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1.
Int J Cancer ; 65(3): 332-7, 1996 Jan 26.
Article in English | MEDLINE | ID: mdl-8575854

ABSTRACT

Transforming growth factors-beta 1 and -beta 2 (TGF-beta 1 and -beta 2) are important growth-regulatory proteins for astroglial neoplasms. We analyzed their role in tumor-cell proliferation in 12 glioma cell lines, employing phosphorothioate antisense oligodeoxynucleotides (S-ODNs, 14 mer), specifically targeted against the coding sequences of TGF-beta 1-mRNA and TGF-beta 2-mRNA. TGF-beta 1-S-ODNs inhibited cell proliferation in 5 of 12 gliomas, whereas TGF-beta 2-S-ODNs reduced the cell proliferation in all glioma cell lines, compared to nonsense-S-ODN-treated and S-ODN-untreated cells as controls. The efficacy and specificity of antisense effects was validated by Northern-blot analysis and determination of protein concentrations in culture supernatants (ELISA). Exogenous hrTGF-beta 1 either stimulated or inhibited the cell lines, whereas pnTGF-beta 2 stimulated the proliferation of most glioma cells. Blocking the extracellular pathway of TGF-beta by neutralizing antibodies only slightly inhibited those cell lines, which were markedly stimulated by TGF-betas. As the effects of TGF-beta 2-S-ODNs were much stronger than those of TGF-beta neutralizing antibodies, we postulate that the endogenously produced TGF-beta 2 control glioma-cell proliferation, in part by an intracellular loop.


Subject(s)
Glioma/pathology , Oligonucleotides, Antisense/pharmacology , Thionucleotides/pharmacology , Transforming Growth Factor beta/metabolism , Base Sequence , Cell Division/drug effects , Glioma/metabolism , Humans , Molecular Sequence Data , Oligonucleotides, Antisense/metabolism , Thionucleotides/metabolism , Transforming Growth Factor beta/genetics , Tumor Cells, Cultured
2.
Cell Immunol ; 165(1): 125-33, 1995 Oct 01.
Article in English | MEDLINE | ID: mdl-7671316

ABSTRACT

Transforming growth factor-beta (TGF-beta) is a potent cytokine that has influence upon immunosuppressive as well as proinflammatory processes. In this context we have investigated the role of endogenous TGF-beta in human peripheral blood mononuclear cells (PBMCs) by TGF-beta 1 phosphorothioate antisense oligodeoxynucleotides (TGF-beta 1-S-ODNs). In short-term cultures (up to 3 days), TGF-beta 1-S-ODNs-treated, interleukin 2-activated PBMCs displayed a growth advantage (up to 148%) compared to nonsense or untreated controls as measured by cell counting and [3H]thymidine incorporation. Long-term antagonization of TGF-beta production (up to 12 days) showed no significant differences between both antisense- and nonsense-treated PBMCs. The efficacy and specificity of TGF-beta 1-S-ODNs effects was validated by gene expression studies (Northern blot and ELISA) and analysis of cellular uptake of BrdU-labeled S-ODN (Immunocytochemistry). TGF-beta 1-S-ODNs at the final concentration of 1 microM reduced TGF-beta 1 protein concentration up to 65% in PBMCs cultures without significant changes in TGF-beta 1 mRNA expression. These experiments demonstrate that TGF-beta 1-S-ODNs specifically antagonize TGF-beta 1-mediated autocrine suppression of IL-2-dependent PBMC activation. TGF-beta 1-specific antisense oligonucleotides may represent a promising immunoresponse modifying agent that could be used for T-cell directed immunostimulation.


Subject(s)
Leukocytes, Mononuclear/cytology , Oligonucleotides, Antisense/pharmacology , Thionucleotides/pharmacology , Transforming Growth Factor beta/pharmacology , Base Sequence , Cell Division/drug effects , Cells, Cultured , Humans , Molecular Sequence Data , Oligonucleotides, Antisense/metabolism , RNA, Messenger/analysis , Thionucleotides/metabolism , Time Factors , Transforming Growth Factor beta/biosynthesis , Transforming Growth Factor beta/genetics
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