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Blood, 15 March 2006, Vol. 107, No. 6, pp. 2517-2524. Prepublished online as a Blood First Edition Paper on November 17, 2005; DOI 10.1182/blood-2005-08-3351. This Article Full Text (PDF) All Versions of this Article: 2005-08-3351v1 107/6/2517    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Sampath, D. Articles by Plunkett, W. Search for Related Content PubMed PubMed Citation Articles by Sampath, D. Articles by Plunkett, W. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted August 18, 2005 Accepted November 3, 2005 Pharmacodynamics of cytarabine alone and in combination with 7-hydroxystaurosporine (UCN-01) in AML blasts in vitro and during a clinical trial Deepa Sampath, Jorge Cortes, Zeev Estrov, Min Du, Zheng Shi, Michael Andreeff, Varsha Gandhi, and William Plunkett* Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA Department of Blood and Bone Marrow Transplant, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA; Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA * Corresponding author; email: wplunket{at}mdanderson.org. Chk1 and Akt signaling facilitate survival of cells treated with nucleoside analogues. Activation of Chk1 in response to ara-C induced an S-phase checkpoint characterized by the inhibition of Cdk2, cell cycle arrest, no change in constitutively active Akt or low stress kinase signaling in ML-1 cells. However, inhibition of Chk1 by UCN-01 in S-arrested cells resulted in an abrogation of the checkpoint, inhibition of Akt, activation of JNK and a rapid induction of apoptosis. Similarly, primary AML blasts exposed to ara-C and UCN-01 demonstrated a selective loss in cloning potential when compared to normal progenitors. Therefore, we evaluated a pilot clinical trial of ara-C in combination with UCN-01 in patients with relapsed AML. Blasts from some patients demonstrated a previously activated Chk1-Cdk2 DNA damage response pathway that decreased during therapy. Constitutively phosphorylated Akt kinase declined on addition of UCN-01 to the ara-C infusion, an action accompanied by an activation of JNK and reduction in absolute AML blast counts. Thus, use of UCN-01 in combination with ara-C decreases Chk1 phosphorylation, inhibits the Akt survival pathway and activates JNK during the course of therapy, offering a rationale for the cytotoxic action of this combination during AML treatment. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: Y. Wang, X. Liu, A. Matsuda, and W. Plunkett Repair of 2'-C-Cyano-2'-Deoxy-1-{beta}-D-arabino-Pentofuranosylcytosine-Induced DNA Single-Strand Breaks by Transcription-Coupled Nucleotide Excision Repair Cancer Res., May 15, 2008; 68(10): 3881 - 3889. [Abstract] [Full Text] [PDF] X. Liu, A. Matsuda, and W. Plunkett Ataxia-telangiectasia and Rad3-related and DNA-dependent protein kinase cooperate in G2 checkpoint activation by the DNA strand-breaking nucleoside analogue 2'-C-cyano-2'-deoxy-1- -D-arabino-pentofuranosylcytosine Mol. Cancer Ther., January 1, 2008; 7(1): 133 - 142. [Abstract] [Full Text] [PDF] X.-Y. Pei, Y. Dai, S. Tenorio, J. Lu, H. Harada, P. Dent, and S. Grant MEK1/2 inhibitors potentiate UCN-01 lethality in human multiple myeloma cells through a Bim-dependent mechanism Blood, September 15, 2007; 110(6): 2092 - 2101. [Abstract] [Full Text] [PDF] L. Guo, X. Liu, K. Nishikawa, and W. Plunkett Inhibition of topoisomerase II{alpha} and G2 cell cycle arrest by NK314, a novel benzo[c]phenanthridine currently in clinical trials Mol. Cancer Ther., May 1, 2007; 6(5): 1501 - 1508. [Abstract] [Full Text] [PDF] M. J. Edelman, K. S. Bauer Jr., S. Wu, R. Smith, S. Bisacia, and J. Dancey Phase I and Pharmacokinetic Study of 7-Hydroxystaurosporine and Carboplatin in Advanced Solid Tumors Clin. Cancer Res., May 1, 2007; 13(9): 2667 - 2674. [Abstract] [Full Text] [PDF] A. N. Tse, R. Carvajal, and G. K. Schwartz Targeting Checkpoint Kinase 1 in Cancer Therapeutics Clin. Cancer Res., April 1, 2007; 13(7): 1955 - 1960. [Abstract] [Full Text] [PDF] B. Ewald, D. Sampath, and W. Plunkett H2AX phosphorylation marks gemcitabine-induced stalled replication forks and their collapse upon S-phase checkpoint abrogation Mol. Cancer Ther., April 1, 2007; 6(4): 1239 - 1248. [Abstract] [Full Text] [PDF] X.-Y. Pei, W. Li, Y. Dai, P. Dent, and S. Grant Dissecting the Roles of Checkpoint Kinase 1/CDC2 and Mitogen-Activated Protein Kinase Kinase 1/2/Extracellular Signal-Regulated Kinase 1/2 in Relation to 7-Hydroxystaurosporine-Induced Apoptosis in Human Multiple Myeloma Cells Mol. Pharmacol., December 1, 2006; 70(6): 1965 - 1973. [Abstract] [Full Text] [PDF]

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