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

Leukemia. 2003 Jan;17(1):211-9. doi: 10.1038/sj.leu.2402768.


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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Dexamethasone / therapeutic use
  • Doxorubicin / adverse effects
  • Doxorubicin / therapeutic use
  • Drug Resistance, Neoplasm
  • Female
  • Humans
  • Male
  • Middle Aged
  • Multiple Myeloma / drug therapy*
  • Multiple Myeloma / genetics
  • Multiple Myeloma / pathology
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins / metabolism
  • Oligonucleotides, Antisense / therapeutic use*
  • Oligonucleotides, Antisense / toxicity
  • Plasma Cells / drug effects
  • Plasma Cells / metabolism*
  • Plasma Cells / pathology
  • Polymerase Chain Reaction
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / genetics*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • RNA, Messenger / metabolism
  • Thionucleotides / therapeutic use*
  • Vincristine / adverse effects
  • bcl-2-Associated X Protein
  • bcl-X Protein


  • 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

Supplementary concepts

  • VAD protocol