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Berlin Brandenburg

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  • 1
    Language: English
    In: Antisense & nucleic acid drug development, December 2002, Vol.12(6), pp.359-67
    Description: The Bcl-2 antisense oligonucleotide (AS-ODN) G3139 chemosensitizes human malignancies by downregulating the antiapoptotic protein Bcl-2. Because G3139 contains two potential immunostimulatory CpG motifs, we asked if immune stimulation contributes to the antitumor activity observed previously. 5'-Methylation of cytosines in CpG motifs abrogates immune stimulation by oligonucleotides. We, therefore, studied the antitumor and immunostimulatory potential of G3139 vs. an identical oligonucleotide, except for methylation of cytosines in the two CpG motifs (G4232). In a human melanoma SCID mouse xenotransplantation model, G3139 or G4232 was administered by continuous subcutaneous (s.c.) or bolus intraperitoneal (i.p.) infusion. Both G3139 and G4232 significantly reduced tumor growth by about one third relative to the saline-treated group. Furthermore, we noted a similar downregulation of Bcl-2 expression and increase in tumor cell apoptosis caused by G3139 and G4232 compared with saline controls. However, mice treated with G3139 had a pronounced increase in spleen weight and interleukin-12 (IL-12) plasma levels relative to mice treated with either G4232 or saline. Splenomegaly and elevated IL-12 plasma levels suggest that G3139 can be immunostimulatory. However, there is clear evidence that the antitumor effect of G3139 in this model appears to be a Bcl-2 antisense effect that is independent of immune stimulation, as G3139 and its immune-silent counterpart G4232 caused similar tumor suppression and apoptosis induction.
    Keywords: Antineoplastic Agents -- Pharmacology ; Cpg Islands -- Immunology ; Genes, Bcl-2 -- Genetics ; Oligonucleotides, Antisense -- Pharmacology ; Thionucleotides -- Pharmacology
    ISSN: 1087-2906
    E-ISSN: 21686599
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  • 2
    Language: English
    In: Oligonucleotides, 2003, Vol.13(5), pp.393-400
    Description: Malignant melanoma is a prime example of a treatment-resistant tumor with poor prognosis. Even with innovative treatment regimens, response rates remain low, and the duration of responses is short. More than 90% of all melanomas express the antiapoptotic protein Bcl-2, shown to contribute to a chemoresistant phenotype in melanoma. We previously demonstrated that antisense-mediated inhibition of Bcl-2 sensitizes malignant melanoma to apoptosis-inducing treatment modalities. In the present study, we evaluated synthetic small interfering RNA (siRNA) compounds targeting Bcl-2 as a novel approach to downregulate Bcl-2 expression in melanoma cells. siRNA treatment led up to a 19-fold reduction of bcl-2 mRNA levels and only barely detectable Bcl-2 protein expression at low nanomolar concentrations. Silencing of Bcl-2 in melanoma cells by specific siRNA led to a moderate increase in apoptotic cell death and inhibition of cell growth. However, if siRNA compounds targeting Bcl-2 were combined with the apoptosis-inducing chemotherapeutic agent cisplatin, a massive increase in apoptotic cell death compared with controls was observed. Notably, the combination of Bcl2 siRNA and low-dose cisplatin resulted in a supra-additive effect, with nearly complete suppression of cell growth, whereas cell growth in cisplatin-only-treated cells was only moderately affected (96% vs. 25%, p 〈 0.001). These findings underline a key role for Bcl-2 in conferring chemoresistance to melanoma and highlight Bcl-2 siRNA strategies as novel and highly effective tools, with the potential for future targeted therapy of malignant melanoma.
    Keywords: Melanoma -- Genetics ; RNA, Small Interfering -- Genetics
    ISSN: 1545-4576
    E-ISSN: 15578526
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