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Small-molecule cyclin-dependent kinase modulators

Oncogene volume 22, pages 6609–6620 (2003)Cite this article

Abstract

Aberrations in cell cycle progression occur in the majority of human malignancies. The main pathway affected is the retinoblastoma (Rb) pathway. The tumor suppressor gene Rb is an important component in the G1/S transition and its function is abnormal in most human neoplasms. Loss in Rb function occurs by the hyperactivation of the cyclin-dependent kinases (cdk's). Therefore, modulation of cdk's may have an important use for the therapy and prevention of human neoplasms. Efforts to obtain small-molecule cdk modulators yielded two classes of modulators: direct and indirect modulators. Direct cdk modulators are small molecules that specifically target the ATP binding site of cdk's. Examples for this group include flavopiridol, roscovitine and BMS-387032. In contrast, indirect cdk modulators affect cdk function due to modulation of upstream pathways required for cdk activation. Some examples include perifosine, lovastatin, and UCN-01. The first example of a direct small-molecule cdk modulator tested in the clinic, flavopiridol, is a pan-cdk inhibitor that not only promotes cell cycle arrest but also halts transcriptional elongation, promotes apoptosis, induces differentiation, and has antiangiogenic properties. Clinical trials with this agent were performed with at least three different schedules of administration: 1-, 24- and 72-h infusions. The main toxicities for infusions ⩾24-h are secretory diarrhea and proinflammatory syndrome. In addition, patients receiving shorter infusions have nausea/vomiting and neutropenia. A phase II trial of patients with advanced non-small-cell lung carcinoma using the 72-h infusion every 2 weeks was recently completed. The median overall survival for the 20 patients who received treatment was 7.5 months, a survival similar to that obtained in a randomized trial of four chemotherapy regimens containing platinum analogues in combination with taxanes or gemcitabine, or with gefitinib, a recently approved EGFR inhibitor for the treatment of advanced lung cancer. Based on these encouraging results, a phase III trial comparing standard combination chemotherapy versus combination chemotherapy plus flavopiridol is currently under investigation. The second example of direct small-molecule cdk modulator tested in clinical trials is UCN-01 (7-hydroxystaurosporine). UCN-01 has interesting preclinical features: it inhibits Ca2+-dependent PKCs, promotes apoptosis, arrests cell cycle progression at G1/S, and abrogates checkpoints upon DNA damage. The first phase I trial of UCN-01 demonstrated a very prolonged half-life. Based on this novel feature, UCN-01 is administered as a 72-h continuous infusion every 4 weeks (in second and subsequent cycles UCN-01 is administered as a 36-h infusion). Other shorter schedules (i.e. 3 h) are being tested. Dose-limiting toxicities include nausea/vomiting, hypoxemia, and insulin-resistant hyperglycemia. Combination trials with cisplatin and other DNA-damaging agents are being tested. Recently, phase I trials with two novel small-molecule cdk modulators, BMS 387032 and R-Roscovitine (CYC202), have commenced with good tolerability. In summary, novel small-molecule cdk modulators are being tested in the clinic with interesting results. Although these small molecules are directed towards a very prevalent cause of carcinogenesis, we need to test them in advanced clinical trials to determine the future of this class of agents for the prevention and therapy of human malignancies.

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References

  • Aagaard L, Lukas J, Bartkova J, Kjerulff AA, Strauss M and Bartek J . (1995). Int. J. Cancer, 61, 115–120.

  • Adams J, Palombella VJ and Elliott PJ . (2000). Invest. New Drugs, 18, 109–121.

  • Akinaga S, Gomi K, Morimoto M, Tamaoki T and Okabe M . (1991). Cancer Res, 51, 4888–4892.

  • Akinaga S, Nomura K, Gomi K and Okabe M . (1993). Cancer Chemother. Pharmacol, 32, 183–189.

  • Akinaga S, Nomura K, Gomi K and Okabe M . (1994). Cancer Chemother. Pharmacol., 33, 273–280.

  • Akiyama T, Shimizu M, Okabe M, Tamaoki T and Akinaga S . (1999). Anticancer Drugs, 10, 67–78.

  • Akiyama T, Yoshida T, Tsujita T, Shimizu M, Mizukami T, Okabe M and Akinaga S . (1997). Cancer Res., 57, 1495–1501.

  • An HX, Beckmann MW, Reifenberger G, Bender HG and Niederacher D . (1999). Am. J. Pathol., 154, 113–118.

  • 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 and Sausville E . (1998). Blood, 91, 2482–2490.

  • Baratte B, Meijer L, Galaktionov K and Beach D . (1992). Anticancer Res., 12, 873–880.

  • Bartek J, Staskova Z, Draetta G and Lukas J . (1993). Stem Cells (Dayt), 11 (Suppl. 1), 51–58.

  • Bartkova J, Lukas J, Guldberg P, Alsner J, Kirkin AF, Zeuthen J and Bartek J . (1996). Cancer Res., 56, 5475–5483.

  • Bartkova J, Lukas J, Muller H, Strauss M, Gusterson B and Bartek J . (1995). Cancer Res., 55, 949–956.

  • Bennett S, Mani S, O'Reilly S, Wright J, Schilsky R, Vokes E and Grochow L . (1999). Proc. Am. Soc. Clin. Oncol., 18, 156.

  • Bible KC and Kaufmann SH . (1996). Cancer Res., 56, 4856–4861.

  • Bible KC and Kaufmann SH . (1997). Cancer Res., 57, 3375–3380.

  • Blanchard JL, Epstein DM, Boisclair MD, Rudolph J and Pal K . (1999). Bioorg. Med. Chem. Lett., 9, 2537–2538.

  • Bonfanti M, Taverna S, Salmona M, D'Incalci M and Broggini M . (1997). Cancer Res., 57, 1442–1446.

  • Bramson HN, Corona J, Davis ST, Dickerson SH, Edelstein M, Frye SV, Gampe Jr RT, Harris PA, Hassell A, Holmes WD, Hunter RN, Lackey KE, Lovejoy B, Luzzio MJ, Montana V, Rocque WJ, Rusnak D, Shewchuk L, Veal JM, Walker DH and Kuyper LF . (2001). J. Med. Chem., 44, 4339–4358.

  • Brooks EE, Gray NS, Joly A, Kerwar SS, Lum R, Mackman RL, Norman TC, Rosete J, Rowe M, Schow SR, Schultz PG, Wang X, Wick MM and Shiffman D . (1997). J. Biol. Chem., 272, 29207–29211.

  • Brusselbach S, Nettelbeck DM, Sedlacek HH and Muller R . (1998). Int. J. Cancer, 77, 146–152.

  • Bunch RT and Eastman A . (1996). Clin. Cancer Res., 2, 791–797.

  • Bunch RT and Eastman A . (1997). Cell Growth Differ., 8, 779–788.

  • Buquet-Fagot C, Lallemand F, Montagne M and Mester J . (1997). Anti-Cancer Drugs, 8, 623–631.

  • Busby EC, Leistritz DF, Abraham RT, Karnitz LM and Sarkaria JN . (2000). Cancer Res., 60, 2108–2112.

  • Byrd JC, Shinn, C, Waselenko JK, Fuchs EJ, Lehman TA, Nguyen PL, Flinn IW, Diehl LF, Sausville E and Grever MR . (1998). Blood, 92, 3804–3816.

  • Cagnoli M, Barbieri F, Bruzzo C and Alama A . (1998). Gynecol. Oncol., 70, 372–377.

  • Carlson BA, Dubay MM, Sausville EA, Brizuela L and Worland PJ . (1996b). Cancer Res., 56, 2973–2978.

  • Carlson B, Lahusen T, Singh S, Loaiza-Perez A, Worland PJ, Pestell R, Albanese C, Sausville EA and Senderowicz AM . (1999). Cancer Res., 59, 4634–4641.

  • Carlson B, Pearlstein R, Naik R, Sedlacek H, Sausville E and Worland P . (1996a). Proc. Am. Assoc. Cancer Res., 37, 424.

  • Chao SH, Fujinaga K, Marion JE, Taube R, Sausville EA, Senderowicz AM, Peterlin BM and Price DH . (2000). J. Biol. Chem., 275, 28345–28348.

  • Chen X, Lowe M and Keyomarsi K . (1999a). Oncogene, 18, 5691–5702.

  • Chen YN, Sharma SK, Ramsey TM, Jiang L, Martin MS, Baker K, Adams PD, Bair KW and Kaelin Jr WG . (1999b). Proc. Natl. Acad. Sci. USA, 96, 4325–4329.

  • Chien M, Astumian M, Liebowitz D, Rinker-Schaeffer C and Stadler W . (1999). Cancer Chemother Pharmacol., 44, 81–87.

  • Chintala SK, Fueyo J, Gomez-Manzano C, Venkaiah B, Bjerkvig R, Yung WK, Sawaya R, Kyritsis AP and Rao JS . (1997). Oncogene, 15, 2049–2057.

  • Choi YH, Lee, SJ, Nguyen P, Jang JS, Lee J, Wu ML, Takano E, Maki M, Henkart PA and Trepel JB . (1997). J. Biol. Chem., 272, 28479–28484.

  • Colas P, Cohen B, Jessen T, Grishina I, McCoy J and Brent R . (1996). Nature, 380, 548–550.

  • Craig C, Wersto R, Kim M, Ohri E, Li Z, Katayose D, Lee SJ, Trepel J, Cowan K and Seth P . (1997). Oncogene, 14, 2283–2289.

  • De Azevedo WF, Leclerc S, Meijer L, Havlicek L, Strnad M and Kim SH . (1997). Eur. J. Biochem., 243, 518–526.

  • De Azevedo Jr WF, Mueller-Dieckmann HJ, Schulze-Gahmen U, Worland PJ, Sausville E and Kim SH . (1996). Proc. Natl. Acad. Sci. USA, 93, 2735–2740.

  • Dees E, O'Reilly S, Figg W, Elza-Brown K, Aylesworth C, Carducci M, Byrd J, Grever M and Donehower R . (2000). Proc. Am. Soc. Clin. Oncol., 19, 154.

  • DeGregori J, Leone G, Ohtani K, Miron A and Nevins JR . (1995). Genes Dev., 9, 2873–2887.

  • Dermatakis A, Luk KC and DePinto W . (2003). Bioorg. Med. Chem., 11, 1873–1881.

  • Dodo K, Takahashi M, Yamada Y, Sugimoto Y, Hashimoto Y and Shirai R . (2000). Bioorg. Med. Chem. Lett., 10, 615–617.

  • Drees M, Dengler W, Roth T, Labonte H, Mayo J, Malspeis L, Grever M, Sausville E and Fiebig H . (1997). Clin. Cancer Res., 32, 273–279.

  • Driscoll B, Buckley S, Barsky L, Weinberg K, Anderson KD and Warburton D . (1999). Am. J. Physiol., 276, L679–L687.

  • Eastham JA, Hall SJ, Sehgal I, Wang J, Timme TL, Yang G, Connell-Crowley L, Elledge SJ, Zhang WW and Harper JW et al (1995). Cancer Res., 55, 5151–5155.

  • Eicher SA, Clayman GL, Liu TJ, Shillitoe EJ, Storthz KA, Roth JA and Lotan R . (1996). Clin. Cancer Res., 2, 1659–1664.

  • Fahraeus R, Paramio JM, Ball KL, Lain S and Lane DP . (1996). Curr. Biol., 6, 84–91.

  • Fingert HJ, Pu AT, Chen ZY, Googe PB, Alley MC and Pardee AB . (1988). Cancer Res., 48, 4375–4381.

  • Fowler L, Dong L, Bowes III RC, van de Water B, Stevens JL and Jaken S . (1998). Cell Growth Differ., 9, 177–184.

  • Fredersdorf S, Burns J, Milne AM, Packham G, Fallis L, Gillett CE, Royds JA, Peston D, Hall PA, Hanby AM, Barnes DM, Shousha S, O Hare MJ and Lu X . (1997). Proc. Natl. Acad. Sci. USA, 94, 6380–6385.

  • Fry DW, Bedford DC, Harvey PH, Fritsch A, Keller PR, Wu Z, Dobrusin E, Leopold WR, Fattaey A and Garrett MD . (2001). J. Biol. Chem., 276, 16617–16623.

  • Fuse E, Tanii H, Kurata N, Kobayashi H, Shimada Y, Tamura T, Sasaki Y, Tanigawara Y, Lush RD, Headlee D, Figg W, Arbuck SG, Senderowicz AM, Sausville EA, Akinaga S, Kuwabara T and Kobayashi S . (1998). Cancer Res., 58, 3248–3253.

  • Gansauge S, Gansauge F, Ramadani M, Stobbe H, Rau B, Harada N and Beger HG . (1997). Cancer Res., 57, 1634–1637.

  • Gius DR, Ezhevsky SA, Becker-Hapak M, Nagahara H, Wei MC and Dowdy SF . (1999). Cancer Res., 59, 2577–2580.

  • Graves PR, Yu L, Schwarz JK, Gales J, Sausville EA, O'Connor PM and Piwnica-Worms H . (2000). J. Biol. Chem., 275, 5600–5605.

  • Gray-Bablin J, Rao S and Keyomarsi K . (1997). Cancer Res., 57, 604–609.

  • Gray N, Detivaud L, Doerig C and Meijer L . (1999). Curr. Med. Chem., 6, 859–875.

  • Gray NS, Wodicka L, Thunnissen AM, Norman TC, Kwon S, Espinoza FH, Morgan DO, Barnes G, LeClerc S, Meijer L, Kim SH, Lockhart DJ and Schultz PG . (1998). Science, 281, 533–538.

  • Hashemolhosseini S, Nagamine Y, Morley SJ, Desrivieres S, Mercep L and Ferrari S . (1998). J. Biol. Chem., 273, 14424–14429.

  • Hatakeyama M and Weinberg RA . (1995). Prog. Cell Cycle Res., 1, 9–19.

  • Hsueh CT, Kelsen D and Schwartz GK . (1998). Clin. Cancer Res., 4, 2201–2206.

  • Hunter T and Pines J . (1994). Cell, 79, 573–582.

  • Husain A, Yan XJ, Rosales N, Aghajanian C, Schwartz GK and Spriggs DR . (1997). Clin. Cancer Res., 3, 2089–2097.

  • Ichimura K, Schmidt EE, Goike HM and Collins VP . (1996). Oncogene, 13, 1065–1072.

  • Innocenti F, Stadler W M, Iyer L, Ramirez J, Vokes E and Ratain M . (2000). Clin. Cancer Res., 6, 3400–3405.

  • Jacks T and Weinberg RA . (1998). Science, 280, 1035–1036.

  • Jeong HW, Kim MR, Son KH, Han MY, Ha JH, Garnier, M, Meijer L and Kwon BM . (2000). Bioorg. Med. Chem. Lett., 10, 1819–1822.

  • Jin X, Nguyen D, Zhang WW, Kyritsis AP and Roth JA . (1995). Cancer Res., 55, 3250–3253.

  • Jones CB, Clements MK, Wasi S and Daoud SS . (2000). Cancer Chemother. Pharmacol., 45, 252–258.

  • Kanoe H, Nakayama T, Murakami H, Hosaka T, Yamamoto H, Nakashima Y, Tsuboyama T, Nakamura T, Sasaki MS and Toguchida J . (1998). Anticancer Res., 18, 2317–2321.

  • Katayose Y, Kim M, Rakkar AN, Li Z, Cowan KH and Seth P . (1997). Cancer Res., 57, 5441–5445.

  • Kaur G, Stetler-Stevenson M, Sebers S, Worland P, Sedlacek H, Myers C, Czech J, Naik R and Sausville E . (1992). J. Natl. Cancer Inst., 84, 1736–1740.

  • Kawakami K, Futami H, Takahara J and Yamaguchi K . (1996). Biochem. Biophys. Res. Commun., 219, 778–783.

  • Kent LL, Hull-Campbell NE, Lau T, Wu JC, Thompson SA and Nori M . (1999). Biochem. Biophys. Res. Commun., 260, 768–774.

  • Kerr JS, Wexler RS, Mousa SA, Robinson CS, Wexler EJ, Mohamed S, Voss ME, Devenny JJ, Czerniak PM, Gudzelak Jr A and Slee AM . (1999). Anticancer Res., 19, 959–968.

  • Kim KS, Kimball SD, Misra RN, Rawlins DB, Hunt JT, Xiao HY, Lu S, Qian L, Han WC, Shan W, Mitt T, Cai ZW, Poss MA, Zhu H, Sack JS, Tokarski JS, Chang CY, Pavletich N, Kamath A, Humphreys, WG, Marathe P, Bursuker I, Kellar KA, Roongta U, Batorsky R, Mulheron JG, Bol D, Fairchild CR, Lee FY and Webster KR . (2002). J. Med. Chem., 45, 3905–3927.

  • Kitagawa M, Okabe T, Ogino H, Matsumoto H, Suzuki-Takahashi I, Kokubo T, Higashi H, Saitoh S, Taya Y and Yasuda H et al (1993). Oncogene, 8, 2425–2432.

  • Konig A, Schwartz GK, Mohammad RM, Al-Katib A and Gabrilove JL . (1997). Blood, 90, 4307–4312.

  • Kornmann M, Arber N and Korc M . (1998). J. Clin. Invest., 101, 344–352.

  • Kris M, Natale N, Herbst RS, Lynch Jr TJ, Prager D, Belani CP, Schiller JH, Kelly K, Spiridonidis C, Albain KS, Brahmer JR, Sandler A, Crawford J, Lutzker SG, Lilenbaum R, Helms L, Wolf M, Averbuch S, Ochs J and Kay A . (2002). Proc. Am. Soc. Clin. Oncol., 21, 1166.

  • Lahusen T, De Siervi A, Kunick C and Senderowicz AM . (2003). Mol Carcinogen., 36, 183–194.

  • Lahusen J, Loaiza-Perez A, Sausville EA and Senderowicz AM . (2000). Proceedings of the Twentieth Annual Meeting of the American Association of Cancer Research. San Francisco, CA.

    Google Scholar 

  • Lane ME, Yu B, Rice A, Lipson KE, Liang C, Sun L, Tang C, McMahon G, Pestell RG and Wadler S . (2001). Cancer Res., 61, 6170–6177.

  • Leclerc S, Garnier M, Hoessel R, Marko D, Bibb JA, Snyder GL, Greengard P, Biernat J, Wu YZ, Mandelkow EM, Eisenbrand G and Meijer L . (2001). J. Biol. Chem., 276, 251–260.

  • Lee HR, Chang TH, Tebalt III MJ, Senderowicz AM and Szabo E . (1999). Int. J. Oncol., 15, 161–166.

  • Lees JA, Saito M, Vidal M, Valentine M, Look T, Harlow E, Dyson N and Helin K . (1993). Mol. Cell. Biol., 13, 7813–7825.

  • Losiewicz MD, Carlson BA, Kaur G, Sausville EA and Worland PJ . (1994). Biochem. Biophys. Res. Commun., 201, 589–5895.

  • Lowe SW, Bodis S, Bardeesy N, McClatchey A, Remington L, Ruley HE, Fisher DE, Jacks T, Pelletier J and Housman DE . (1994). Cold Spring Harbor Symp. Quant. Biol., 59, 419–426.

  • Lukas J, Aagaard L, Strauss M and Bartek J . (1995a). Cancer Res., 55, 4818–4823.

  • Lukas J, Bartkova J, Rohde M, Strauss M and Bartek J . (1995b). Mol. Cell. Biol., 15, 2600–2611.

  • Marchetti A, Buttitta F, Merlo G, Diella F, Pellegrini S, Pepe S, Macchiarini P, Chella A, Angeletti CA and Callahan R et al (1993). Cancer Res., 53, 2846–2851.

  • Masciullo V, Scambia G, Marone M, Giannitelli C, Ferrandina G, Bellacosa A, Benedetti Panici P and Mancuso S . (1997). Int. J. Cancer, 74, 390–395.

  • McClue SJ, Blake D, Clarke R, Cowan A, Cummings L, Fischer PM, MacKenzie M, Melville J, Stewart K, Wang S, Zhelev N, Zheleva D and Lane DP . (2002). Int. J. Cancer, 102, 463–468.

  • Meijer L . (2000). Drug Resist. Updat., 3, 83–88.

  • Meijer L, Borgne A, Mulner O, Chong JP, Blow JJ, Inagaki N, Inagaki M, Delcros JG and Moulinoux JP . (1997). Eur. J. Biochem., 243, 527–536.

  • Meijer L and Kim SH . (1997). Methods Enzymol., 283, 113–128.

  • Melillo G, Sausville EA, Cloud K, Lahusen T, Varesio L and Senderowicz AM . (1999). Cancer Res., 59, 5433–5437.

  • Mesguiche V, Parsons RJ, Arris CE, Bentley J, Boyle FT, Curtin NJ, Davies TG, Endicott JA, Gibson AE, Golding BT, Griffin RJ, Jewsbury P, Johnson LN, Newell DR, Noble ME, Wang LZ and Hardcastle IR . (2003). Bioorg. Med. Chem. Lett., 13, 217–222.

  • Mettey Y, Gompel M, Thomas V, Garnier M, Leost M, Ceballos-Picot I, Noble M, Endicott J, Vierfond JM and Meijer L . (2003). J. Med. Chem., 46, 222–236.

  • Michalides R, van Veelen N, Hart A, Loftus B, Wientjens E and Balm A . (1995). Cancer Res., 55, 975–978.

  • Misra RN, Rawlins DB, Xiao H, Shan W, Bursuker I, Kellar KA, Mulheron JG, Sack JS, Tokarski JS, Kimball SD and Webster KR . (2003). Bioorg. Med. Chem. Lett., 13, 1133–1136.

  • Morgan DO . (1997). Annu. Rev. Cell. Dev. Biol., 13, 261–291.

  • Motokura T and Arnold A . (1993). Curr. Opin. Genet. Dev., 3, 5–10.

  • Muise-Helmericks RC, Grimes HL, Bellacosa A, Malstrom SE, Tsichlis PN and Rosen N . (1998). J. Biol. Chem., 273, 29864–29872.

  • Nugiel DA, Etzkorn AM, Vidwans A, Benfield PA, Boisclair M, Burton CR, Cox S, Czerniak PM, Doleniak D and Seitz SP . (2001). J. Med. Chem., 44, 1334–1336.

  • Ortega MA, Montoya ME, Zarranz B, Jaso A, Aldana I, Leclerc S, Meijer L and Monge A . (2002). Bioorg. Med. Chem., 10, 2177–2184.

  • Park S, Cheon J, Lee Y, Park Y, Lee K, Lee C and Lee S . (1996). Mol. Cells, 6, 679–683.

  • Parker B, Kaur G, Nieves-Neira W, Taimi M, Kolhagen G, Shimizu T, Pommier Y, Sausville E and Senderowicz AM . (1998). Blood, 91, 458–465.

  • Patel V, Lahusen T, Leethanakul C, Igishi T, Kremer M, Quintanilla-Martinez L, Ensley JF, Sausville EA, Gutkind JS and Senderowicz AM . (2002a). Clin. Cancer Res., 8, 3549–3560.

  • Patel V, Lahusen T, Sy T, Sausville EA, Gutkind JS and Senderowicz AM . (2002b). Cancer Res., 62, 1401–1409.

  • Patel V, Senderowicz AM, Pinto D, Igishi T, Raffeld M, Quintanilla-Martinez L, Ensley JF, Sausville EA and Gutkind JS . (1998). J. Clin. Invest., 102, 1674–1681.

  • Pollack IF, Kawecki S and Lazo JS . (1996). J. Neurosurg., 84, 1024–1032.

  • Roberge M, Tudan C, Hung SM, Harder KW, Jirik FR and Anderson H . (1994). Cancer Res., 54, 6115–6121.

  • Robles AI, Rodriguez-Puebla ML, Glick AB, Trempus C, Hansen L, Sicinski P, Tennant RW, Weinberg RA, Yuspa SH and Conti CJ . (1998). Genes Dev, 12, 2469–2474.

  • Rodriguez-Puebla ML, LaCava M and Conti CJ . (1999). Cell Growth Differ., 10, 467–472.

  • Rosania GR, Merlie Jr J, Gray N, Chang YT, Schultz PG and Heald R . (1999). Proc. Natl. Acad. Sci. USA, 96, 4797–4802.

  • Ryu CK, Kang HY, Lee SK, Nam KA, Hong CY, Ko WG and Lee BH . (2000). Bioorg. Med. Chem. Lett., 10, 461–464.

  • Sandig V, Brand K, Herwig S, Lukas J, Bartek J and Strauss M . (1997). Nat. Med., 3, 313–319.

  • Sarkaria JN, Busby EC, Tibbetts RS, Roos P, Taya Y, Karnitz LM and Abraham RT . (1999). Cancer Res., 59, 4375–4382.

  • Sato S, Fujita N and Tsuruo T . (2002). Oncogene, 21, 1727–1738.

  • Sausville EA, Arbuck SG, Messmann R, Headlee D, Bauer KS, Lush RM, Murgo A, Figg WD, Lahusen T, Jaken S, Jing X, Roberge M, Fuse E, Kuwabara T and Senderowicz AM . (2001). J. Clin. Oncol., 19, 2319–2333.

  • Sausville EA, Lush RD, Headlee D, Smith AC, Figg WD, Arbuck SG, Senderowicz AM, Fuse E, Tanii H, Kuwabara T and Kobayashi S . (1998). Cancer Chemother. Pharmacol., 42 (Suppl), S54–S59.

  • Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J and Johnson DH . (2002). N. Engl. J. Med., 346, 92–98.

  • Schoepfer J, Fretz H, Chaudhuri B, Muller L, Seeber E, Meijer L, Lozach O, Vangrevelinghe E and Furet P . (2002). J. Med. Chem., 45, 1741–1747.

  • Schrump DS, Matthews W, Chen GA, Mixon A and Altorki NK . (1998). Clin. Cancer Res., 4, 2885–2890.

  • Schultz C, Link, A, Leost M, Zaharevitz DW, Gussio R, Sausville EA, Meijer L and Kunick C . (1999). J. Med. Chem., 42, 2909–2919.

  • Schutte B, Nieland L, van Engeland M, Henfling ME, Meijer L and Ramaekers FC . (1997). Exp. Cell. Res., 236, 4–15.

  • Schwartz G, Farsi K, Maslak P, Kelsen D and Spriggs D . (1997). Clin. Cancer Res., 3, 1467–1472.

  • Schwartz GK, O'Reilly E, Ilson D, Saltz L, Sharma S, Tong W, Maslak P, Stoltz M, Eden L, Perkins P, Endres S, Barazzoul J, Spriggs D and Kelsen D . (2002). J. Clin. Oncol., 20, 2157–2170.

  • Sedlacek HH, Czech J, Naik R, Kaur G, Worland P, Losiewicz M, Parker B, Carlson B, Smith A, Senderowicz A and Sausville E . (1996). Int. J. Oncol., 9, 1143–1168.

  • Senderowicz AM . (1999). Invest. New Drugs, 17, 313–320.

  • Senderowicz AM . (2000). Oncogene, 19, 6600–6606.

  • Senderowicz AM . (2001a). Cancer Chemother. Biol. Response Modif., 19, 165–188.

  • Senderowicz AM . (2001b). Cancer Chemother. Biol. Response Modif., 19, 165–188.

  • Senderowicz AM . (2002a). Oncologist, 7, 12–19.

  • Senderowicz AM . (2002b). Hematol. Oncol. Clin. N. Am., 16, 1229–1253.

  • Senderowicz AM, Headlee D, Lush R, Bauer K, Figg W, Murgo A, S, Arbuck S, Inoue K, Kobashi S, Kuwabara T and Sausville E . (1998a). 10th National Cancer Institute-European Organisation for Research on Treatment of Cancer Symposium Proceedings, Amsterdam, Holland, pp. 78.

    Google Scholar 

  • Senderowicz AM, Headlee D, Lush R, Bauer K, Figg W, Murgo AS, Arbuck S, Inoue K, Kobashi S, Kuwabara T and Sausville E . (1999). Proceedings of the Thirty-fifth Annual Meeting of the American Society of Clinical Oncology Vol. 18, Atlanta, GA.

    Google Scholar 

  • Senderowicz AM, Headlee D, Stinson SF, Lush RM, Kalil N, Villalba L, Hill K, Steinberg SM, Figg WD, Tompkins A, Arbuck SG and Sausville EA . (1998b). J. Clin. Oncol., 16, 2986–2999.

  • Senderowicz AM, Messmann R, Arbuck S, Headlee D, Zhai S, Murgo A, Melillo G, Figg W and Sausville E . (2000). Proceedings of the Annual Meeting of the American Society of Clinical Oncology, New Orleans.

  • Senderowicz AM and Sausville EA . (2000). J. Natl. Cancer Inst., 92, 376–387.

  • Seynaeve CM, Kazanietz MG, Blumberg PM, Sausville EA and Worland PJ . (1994). Mol. Pharmacol., 45, 1207–1214.

  • Seynaeve CM, Stetler-Stevenson M, Sebers S, Kaur G, Sausville EA and Worland PJ . (1993). Cancer Res., 53, 2081–2086.

  • Shao RG, Cao CX, Shimizu T, O'Connor PM, Kohn KW and Pommier Y . (1997). Cancer Res., 57, 4029–4035.

  • Shapiro GI, Koestner DA, Matranga CB and Rollins BJ . (1999b). Clin. Cancer Res., 5, 2925–2938.

  • Shapiro G, Patterson A, Lynch C, Lucca J, Anderson L, Boral A, Elias A, Lu H, Salgia R, Skarin A, Panek-Clark C, McKenna R, Rabin M, Vasconcelles M, Eder P, Supko J, Lynch T and Rollins B . (1999a). Proceedings of the American Society of Clinical Oncology Vol. 18, Atlanta, GA.

  • Shapiro GI, Supko JG, Patterson A, Lynch C, Lucca J, Zacarola PF, Muzikansky A, Wright JJ, Lynch Jr TJ and Rollins BJ . (2001). Clin. Cancer Res., 7, 1590–1599.

  • Sherr CJ . (1996). Science, 274, 1672–1677.

  • Shimizu E, Zhao MR, Nakanishi H, Yamamoto A, Yoshida S, Takada M, Ogura T and Sone S . (1996). Oncology, 53, 494–504.

  • Sielecki TM, Johnson TL, Liu J, Muckelbauer JK, Grafstrom RH, Cox S, Boylan J, Burton CR, Chen H, Smallwood A, Chang CH, Boisclair M, Benfield PA, Trainor GL and Seitz SP . (2001). Bioorg. Med. Chem. Lett., 11, 1157–1160.

  • Soni R, Muller L, Furet P, Schoepfer J, Stephan C, Zumstein-Mecker S, Fretz H and Chaudhuri B . (2000). Biochem. Biophys. Res. Commun., 275, 877–884.

  • Soni R, O'Reilly T, Furet P, Muller L, Stephan C, Zumstein-Mecker S, Fretz H, Fabbro D and Chaudhuri B . (2001). J. Natl. Cancer Inst., 93, 436–446.

  • Sonoda Y, Yoshimoto T and Sekiya T . (1995). Oncogene, 11, 2145–2149.

  • Spitz FR, Nguyen D, Skibber JM, Cusack J, Roth JA and Cristiano RJ . (1996). Anticancer Res., 16, 3415–3422.

  • Stadler WM, Vogelzang NJ, Amato R, Sosman J, Taber D, Liebowitz D and Vokes EE . (2000). J. Clin. Oncol., 18, 371–375.

  • Sugiyama K, Shimizu M, Akiyama T, Tamaoki T, Yamaguchi K, Takahashi R, Eastman A and Akinaga S . (2000). Int. J. Cancer., 85, 703–709.

  • Takahashi I, Kobayashi E, Asano K, Yoshida M and Nakano H . (1987). J. Antibiot (Tokyo), 40, 1782–1784.

  • Takahashi I, Saitoh Y, Yoshida M, Sano H, Nakano H, Morimoto M and Tamaoki T . (1989). J. Antibiot (Tokyo), 42, 571–576.

  • Tamaoki T . (1991). Methods Enzymol., 201, 340–347.

  • Tamura T, Sasaki Y, Minami H, Fujii H, Ito K, Igarashi T, Kamiya Y, Kurata T, Ohtsu T, Onozawa Y, Yamamoto N, Yamamoto N, Watanabe Y, Tanigaara Y, Fuse E, Kuwabara T, Kobayahsi S and Shimada Y . (1999). Proc. Am. Soc. Clin. Oncol., 18, 159.

  • Tan AR, Headlee D, Messmann R, Sausville EA, Arbuck SG, Murgo AJ, Melillo G, Zhai S, Figg WD, Swain SM and Senderowicz AM . (2002). J. Clin. Oncol., 20, 4074–4082.

  • Testa JR and Bellacosa A . (2001). Proc. Natl. Acad. Sci. USA, 98, 10983–10985.

  • Thomas JP, Tutsch KD, Cleary JF, Bailey HH, Arzoomanian R, Alberti D, Simon K, Feierabend C, Binger K, Marnocha R, Dresen A and Wilding G . (2002). Cancer Chemother. Pharmacol., 50, 465–472.

  • Tsuchida E and Urano M . (1997). Int. J. Radiat. Oncol. Biol. Phys., 39, 1153–1161.

  • Usuda J, Saijo N, Fukuoka K, Fukumoto H, Kuh HJ, Nakamura T, Koh Y, Suzuki T, Koizumi F, Tamura T, Kato H and Nishio K . (2000). Int. J. Cancer, 85, 275–280.

  • Walker DH . (1998). Curr. Top. Microbiol. Immunol., 227, 149–165.

  • Wang MB, Billings KR, Venkatesan N, Hall FL and Srivatsan ES . (1998). Otolaryngol. Head Neck Surg., 119, 593–599.

  • Wang C, Fu M, Mani S, Wadler S, Senderowicz AM and Pestell RG . (2001). Front. Biosci., 6, D610–D629.

  • Wang Q, Fan S, Eastman A, Worland PJ, Sausville EA and O'Connor P . (1996). J. Natl. Cancer Inst., 88, 956–965.

  • Wang Q, Worland PJ, Clark JL, Carlson BA and Sausville EA . (1995). Cell Growth Differ., 6, 927–936.

  • Warbrick E, Lane DP, Glover DM and Cox LS . (1995). Curr Biol, 5, 275–282.

  • Weinberg RA . (1996). Cytokines Mol. Ther., 2, 105–110.

  • Werner J, Kelsen D, Karpeh M, Inzeo D, Barazzuol J, Sugarman A and Schwartz GK . (1998). Proceedings of the American Society of Clinical Oncology Vol. 17, Los Angeles, CA.

    Google Scholar 

  • Wilcken NR, Sarcevic B, Musgrove EA and Sutherland RL . (1996). Cell Growth Differ., 7, 65–74.

  • Wilson WH, Sorbara L, Figg WD, Mont EK, Sausville E, Warren KE, Balis FM, Bauer K, Raffeld M, Senderowicz AM and Monks A . (2000). Clin. Cancer Res., 6, 415–421.

  • Wolfel T, Hauer M, Schneider J, Serrano M, Wolfel C, Klehmann-Hieb E, De Plaen E, Hankeln T, Meyer zum Buschenfelde KH and Beach D . (1995). Science, 269, 1281–1284.

  • Worland PJ, Kaur G, Stetler-Stevenson M, Sebers S, Sartor O and Sausville EA . (1993). Biochem. Pharmacol., 46, 1831–1840.

  • Wright J, Blatner GL and Cheson BD . (1998). Oncology (Huntingt), 12 1018, 1023–1024.

  • Yu JT, Foster RG and Dean DC . (2001). Mol. Cell. Biol., 21, 3325–3335.

  • Yu L, Orlandi L, Wang P, Orr M, Senderowicz AM, Sausville EA, Silvestrini Ra and O'Connor P . (1998). J. Biol. Chem., 273, 33455–33464.

  • Zaharevitz DW, Gussio R, Leost M, Senderowicz AM, Lahusen T, Kunick C, Meijer L and Sausville EA . (1999). Cancer Res., 59, 2566–2569.

  • Zhou Q, Stetler-Stevenson M and Steeg PS . (1997). Oncogene, 15, 107–115.

  • Zhu G, Conner S, Zhou X, Shih C, Brooks HB, Considine E, Dempsey JA, Ogg C, Patel B, Schultz RM, Spencer CD, Teicher B and Watkins SA . (2003a). Bioorg. Med. Chem. Lett., 13, 1231–1255.

  • Zhu G, Conner SE, Zhou X, Shih C, Li T, Anderson BD, Brooks HB, Campbell RM, Considine E, Dempsey JA, Faul MM, Ogg C, Patel B, Schultz RM, Spencer CD, Teicher B and Watkins SA . (2003b). J. Med. Chem., 46, 2027–2030.

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  1. Molecular Therapeutics Unit, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, 20892-4330, MD, USA

    Adrian M Senderowicz

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Senderowicz, A. Small-molecule cyclin-dependent kinase modulators. Oncogene 22, 6609–6620 (2003). https://doi.org/10.1038/sj.onc.1206954

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