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  • Molecular Targets For Therapy (MTT)
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Molecular Targets for Therapy (MTT)

Chemosensitization of myeloma plasma cells by an antisense-mediated downregulation of Bcl-2 protein

Leukemia volume 17, pages 211–219 (2003)Cite this article

Abstract

An antisense oligodeoxynucleotide (ODN) complementary to the first six codons of the Bcl-2 mRNA, G3139 (oblimersen sodium; Genasense), has been shown to downregulate Bcl-2 and produce responses in a variety of malignancies including drug-resistant lymphoma. Incubation of ex vivo purified plasma cells from patients with multiple myeloma (MM) with carboxyfluorescein (FAM)-labeled antisense ODNs resulted in a time- and dose-dependent uptake in the cytoplasm and nucleus. No major differences in uptake of Bcl-2 antisense ODNs were observed among patients’ samples. Incubation of purified myeloma plasma cells with G3139, but not solvent or reverse polarity control ODNs, resulted in a reduction (>75%) of Bcl-2 mRNA levels after 2 and 4 days, as measured by Real-Time PCR. Treatment with G3139 led to a sequence-specific reduction of Bcl-2 protein levels within 4 days of exposure in 10 out of 11 clinical samples from patients with chemosensitive and multidrug-resistant disease, without significant reduction of α-Actin, Bax, Bcl-XL, or Mcl-1 proteins. This resulted in a significantly enhanced sensitivity of the myeloma tumor cells to dexamethasone or doxorubicin-induced apoptosis. G3139 can consistently enter myeloma cells, downregulate the expression of Bcl-2, and enhance the efficacy of myeloma therapy. These data support further clinical evaluation of G3139 therapy in multiple myeloma.

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Acknowledgements

This study was financially supported by a grant from the Dutch Cancer Society (KWF).

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  1. Department of Immunology, University Medical Center Utrecht, Utrecht, The Netherlands

    N W C J van de Donk, M M J Kamphuis, H P E Borst & A C Bloem

  2. Department of Hematology, University Medical Center Utrecht, Utrecht, The Netherlands

    M van Dijk & H M Lokhorst

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van de Donk, N., Kamphuis, M., van Dijk, M. et al. Chemosensitization of myeloma plasma cells by an antisense-mediated downregulation of Bcl-2 protein. Leukemia 17, 211–219 (2003). https://doi.org/10.1038/sj.leu.2402768

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