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 Blood, 15 August 2006, Vol. 108, No. 4, pp. 1174-1182.
Prepublished online as a Blood First Edition Paper on May 4, 2006; DOI 10.1182/blood-2005-09-008086.

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CLINICAL TRIALS AND OBSERVATIONS

Antileukemia activity of the combination of an anthracycline with a histone deacetylase inhibitor

Blanca Sanchez-Gonzalez, Hui Yang, Carlos Bueso-Ramos, Koyu Hoshino, Alfonso Quintas-Cardama, Victoria M. Richon, and Guillermo Garcia-Manero

From the Departments of Leukemia and Hematopathology, University of Texas M.D. Anderson Cancer Center, Houston, TX; and Merck & Co, Boston, MA.

We studied the cellular and molecular effects of the combination of an anthracycline with 2 different histone deacetylase inhibitors (HDACIs): vorinostat (suberoylanilide hydroxamic acid) and valproic acid (VPA). The 10% inhibitory concentration (IC10) of idarubicin was 0.5 nM in MOLT4 and 1.5 nM in HL60 cells. Concentrations above 0.675 µM of vorinostat resulted in at least 80% loss of cell viability in both cell lines. Concentrations of 1.5 to 3 mM of VPA induced 50% to 60% loss in viability in HL60 and 80% in MOLT4 cells. The combination of idarubicin with vorinostat at 0.075 µM or VPA at 0.25 mM resulted in at least an additive loss of cell viability in both lines. Vorinostat (0.35 µM) and VPA (0.25 mM) in combination with idarubicin (0.5 nM) resulted in a significant increase in apoptotic cells in MOLT4 cells. The combination resulted in an increase in histone H3 and H4 acetylation at 24 hours, phosphorylated H2AX, as well as in the induction of p21CIP1 mRNA. No effect on cell cycle transition was observed. Of importance, the cellular and molecular effects observed were independent of the sequence used. In summary, the combination of an anthracycline with an HDACI should have significant clinical activity in patients with leukemia.


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