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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.
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NEOPLASIA
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
From the Departments of Experimental Therapeutics, Leukemia, and Blood and Marrow Transplantation, The University of Texas M. D. Anderson Cancer Center, Houston, TX.
Chk1 and Akt signaling facilitate survival of cells treated with nucleoside analogues. Activation of Chk1 in response to cytarabine (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-phase-arrested cells resulted in an abrogation of the checkpoint, inhibition of Akt, activation of JNK, and a rapid induction of apoptosis. Similarly, primary acute myelogenous leukemia (AML) blasts exposed to ara-C and UCN-01 demonstrated a selective loss in cloning potential when compared with 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. (Blood. 2006;107:2517-2524)
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