gastric carcinomas. Main side effects were secretory diarrhea and a pro-inflammatory syndrome associated with hypotension. Biologically active plasma concentrations of flavopiridol (∼300–500 nM) are easily achievable in patients receiving infusional flavopiridol. Phase 2 trials with infusional flavopiridol in several tumor types, other schedules and combination with standard chemotherapies are being assessed. In conclusion, flavopiridol is the first cdk inhibitor to be tested in clinical trials. Although important questions remain to be answered, this positive experience will stimulate the development of novel cdk modulators for cancer therapy.

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References

  1. Sherr CJ: Cancer cell cycles. Science 274: 1672, 1996

    Google Scholar 

  2. Hatakeyama M, Weinberg RA: The role of RB in cell cycle control. Prog Cell Cycle Res 1: 9, 1995

    Google Scholar 

  3. Morgan DO, Fisher RP, Espinoza FH, Farrell A, Nourse J, Chamberlin H, Jin P: Control of eukaryotic cell cycle progression by phosphorylation of cyclin-dependent kinases [In Process Citation]. Cancer J Sci Am 4 Suppl 1: S77, 1998

    Google Scholar 

  4. Morgan DO: Cyclin-dependent kinases: engines, clocks, and microprocessors. Annu Rev Cell Dev Biol 13: 261, 1997

    Google Scholar 

  5. Rickert P, Seghezzi W, Shanahan F, Cho H, Lees E: Cyclin C/CDK8 is a novel CTD kinase associated with RNA polymerase II. Oncogene 12: 2631, 1996

    Google Scholar 

  6. Wei P, Garber ME, Fang SM, Fischer WH, Jones KA: A novel CDK9-associated C-type cyclin interacts directly with HIV-1 Tat and mediates its high-affinity, loop-specific binding to TAR RNA. Cell 92: 451, 1998

    Google Scholar 

  7. Grana X, De Luca A, Sang N, Fu Y, Claudio PP, Rosenblatt J, Morgan DO, Giordano A: PITALRE, a nuclear CDC2-related protein kinase that phosphorylates the retinoblastoma protein in vitro. Proc Natl Acad Sci USA 91: 3834, 1994

    Google Scholar 

  8. MacLachlan TK, Sang N, Giordano A: Cyclins, cyclindependent kinases and cdk inhibitors: implications in cell cycle control and cancer. Crit Rev Eukaryot Gene Expr 5: 127, 1995

    Google Scholar 

  9. Edwards MC, Wong C, Elledge SJ: Human cyclin K, a novel RNA polymerase II-associated cyclin possessing both carboxy-terminal domain kinase and Cdk-activating kinase activity. Mol Cell Biol 18: 4291, 1998

    Google Scholar 

  10. Peng J, Zhu Y. Milton JT, Price DH: Identification of multiple cyclin subunits of human P-TEFb. Genes Dev 12: 755, 1998

    Google Scholar 

  11. Kaldis P, Russo AA, Chou HS, Pavletich NP, Solomon MJ: Human and Yeast Cdk-activating Kinases (CAKs) Display Distinct Substrate Specificities. Mol Biol Cell 9: 2545, 1998

    Google Scholar 

  12. Tassan JP, Schultz SJ, Bartek J, Nigg EA: Cell cycle analysis of the activity, subcellular localization, and subunit composition of human CAK (CDK-activating kinase). J Cell Biol 127: 467, 1994

    Google Scholar 

  13. Sherr CJ, Roberts JM: CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 13: 1501, 1999

    Google Scholar 

  14. Zhang HS, Postigo AA, Dean DC: Active transcriptional repression by the Rb-E2F complex mediates G1 arrest triggered by p16INK4a, TGFbeta, and contact inhibition. Cell 97: 53, 1999

    Google Scholar 

  15. Dyson N: The regulation of E2F by pRB-family proteins. Genes Dev 12: 2245, 1998

    Google Scholar 

  16. DelSal G, Loda M, Pagano M: Cell cycle and cancer: critical events at the G1 restriction point. Crit Rev Oncog 7: 127, 1996

    Google Scholar 

  17. Grana X, Reddy EP: Cell cycle control in mammalian cells: role of cyclins, dependent kinases (CDKs), growth suppressor genes and cyclin-dependent kinase inhibitors (CKls). Oncogene 11: 211, 1995

    Google Scholar 

  18. Pardee AB: Multiple molecular levels of cell cycle regulation. J Cell Biochem 54: 375, 1994

    Google Scholar 

  19. Pines J: Cyclins and cyclin-dependent kinases: theme and variations. Adv Cancer Res 66: 181, 1995

    Google Scholar 

  20. Weinberg RA: The retinoblastoma protein and cell cycle control. Cell 81: 323, 1995

    Google Scholar 

  21. Sausville EA, Zaharevitz DW, Gussio R, Meijer L, Leost M, Kunick C, Schultz R, Lahusen T, Headlee D, Stinson S, Arbuck S, Senderowicz AM: Cyclin-dependent kinases: Initial 319 approaches to exploit a novel therapeutic target. Pharmacol Ther 82: 285, 1999

    Google Scholar 

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

    Google Scholar 

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

    Google Scholar 

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

    Google Scholar 

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

    Google Scholar 

  26. Carlson B, Pearlstein R, Naik R, Sedlacek H, Sausville E, Worland P: Inhibition of CDK2, CDK4 and CDK7 by flavopiridol and structural analogs. Proceedings of the American Association for Cancer Research, 1996

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

    Google Scholar 

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

    Google Scholar 

  29. Michalides R, van Veelen N, Hart A, Loftus B, Wientjens E, Balm A: Overexpression of cyclin D1 correlates with recurrence in a group of forty-seven operable squamous cell carcinomas of the head and neck. Cancer Res 55: 975, 1995

    Google Scholar 

  30. Gansauge S, Gansauge F, Ramadani M, Stobbe H, Rau B, Harada N, Beger HG: Overexpression of cyclin D1 in human pancreatic carcinoma is associated with poor prognosis. Cancer Res 57: 1634, 1997

    Google Scholar 

  31. Fredersdorf S, Burns J, Milne AM, Packham G, Fallis L, Gillett CE, Royds JA, Peston D, Hall PA, Hanby AM, Barnes DM, Shousha S, MJ OH, Lu X: 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, 1997

    Google Scholar 

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

  33. Gray NS, Wodicka L, Thunnissen AM, Norman TC, Kwon S, Espinoza FH, Morgan DO, Barnes G, LeClerc S, Meijer L, Kim SH, Lockhart DJ, Schultz PG: Exploiting chemical libraries, structure, and genomics in the search for kinase inhibitors. Science 281: 533, 1998

    Google Scholar 

  34. Arguello F, Alexander M, Sterry J, Tudor G, Smith E, Kalavar N, Greene J, Koss W, Morgan D, Stinson S, Siford T, Alvord W, Labansky R, Sausville E: Flavopiridol induces apoptosis of normal lymphoid cells, causes immunosuppresion, and has potent antitumor activity in vivo against human and leukemia xenografts. Blood 91: 2482, 1998

    Google Scholar 

  35. Byrd JC, Shinn C, Waselenko JK, Fuchs EJ, Lehman TA, Nguyen FL, Flinn IW, Diehl LF, Sausville E, Grever MR: 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, 1998

    Google Scholar 

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

    Google Scholar 

  37. Konig A, Schwartz GK, Mohammad RM, Al-Katib A, Gabrilove JL: 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, 1997

    Google Scholar 

  38. Patel V, Senderowicz AM, Pinto D, Igishi T, Raffeld M, Quintanilla-Martinet L, Ensley JF, Sausville EA, Gutkind JS: 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, 1998

    Google Scholar 

  39. Chien M, Astumian M, Liebowitz D, Rinker-Schaeffer C, Stadler W: In vitro evaluation of flavopinidol, a novel cell cycle inhibitor, in bladder cancer. Cancer Chemother Pharmacol 44: 81, 1999

    Google Scholar 

  40. Schrump DS, Matthews W, Chen GA, Mixon A, Altorki NK: Flavopiridol mediates cell cycle arrest and apoptosis in esophageal cancer cells [In Process Citation]. Clin Cancer Res 4: 2885, 1998

    Google Scholar 

  41. Bible KC, Kaufmann SH: Flavopiridol: a cytotoxic flavone that induces cell death in noncycling A549 human lung carcinoma cells. Cancer Res 56: 4856, 1996

    Google Scholar 

  42. Park DS, Farinelli SE, Greene LA: Inhibitors of cyclindependent kinases promote survival of post-mitotic neuronally differentiated PC12 cells and sympathetic neurons. J Biol Chem 271: 8161, 1996

    Google Scholar 

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

    Google Scholar 

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

    Google Scholar 

  45. Melillo G, Sausville E, Cloud K, Lahusen T, Varresio L, Senderowicz A: Flavopiridol, a protein kinase inhibitor, downregulates hypoxic induction of VEGF expression in human monocytes. Cancer Research (in press), 1999

  46. Lee HR, Chang TH, Tebalt MJ, 3rd, Senderowicz AM, Szabo E: Induction of differentiation accompanies inhibition of cdk2 in a non-small cell lung cancer cell line [In Process Citation]. Int J Oncol 15: 161, 1999

    Google Scholar 

  47. Schwartz G, Farsi K, Maslak P, Kelsen D, Spriggs D: Potentiation of apoptosis by flavopiridol in mitomycin-C-treated gastric and breast cancer cells. Clinical Cancer Research 3: 1467, 1997

    Google Scholar 

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

    Google Scholar 

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

    Google Scholar 

  50. Jager W, Zembsch B, Wolschann P, Pittenauer E, Senderowicz AM, Sausville E, Sedlacek H, Graf J, Thalhammer T: Metabolism of the anticancer drug flavopiridol, a new inhibitor of cyclin dependent kinases, in rat liver. Life Sci 62 1861–1873: 1861, 1998

    Google Scholar 

  51. Lush R, Stinson S, Senderowicz A, Hill K, Feuer J, Headlee D, Figg WES: Flavopiridol pharmacokinetics suggest entoerohepatic circulation. Clinical Pharmacology and Therapeutics 61: 145, 1997

    Google Scholar 

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

    Google Scholar 

  53. Thomas J, Cleary J, Tutsch K, Arzoomanian R, Alberti D, Simon K, Feierabend D, Morgan K, Wilding G: Phase I clinical and pharmacokinetic trial of flavopiridol. Proc eightyeightieth Annual Meeting of the American Association of Cancer Research. San Diego, CA, 1997

  54. Shenfeld M, Senderowicz AM, Sausville EA, Ke B: A novel chemotherapeutic agent, flavopiridol, modulates intestinal epithelial chloride secretion. Gastroenterology 112: 404, 1997

    Google Scholar 

  55. Wright J, Blatner GL, Cheson BD: Clinical trials referral resource. Clinical trials of flavopiridol. Oncology (Huntingt) 12: 1018, 1998

    Google Scholar 

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  1. DTP Clinical Trials Unit, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, USA

    Adrian M. Senderowicz

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Senderowicz, A.M. Flavopiridol: the First Cyclin-Dependent Kinase Inhibitor in Human Clinical Trials. Invest New Drugs 17, 313–320 (1999). https://doi.org/10.1023/A:1006353008903

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