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 β©Ύ24-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. 3βh) 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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Aagaard L, Lukas J, Bartkova J, Kjerulff AA, Strauss M and Bartek J . (1995). Int. J. Cancer, 61, 115β120.
Adams J, Palombella VJ and Elliott PJ . (2000). Invest. New Drugs, 18, 109β121.
Akinaga S, Gomi K, Morimoto M, Tamaoki T and Okabe M . (1991). Cancer Res, 51, 4888β4892.
Akinaga S, Nomura K, Gomi K and Okabe M . (1993). Cancer Chemother. Pharmacol, 32, 183β189.
Akinaga S, Nomura K, Gomi K and Okabe M . (1994). Cancer Chemother. Pharmacol., 33, 273β280.
Akiyama T, Shimizu M, Okabe M, Tamaoki T and Akinaga S . (1999). Anticancer Drugs, 10, 67β78.
Akiyama T, Yoshida T, Tsujita T, Shimizu M, Mizukami T, Okabe M and Akinaga S . (1997). Cancer Res., 57, 1495β1501.
An HX, Beckmann MW, Reifenberger G, Bender HG and Niederacher D . (1999). Am. J. Pathol., 154, 113β118.
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, 2482β2490.
Baratte B, Meijer L, Galaktionov K and Beach D . (1992). Anticancer Res., 12, 873β880.
Bartek J, Staskova Z, Draetta G and Lukas J . (1993). Stem Cells (Dayt), 11 (Suppl. 1), 51β58.
Bartkova J, Lukas J, Guldberg P, Alsner J, Kirkin AF, Zeuthen J and Bartek J . (1996). Cancer Res., 56, 5475β5483.
Bartkova J, Lukas J, Muller H, Strauss M, Gusterson B and Bartek J . (1995). Cancer Res., 55, 949β956.
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, 4856β4861.
Bible KC and Kaufmann SH . (1997). Cancer Res., 57, 3375β3380.
Blanchard JL, Epstein DM, Boisclair MD, Rudolph J and Pal K . (1999). Bioorg. Med. Chem. Lett., 9, 2537β2538.
Bonfanti M, Taverna S, Salmona M, D'Incalci M and Broggini M . (1997). Cancer Res., 57, 1442β1446.
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, 4339β4358.
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, 29207β29211.
Brusselbach S, Nettelbeck DM, Sedlacek HH and Muller R . (1998). Int. J. Cancer, 77, 146β152.
Bunch RT and Eastman A . (1996). Clin. Cancer Res., 2, 791β797.
Bunch RT and Eastman A . (1997). Cell Growth Differ., 8, 779β788.
Buquet-Fagot C, Lallemand F, Montagne M and Mester J . (1997). Anti-Cancer Drugs, 8, 623β631.
Busby EC, Leistritz DF, Abraham RT, Karnitz LM and Sarkaria JN . (2000). Cancer Res., 60, 2108β2112.
Byrd JC, Shinn, C, Waselenko JK, Fuchs EJ, Lehman TA, Nguyen PL, Flinn IW, Diehl LF, Sausville E and Grever MR . (1998). Blood, 92, 3804β3816.
Cagnoli M, Barbieri F, Bruzzo C and Alama A . (1998). Gynecol. Oncol., 70, 372β377.
Carlson BA, Dubay MM, Sausville EA, Brizuela L and Worland PJ . (1996b). Cancer Res., 56, 2973β2978.
Carlson B, Lahusen T, Singh S, Loaiza-Perez A, Worland PJ, Pestell R, Albanese C, Sausville EA and Senderowicz AM . (1999). Cancer Res., 59, 4634β4641.
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, 28345β28348.
Chen X, Lowe M and Keyomarsi K . (1999a). Oncogene, 18, 5691β5702.
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, 4325β4329.
Chien M, Astumian M, Liebowitz D, Rinker-Schaeffer C and Stadler W . (1999). Cancer Chemother Pharmacol., 44, 81β87.
Chintala SK, Fueyo J, Gomez-Manzano C, Venkaiah B, Bjerkvig R, Yung WK, Sawaya R, Kyritsis AP and Rao JS . (1997). Oncogene, 15, 2049β2057.
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, 28479β28484.
Colas P, Cohen B, Jessen T, Grishina I, McCoy J and Brent R . (1996). Nature, 380, 548β550.
Craig C, Wersto R, Kim M, Ohri E, Li Z, Katayose D, Lee SJ, Trepel J, Cowan K and Seth P . (1997). Oncogene, 14, 2283β2289.
De Azevedo WF, Leclerc S, Meijer L, Havlicek L, Strnad M and Kim SH . (1997). Eur. J. Biochem., 243, 518β526.
De Azevedo Jr WF, Mueller-Dieckmann HJ, Schulze-Gahmen U, Worland PJ, Sausville E and Kim SH . (1996). Proc. Natl. Acad. Sci. USA, 93, 2735β2740.
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, 2873β2887.
Dermatakis A, Luk KC and DePinto W . (2003). Bioorg. Med. Chem., 11, 1873β1881.
Dodo K, Takahashi M, Yamada Y, Sugimoto Y, Hashimoto Y and Shirai R . (2000). Bioorg. Med. Chem. Lett., 10, 615β617.
Drees M, Dengler W, Roth T, Labonte H, Mayo J, Malspeis L, Grever M, Sausville E and Fiebig H . (1997). Clin. Cancer Res., 32, 273β279.
Driscoll B, Buckley S, Barsky L, Weinberg K, Anderson KD and Warburton D . (1999). Am. J. Physiol., 276, L679βL687.
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, 5151β5155.
Eicher SA, Clayman GL, Liu TJ, Shillitoe EJ, Storthz KA, Roth JA and Lotan R . (1996). Clin. Cancer Res., 2, 1659β1664.
Fahraeus R, Paramio JM, Ball KL, Lain S and Lane DP . (1996). Curr. Biol., 6, 84β91.
Fingert HJ, Pu AT, Chen ZY, Googe PB, Alley MC and Pardee AB . (1988). Cancer Res., 48, 4375β4381.
Fowler L, Dong L, Bowes III RC, van de Water B, Stevens JL and Jaken S . (1998). Cell Growth Differ., 9, 177β184.
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, 6380β6385.
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, 16617β16623.
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, 3248β3253.
Gansauge S, Gansauge F, Ramadani M, Stobbe H, Rau B, Harada N and Beger HG . (1997). Cancer Res., 57, 1634β1637.
Gius DR, Ezhevsky SA, Becker-Hapak M, Nagahara H, Wei MC and Dowdy SF . (1999). Cancer Res., 59, 2577β2580.
Graves PR, Yu L, Schwarz JK, Gales J, Sausville EA, O'Connor PM and Piwnica-Worms H . (2000). J. Biol. Chem., 275, 5600β5605.
Gray-Bablin J, Rao S and Keyomarsi K . (1997). Cancer Res., 57, 604β609.
Gray N, Detivaud L, Doerig C and Meijer L . (1999). Curr. Med. Chem., 6, 859β875.
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, 533β538.
Hashemolhosseini S, Nagamine Y, Morley SJ, Desrivieres S, Mercep L and Ferrari S . (1998). J. Biol. Chem., 273, 14424β14429.
Hatakeyama M and Weinberg RA . (1995). Prog. Cell Cycle Res., 1, 9β19.
Hsueh CT, Kelsen D and Schwartz GK . (1998). Clin. Cancer Res., 4, 2201β2206.
Hunter T and Pines J . (1994). Cell, 79, 573β582.
Husain A, Yan XJ, Rosales N, Aghajanian C, Schwartz GK and Spriggs DR . (1997). Clin. Cancer Res., 3, 2089β2097.
Ichimura K, Schmidt EE, Goike HM and Collins VP . (1996). Oncogene, 13, 1065β1072.
Innocenti F, Stadler W M, Iyer L, Ramirez J, Vokes E and Ratain M . (2000). Clin. Cancer Res., 6, 3400β3405.
Jacks T and Weinberg RA . (1998). Science, 280, 1035β1036.
Jeong HW, Kim MR, Son KH, Han MY, Ha JH, Garnier, M, Meijer L and Kwon BM . (2000). Bioorg. Med. Chem. Lett., 10, 1819β1822.
Jin X, Nguyen D, Zhang WW, Kyritsis AP and Roth JA . (1995). Cancer Res., 55, 3250β3253.
Jones CB, Clements MK, Wasi S and Daoud SS . (2000). Cancer Chemother. Pharmacol., 45, 252β258.
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, 2317β2321.
Katayose Y, Kim M, Rakkar AN, Li Z, Cowan KH and Seth P . (1997). Cancer Res., 57, 5441β5445.
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, 1736β1740.
Kawakami K, Futami H, Takahara J and Yamaguchi K . (1996). Biochem. Biophys. Res. Commun., 219, 778β783.
Kent LL, Hull-Campbell NE, Lau T, Wu JC, Thompson SA and Nori M . (1999). Biochem. Biophys. Res. Commun., 260, 768β774.
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, 959β968.
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, 3905β3927.
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, 2425β2432.
Konig A, Schwartz GK, Mohammad RM, Al-Katib A and Gabrilove JL . (1997). Blood, 90, 4307β4312.
Kornmann M, Arber N and Korc M . (1998). J. Clin. Invest., 101, 344β352.
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, 183β194.
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.
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, 6170β6177.
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, 251β260.
Lee HR, Chang TH, Tebalt III MJ, Senderowicz AM and Szabo E . (1999). Int. J. Oncol., 15, 161β166.
Lees JA, Saito M, Vidal M, Valentine M, Look T, Harlow E, Dyson N and Helin K . (1993). Mol. Cell. Biol., 13, 7813β7825.
Losiewicz MD, Carlson BA, Kaur G, Sausville EA and Worland PJ . (1994). Biochem. Biophys. Res. Commun., 201, 589β5895.
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, 419β426.
Lukas J, Aagaard L, Strauss M and Bartek J . (1995a). Cancer Res., 55, 4818β4823.
Lukas J, Bartkova J, Rohde M, Strauss M and Bartek J . (1995b). Mol. Cell. Biol., 15, 2600β2611.
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, 2846β2851.
Masciullo V, Scambia G, Marone M, Giannitelli C, Ferrandina G, Bellacosa A, Benedetti Panici P and Mancuso S . (1997). Int. J. Cancer, 74, 390β395.
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, 463β468.
Meijer L . (2000). Drug Resist. Updat., 3, 83β88.
Meijer L, Borgne A, Mulner O, Chong JP, Blow JJ, Inagaki N, Inagaki M, Delcros JG and Moulinoux JP . (1997). Eur. J. Biochem., 243, 527β536.
Meijer L and Kim SH . (1997). Methods Enzymol., 283, 113β128.
Melillo G, Sausville EA, Cloud K, Lahusen T, Varesio L and Senderowicz AM . (1999). Cancer Res., 59, 5433β5437.
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, 217β222.
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, 222β236.
Michalides R, van Veelen N, Hart A, Loftus B, Wientjens E and Balm A . (1995). Cancer Res., 55, 975β978.
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, 1133β1136.
Morgan DO . (1997). Annu. Rev. Cell. Dev. Biol., 13, 261β291.
Motokura T and Arnold A . (1993). Curr. Opin. Genet. Dev., 3, 5β10.
Muise-Helmericks RC, Grimes HL, Bellacosa A, Malstrom SE, Tsichlis PN and Rosen N . (1998). J. Biol. Chem., 273, 29864β29872.
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, 1334β1336.
Ortega MA, Montoya ME, Zarranz B, Jaso A, Aldana I, Leclerc S, Meijer L and Monge A . (2002). Bioorg. Med. Chem., 10, 2177β2184.
Park S, Cheon J, Lee Y, Park Y, Lee K, Lee C and Lee S . (1996). Mol. Cells, 6, 679β683.
Parker B, Kaur G, Nieves-Neira W, Taimi M, Kolhagen G, Shimizu T, Pommier Y, Sausville E and Senderowicz AM . (1998). Blood, 91, 458β465.
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, 3549β3560.
Patel V, Lahusen T, Sy T, Sausville EA, Gutkind JS and Senderowicz AM . (2002b). Cancer Res., 62, 1401β1409.
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, 1674β1681.
Pollack IF, Kawecki S and Lazo JS . (1996). J. Neurosurg., 84, 1024β1032.
Roberge M, Tudan C, Hung SM, Harder KW, Jirik FR and Anderson H . (1994). Cancer Res., 54, 6115β6121.
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, 2469β2474.
Rodriguez-Puebla ML, LaCava M and Conti CJ . (1999). Cell Growth Differ., 10, 467β472.
Rosania GR, Merlie Jr J, Gray N, Chang YT, Schultz PG and Heald R . (1999). Proc. Natl. Acad. Sci. USA, 96, 4797β4802.
Ryu CK, Kang HY, Lee SK, Nam KA, Hong CY, Ko WG and Lee BH . (2000). Bioorg. Med. Chem. Lett., 10, 461β464.
Sandig V, Brand K, Herwig S, Lukas J, Bartek J and Strauss M . (1997). Nat. Med., 3, 313β319.
Sarkaria JN, Busby EC, Tibbetts RS, Roos P, Taya Y, Karnitz LM and Abraham RT . (1999). Cancer Res., 59, 4375β4382.
Sato S, Fujita N and Tsuruo T . (2002). Oncogene, 21, 1727β1738.
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, 2319β2333.
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), S54βS59.
Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J and Johnson DH . (2002). N. Engl. J. Med., 346, 92β98.
Schoepfer J, Fretz H, Chaudhuri B, Muller L, Seeber E, Meijer L, Lozach O, Vangrevelinghe E and Furet P . (2002). J. Med. Chem., 45, 1741β1747.
Schrump DS, Matthews W, Chen GA, Mixon A and Altorki NK . (1998). Clin. Cancer Res., 4, 2885β2890.
Schultz C, Link, A, Leost M, Zaharevitz DW, Gussio R, Sausville EA, Meijer L and Kunick C . (1999). J. Med. Chem., 42, 2909β2919.
Schutte B, Nieland L, van Engeland M, Henfling ME, Meijer L and Ramaekers FC . (1997). Exp. Cell. Res., 236, 4β15.
Schwartz G, Farsi K, Maslak P, Kelsen D and Spriggs D . (1997). Clin. Cancer Res., 3, 1467β1472.
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, 2157β2170.
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, 1143β1168.
Senderowicz AM . (1999). Invest. New Drugs, 17, 313β320.
Senderowicz AM . (2000). Oncogene, 19, 6600β6606.
Senderowicz AM . (2001a). Cancer Chemother. Biol. Response Modif., 19, 165β188.
Senderowicz AM . (2001b). Cancer Chemother. Biol. Response Modif., 19, 165β188.
Senderowicz AM . (2002a). Oncologist, 7, 12β19.
Senderowicz AM . (2002b). Hematol. Oncol. Clin. N. Am., 16, 1229β1253.
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.
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.
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, 2986β2999.
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, 376β387.
Seynaeve CM, Kazanietz MG, Blumberg PM, Sausville EA and Worland PJ . (1994). Mol. Pharmacol., 45, 1207β1214.
Seynaeve CM, Stetler-Stevenson M, Sebers S, Kaur G, Sausville EA and Worland PJ . (1993). Cancer Res., 53, 2081β2086.
Shao RG, Cao CX, Shimizu T, O'Connor PM, Kohn KW and Pommier Y . (1997). Cancer Res., 57, 4029β4035.
Shapiro GI, Koestner DA, Matranga CB and Rollins BJ . (1999b). Clin. Cancer Res., 5, 2925β2938.
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, 1590β1599.
Sherr CJ . (1996). Science, 274, 1672β1677.
Shimizu E, Zhao MR, Nakanishi H, Yamamoto A, Yoshida S, Takada M, Ogura T and Sone S . (1996). Oncology, 53, 494β504.
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, 1157β1160.
Soni R, Muller L, Furet P, Schoepfer J, Stephan C, Zumstein-Mecker S, Fretz H and Chaudhuri B . (2000). Biochem. Biophys. Res. Commun., 275, 877β884.
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, 436β446.
Sonoda Y, Yoshimoto T and Sekiya T . (1995). Oncogene, 11, 2145β2149.
Spitz FR, Nguyen D, Skibber JM, Cusack J, Roth JA and Cristiano RJ . (1996). Anticancer Res., 16, 3415β3422.
Stadler WM, Vogelzang NJ, Amato R, Sosman J, Taber D, Liebowitz D and Vokes EE . (2000). J. Clin. Oncol., 18, 371β375.
Sugiyama K, Shimizu M, Akiyama T, Tamaoki T, Yamaguchi K, Takahashi R, Eastman A and Akinaga S . (2000). Int. J. Cancer., 85, 703β709.
Takahashi I, Kobayashi E, Asano K, Yoshida M and Nakano H . (1987). J. Antibiot (Tokyo), 40, 1782β1784.
Takahashi I, Saitoh Y, Yoshida M, Sano H, Nakano H, Morimoto M and Tamaoki T . (1989). J. Antibiot (Tokyo), 42, 571β576.
Tamaoki T . (1991). Methods Enzymol., 201, 340β347.
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, 4074β4082.
Testa JR and Bellacosa A . (2001). Proc. Natl. Acad. Sci. USA, 98, 10983β10985.
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, 465β472.
Tsuchida E and Urano M . (1997). Int. J. Radiat. Oncol. Biol. Phys., 39, 1153β1161.
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, 275β280.
Walker DH . (1998). Curr. Top. Microbiol. Immunol., 227, 149β165.
Wang MB, Billings KR, Venkatesan N, Hall FL and Srivatsan ES . (1998). Otolaryngol. Head Neck Surg., 119, 593β599.
Wang C, Fu M, Mani S, Wadler S, Senderowicz AM and Pestell RG . (2001). Front. Biosci., 6, D610βD629.
Wang Q, Fan S, Eastman A, Worland PJ, Sausville EA and O'Connor P . (1996). J. Natl. Cancer Inst., 88, 956β965.
Wang Q, Worland PJ, Clark JL, Carlson BA and Sausville EA . (1995). Cell Growth Differ., 6, 927β936.
Warbrick E, Lane DP, Glover DM and Cox LS . (1995). Curr Biol, 5, 275β282.
Weinberg RA . (1996). Cytokines Mol. Ther., 2, 105β110.
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.
Wilcken NR, Sarcevic B, Musgrove EA and Sutherland RL . (1996). Cell Growth Differ., 7, 65β74.
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, 415β421.
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, 1281β1284.
Worland PJ, Kaur G, Stetler-Stevenson M, Sebers S, Sartor O and Sausville EA . (1993). Biochem. Pharmacol., 46, 1831β1840.
Wright J, Blatner GL and Cheson BD . (1998). Oncology (Huntingt), 12 1018, 1023β1024.
Yu JT, Foster RG and Dean DC . (2001). Mol. Cell. Biol., 21, 3325β3335.
Yu L, Orlandi L, Wang P, Orr M, Senderowicz AM, Sausville EA, Silvestrini Ra and O'Connor P . (1998). J. Biol. Chem., 273, 33455β33464.
Zaharevitz DW, Gussio R, Leost M, Senderowicz AM, Lahusen T, Kunick C, Meijer L and Sausville EA . (1999). Cancer Res., 59, 2566β2569.
Zhou Q, Stetler-Stevenson M and Steeg PS . (1997). Oncogene, 15, 107β115.
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, 1231β1255.
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, 2027β2030.
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Senderowicz, A. Small-molecule cyclin-dependent kinase modulators. Oncogene 22, 6609β6620 (2003). https://doi.org/10.1038/sj.onc.1206954
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DOI: https://doi.org/10.1038/sj.onc.1206954
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