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Acute Leukemias

The histone deacetylase inhibitor valproic acid potently augments gemtuzumab ozogamicin-induced apoptosis in acute myeloid leukemic cells

Leukemia volume 21, pages 248–252 (2007)Cite this article

Abstract

Gemtuzumab ozogamicin (GO) is a calicheamicin-conjugated antibody directed against CD33, an antigen highly expressed on acute myeloid leukemic (AML) cells. CD33-specific binding triggers internalization of GO and subsequent hydrolytic release of calicheamicin. Calicheamicin then translocates to the nucleus, intercalates in the DNA structure and subsequently induces double-strand DNA breaks. GO is part of clinical practice for AML, but is frequently associated with severe side effects. Therefore, combination of GO with other therapeutics is warranted to reduce toxicity, while maximizing therapeutic selectivity. We hypothesized that the histone deacetylase inhibitor valproic acid (VPA) sensitizes AML cells to GO. VPA-induced histone hyperacetylation opens the chromatin structure, whereby the DNA intercalation of calicheamicin should be augmented. We found that clinically relevant concentrations of VPA potently augmented the tumoricidal activity of GO towards AML cell lines and primary AML blasts. Moreover, VPA treatment indeed augmented the DNA intercalation of calicheamicin and enhanced DNA degradation. Importantly, synergy was restricted to CD33-positive AML cells and did not require caspase activation. In conclusion, the synergistic proapoptotic activity of cotreatment of AML cells with VPA and GO indicates the potential value of this strategy for AML.

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Acknowledgements

We thank Arjan A van de Loosdrecht, Martine ED Chamuleau, Geert Mesander and Jelleke Dokter-Fokkens. Supported by grants from the Dutch Cancer Society (RUG 2002-2668 and 2005-3358) to WH.

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Author notes

  1. W Helfrich and E Bremer: These two authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Laboratory for Tumor Immunology, Groningen University Institute for Drug Exploration (GUIDE), Section Medical Biology, University Medical Center Groningen (UMCG), University of Groningen, Groningen, The Netherlands

    B ten Cate, D F Samplonius, T Bijma, L F M H de Leij, W Helfrich & E Bremer

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  1. B ten Cate
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  2. D F Samplonius
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  3. T Bijma
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  4. L F M H de Leij
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Correspondence to W Helfrich.

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ten Cate, B., Samplonius, D., Bijma, T. et al. The histone deacetylase inhibitor valproic acid potently augments gemtuzumab ozogamicin-induced apoptosis in acute myeloid leukemic cells. Leukemia 21, 248–252 (2007). https://doi.org/10.1038/sj.leu.2404477

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