© 2000 by Oxford University Press
Journal of the National Cancer Institute, Vol. 92, No. 5, 376-387,
March 1, 2000
© 2000 Oxford University Press
REVIEW |
Preclinical and Clinical Development of Cyclin-Dependent Kinase Modulators
Affiliation of authors: DTP Clinical Trials Unit, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD.
Correspondence to: Adrian M. Senderowicz, M.D., National Institutes of Health, Bldg. 10, Rm. 6N113, Bethesda, MD 20892 (e-mail: sendero{at}helix. nih.gov).
In the last decade, the discovery and cloning of the cyclin-dependent kinases (cdks), key regulators of cell cycle progression, have led to the identification of novel modulators of cdk activity. Initial experimental results demonstrated that these cdk modulators are able to block cell cycle progression, induce apoptotic cell death, promote differentiation, inhibit angiogenesis, and modulate transcription. Alteration of cdk activity may occur indirectly by affecting upstream pathways that regulate cdk activity or directly by targeting the cdk holoenzyme. Two direct cdk modulators, flavopiridol and UCN-01, are showing promising results in early clinical trials, in which the drugs reach plasma concentrations that can alter cdk activity in vitro. Although modulation of cdk activity is a well-grounded concept and new cdk modulators are being assessed for clinical testing, important scientific questions remain to be addressed. These questions include whether one or more cdks should be inhibited, how cdk inhibitors should be combined with other chemotherapy agents, and which cdk substrates should be used to assess the biologic effects of these drugs in patients. Thus, modulation of cdk activity is an attractive target for cancer chemotherapy, and several agents that modulate cdk activity are in or are approaching entry into clinical trials.
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V. Patel, T. Lahusen, T. Sy, E. A. Sausville, J. S. Gutkind, and A. M. Senderowicz Perifosine, a Novel Alkylphospholipid, Induces p21WAF1 Expression in Squamous Carcinoma Cells through a p53-independent Pathway, Leading to Loss in Cyclin-dependent Kinase Activity and Cell Cycle Arrest Cancer Res., March 1, 2002; 62(5): 1401 - 1409. [Abstract] [Full Text] [PDF]
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C. B. Matranga and G. I. Shapiro Selective Sensitization of Transformed Cells to Flavopiridol-induced Apoptosis following Recruitment to S-Phase Cancer Res., March 1, 2002; 62(6): 1707 - 1717. [Abstract] [Full Text] [PDF]
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M. Filipits, U. Jaeger, G. Pohl, T. Stranzl, I. Simonitsch, A. Kaider, C. Skrabs, and R. Pirker Cyclin D3 Is a Predictive and Prognostic Factor in Diffuse Large B-cell Lymphoma Clin. Cancer Res., March 1, 2002; 8(3): 729 - 733. [Abstract] [Full Text] [PDF]
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T. Yamauchi, M. J. Keating, and W. Plunkett UCN-01 (7-Hydroxystaurosporine) Inhibits DNA Repair and Increases Cytotoxicity in Normal Lymphocytes and Chronic Lymphocytic Leukemia Lymphocytes Mol. Cancer Ther., February 1, 2002; 1(4): 287 - 294. [Abstract] [Full Text] [PDF]
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T. Sandal Molecular Aspects of the Mammalian Cell Cycle and Cancer Oncologist, February 1, 2002; 7(1): 73 - 81. [Abstract] [Full Text] [PDF]
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P. M. Clare, R. A. Poorman, L. C. Kelley, K. D. Watenpaugh, C. A. Bannow, and K. L. Leach The Cyclin-dependent Kinases cdk2 and cdk5 Act by a Random, Anticooperative Kinetic Mechanism J. Biol. Chem., December 14, 2001; 276(51): 48292 - 48299. [Abstract] [Full Text] [PDF]
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H. Wang, J. Guan, H. Wang, A. R. Perrault, Y. Wang, and G. Iliakis Replication Protein A2 Phosphorylation after DNA Damage by the Coordinated Action of Ataxia Telangiectasia-Mutated and DNA-dependent Protein Kinase Cancer Res., December 1, 2001; 61(23): 8554 - 8563. [Abstract] [Full Text] [PDF]
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P. J. Nelson, I. H. Gelman, and P. E. Klotman Suppression of HIV-1 Expression by Inhibitors of Cyclin-Dependent Kinases Promotes Differentiation of Infected Podocytes J. Am. Soc. Nephrol., December 1, 2001; 12(12): 2827 - 2831. [Abstract] [Full Text] [PDF]
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Y. A. Elsayed and E. A. Sausville Selected Novel Anticancer Treatments Targeting Cell Signaling Proteins Oncologist, December 1, 2001; 6(6): 517 - 537. [Abstract] [Full Text] [PDF]
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 D. Wang, C. de la Fuente, L. Deng, L. Wang, I. Zilberman, C. Eadie, M. Healey, D. Stein, T. Denny, L. E. Harrison, et al. Inhibition of Human Immunodeficiency Virus Type 1 Transcription by Chemical Cyclin-Dependent Kinase Inhibitors J. Virol., August 15, 2001; 75(16): 7266 - 7279. [Abstract] [Full Text] [PDF]
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Y. Hirose, M. S. Berger, and R. O. Pieper Abrogation of the Chk1-mediated G2 Checkpoint Pathway Potentiates Temozolomide-induced Toxicity in a p53-independent Manner in Human Glioblastoma Cells Cancer Res., August 1, 2001; 61(15): 5843 - 5849. [Abstract] [Full Text] [PDF]
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M. V. Blagosklonny and A. B. Pardee Exploiting Cancer Cell Cycling for Selective Protection of Normal Cells Cancer Res., June 1, 2001; 61(11): 4301 - 4305. [Abstract] [Full Text] [PDF]
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 R. Weissleder and U. Mahmood Molecular Imaging Radiology, May 1, 2001; 219(2): 316 - 333. [Abstract] [Full Text]
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 B. Hagenauer, A. Salamon, T. Thalhammer, O. Kunert, E. Haslinger, P. Klingler, A. M. Senderowicz, E. A. Sausville, and W. Jäger In Vitro Glucuronidation of the Cyclin-Dependent Kinase Inhibitor Flavopiridol by Rat and Human Liver Microsomes: Involvement of UDP-Glucuronosyltransferases 1A1 and 1A9 Drug Metab. Dispos., April 1, 2001; 29(4): 407 - 414. [Abstract] [Full Text]
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 A. Kubo and F. J. Kaye Searching for Selective Cyclin-Dependent Kinase Inhibitors to Target the Retinoblastoma/p16 Cancer Gene Pathway J Natl Cancer Inst, March 21, 2001; 93(6): 415 - 417. [Full Text] [PDF]
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H. Dosaka-Akita, F. Hommura, T. Mishina, S. Ogura, M. Shimizu, H. Katoh, and Y. Kawakami A Risk-Stratification Model of Non-Small Cell Lung Cancers Using Cyclin E, Ki-67, and ras p21: Different Roles of G1 Cyclins in Cell Proliferation and Prognosis Cancer Res., March 1, 2001; 61(6): 2500 - 2504. [Abstract] [Full Text]
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M. E. S. Kahn, A. Senderowicz, E. A. Sausville, and K. E. Barrett Possible Mechanisms of Diarrheal Side Effects Associated with the Use of a Novel Chemotherapeutic Agent, Flavopiridol Clin. Cancer Res., February 1, 2001; 7(2): 343 - 349. [Abstract] [Full Text]
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R. W. Robey, W. Y. Medina-Pérez, K. Nishiyama, T. Lahusen, K. Miyake, T. Litman, A. M. Senderowicz, D. D. Ross, and S. E. Bates Overexpression of the ATP-binding Cassette Half-Transporter, ABCG2 (MXR/BCRP/ABCP1), in Flavopiridol-resistant Human Breast Cancer Cells Clin. Cancer Res., January 1, 2001; 7(1): 145 - 152. [Abstract] [Full Text]
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X. Chen, M. Lowe, T. Herliczek, M. J. Hall, C. Danes, D. A. Lawrence, and K. Keyomarsi Protection of Normal Proliferating Cells Against Chemotherapy by Staurosporine-Mediated, Selective, and Reversible G1 Arrest J Natl Cancer Inst, December 20, 2000; 92(24): 1999 - 2008. [Abstract] [Full Text] [PDF]
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M. Omura-Minamisawa, M. B. Diccianni, A. Batova, R. C. Chang, L. J. Bridgeman, J. Yu, Esther de Wit, F. H. Kung, J. D. Pullen, and A. L. Yu In Vitro Sensitivity of T-Cell Lymphoblastic Leukemia to UCN-01 (7-Hydroxystaurosporine) Is Dependent on p16 Protein Status: A Pediatric Oncology Group Study Cancer Res., December 1, 2000; 60(23): 6573 - 6576. [Abstract] [Full Text]
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F. Innocenti, W. M. Stadler, L. Iyer, J. Ramírez, E. E. Vokes, and M. J. Ratain Flavopiridol Metabolism in Cancer Patients Is Associated with the Occurrence of Diarrhea Clin. Cancer Res., September 1, 2000; 6(9): 3400 - 3405. [Abstract] [Full Text]
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A. M. Senderowicz and E. A. Sausville RESPONSE: Re: Preclinical and Clinical Development of Cyclin-Dependent Kinase Modulators J Natl Cancer Inst, July 19, 2000; 92(14): 1185 - 1185. [Full Text] [PDF]
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S.-H. Chao, K. Fujinaga, J. E. Marion, R. Taube, E. A. Sausville, A. M. Senderowicz, B. M. Peterlin, and D. H. Price Flavopiridol Inhibits P-TEFb and Blocks HIV-1 Replication J. Biol. Chem., September 8, 2000; 275(37): 28345 - 28348. [Abstract] [Full Text] [PDF]
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S.-H. Chao and D. H. Price Flavopiridol Inactivates P-TEFb and Blocks Most RNA Polymerase II Transcription in Vivo J. Biol. Chem., August 17, 2001; 276(34): 31793 - 31799. [Abstract] [Full Text] [PDF]
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