Efficacy of treatment with antisense oligonucleotides complementary to immunoglobulin sequences of bcl-2/immunoglobulin fusion transcript in a t(14;18) human lymphoma-scid mouse model.
In t(14;18)-positive lymphoma cells, bcl-2 is expressed from a fusion mRNA transcript containing the full coding sequence of bcl-2 and 3' immunoglobulin sequences. We reported previously that antisense oligodeoxyribonucleotides directed at the bcl-2 translational start site, as well as those targeted to immunoglobulin sequences 3' of the translocation breakpoint, down-regulate bcl-2 and inhibit growth of the t(14;18)-positive lymphoma line WSU-FSCCL in vitro. We have developed a scid mouse model with this human cell line and demonstrate that antisense oligodeoxyribonucleotides targeted to immunoglobulin c(mu) sequences down-regulate bcl-2 protein expression and induce apoptosis of WSU-FSCCL cells in vivo. This leads to prolonged survival of the mice. Targeting non-oncogenic sequences outside of the breakpoints of fusion transcripts may be a clinically useful therapeutic strategy.
Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA. m_smith@fccc.edu
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D000818:Animals; D017209:Apoptosis / Q000276:immunology; D015153:Blotting, Western; D002883:Chromosomes, Human, Pair 14; D002887:Chromosomes, Human, Pair 18; D015536:Down-Regulation; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression; D019254:Genes, bcl-2; D006801:Humans; D015151:Immunoblotting / Q000379:methods; D007128:Immunoglobulin Fragments / Q000235:genetics*; D008223:Lymphoma / Q000188:drug therapy*; D051379:Mice; D016513:Mice, SCID; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D016511:Severe Combined Immunodeficiency / Q000188:drug therapy*; D016019:Survival Analysis; D014407:Tumor Cells, Cultured
D007128:Immunoglobulin Fragments; D016376:Oligonucleotides, Antisense; D015514:Oncogene Proteins, Fusion