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.
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Authors | N W C J van de Donk, M M J Kamphuis, M van Dijk, H P E Borst, A C Bloem, H M Lokhorst |
Journal | Leukemia
(Leukemia)
Vol. 17
Issue 1
Pg. 211-9
(Jan 2003)
ISSN: 0887-6924 [Print] England |
PMID | 12529680
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Annexin A5
- Antineoplastic Agents
- Antineoplastic Agents, Hormonal
- BAX protein, human
- BCL2L1 protein, human
- Myeloid Cell Leukemia Sequence 1 Protein
- Neoplasm Proteins
- Oligonucleotides, Antisense
- Proto-Oncogene Proteins
- Proto-Oncogene Proteins c-bcl-2
- RNA, Messenger
- Thionucleotides
- bcl-2-Associated X Protein
- bcl-X Protein
- Vincristine
- Dexamethasone
- Doxorubicin
- oblimersen
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Topics |
- Aged
- Annexin A5
(metabolism)
- Antineoplastic Agents
(therapeutic use)
- Antineoplastic Agents, Hormonal
(therapeutic use)
- Antineoplastic Combined Chemotherapy Protocols
(adverse effects)
- Apoptosis
(drug effects)
- Blotting, Western
- Bone Marrow
(pathology)
- Dexamethasone
(adverse effects, therapeutic use)
- Doxorubicin
(adverse effects, therapeutic use)
- Drug Resistance, Neoplasm
- Female
- Humans
- Male
- Middle Aged
- Multiple Myeloma
(drug therapy, genetics, pathology)
- Myeloid Cell Leukemia Sequence 1 Protein
- Neoplasm Proteins
(metabolism)
- Oligonucleotides, Antisense
(therapeutic use, toxicity)
- Plasma Cells
(drug effects, metabolism, pathology)
- Polymerase Chain Reaction
- Proto-Oncogene Proteins
(metabolism)
- Proto-Oncogene Proteins c-bcl-2
(genetics, metabolism)
- RNA, Messenger
(metabolism)
- Thionucleotides
(therapeutic use)
- Vincristine
(adverse effects)
- bcl-2-Associated X Protein
- bcl-X Protein
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