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

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.
AuthorsN W C J van de Donk, M M J Kamphuis, M van Dijk, H P E Borst, A C Bloem, H M Lokhorst
JournalLeukemia (Leukemia) Vol. 17 Issue 1 Pg. 211-9 (Jan 2003) ISSN: 0887-6924 [Print] England
PMID12529680 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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
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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