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 alpha-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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aged
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Annexin A5 / metabolism
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Antineoplastic Agents / therapeutic use*
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Antineoplastic Agents, Hormonal / therapeutic use
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Antineoplastic Combined Chemotherapy Protocols / adverse effects
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Apoptosis / drug effects
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Blotting, Western
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Bone Marrow / pathology
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Dexamethasone / adverse effects
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Dexamethasone / therapeutic use
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Doxorubicin / adverse effects
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Doxorubicin / therapeutic use
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Drug Resistance, Neoplasm
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Female
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Humans
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Male
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Middle Aged
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Multiple Myeloma / drug therapy*
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Multiple Myeloma / genetics
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Multiple Myeloma / pathology
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Myeloid Cell Leukemia Sequence 1 Protein
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Neoplasm Proteins / metabolism
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Oligonucleotides, Antisense / therapeutic use*
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Oligonucleotides, Antisense / toxicity
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Plasma Cells / drug effects
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Plasma Cells / metabolism*
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Plasma Cells / pathology
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Polymerase Chain Reaction
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-bcl-2 / genetics*
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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RNA, Messenger / metabolism
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Thionucleotides / therapeutic use*
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Vincristine / adverse effects
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bcl-2-Associated X Protein
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bcl-X Protein
Substances
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Annexin A5
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Antineoplastic Agents
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Antineoplastic Agents, Hormonal
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BAX protein, human
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BCL2L1 protein, human
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Myeloid Cell Leukemia Sequence 1 Protein
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Neoplasm Proteins
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Oligonucleotides, Antisense
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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RNA, Messenger
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Thionucleotides
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bcl-2-Associated X Protein
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bcl-X Protein
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Vincristine
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Dexamethasone
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Doxorubicin
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oblimersen