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Thema: News: Adenoviraler CTS1 Gentransfer

News: Adenoviraler CTS1 Gentransfer
02.08.2001 20:52:28
Cancer Res 2001 Aug 1;61(15):5833-5842

Chimeric Tumor Suppressor 1, a p53-derived Chimeric Tumor Suppressor Gene, Kills p53 Mutant and p53 Wild-type Glioma Cells in Synergy with Irradiation and CD95 Ligand.

Naumann U, Kugler S, Wolburg H, Wick W, Rascher G, Schulz JB, Conseiller E, Bahr M, Weller M.

Laboratories of Molecular Neuro-Oncology [U. N., W. W., M. W.], Neuroregeneration [S. K., M. B.], and Neurodegeneration [J. B. S.], Department of Neurology, Institute of Pathology [H. W., G. R.], University of Tubingen, Medical School, 72076 Tubingen, Germany, and Aventis Pharmaceuticals, 94400 Vitry-sur-Seine, France [E. C.].

Adenoviral chimeric tumor suppressor 1 (CTS1) gene transfer was evaluated as a novel approach of somatic gene therapy for malignant glioma. CTS1 is an artificial p53-based gene designed to resist various pathways of p53 inactivation. Here, we report that an adenovirus encoding CTS1 (Ad-CTS1) induces growth arrest and loss of viability in all glioma cell lines examined, in the absence of specific cell cycle changes. In contrast, an adenovirus encoding wild-type p53 (Ad-p53) does not consistently induce apoptosis in the same cell lines. Electron microscopic analysis of Ad-CTS1-infected glioma cells reveals complex cytoplasmic pathology and delayed apoptotic changes. Ad-CTS1 induces prominent activation of various p53 target genes, including p21 and MDM-2, but has no relevant effects on BCL-2 family protein expression. Although Ad-CTS1 strongly enhances CD95 expression at the cell surface, endogenous CD95/CD95 ligand interactions do not mediate CTS1-induced cell death. This is because Ad-CTS1 promotes neither caspase activation nor mitochondrial cytochrome c release and because the caspase inhibitors, z-val-Ala-DL-Asp-fluoromethylketone (zVAD)-fmk or z-Ile-Glu-Thr-Asp- fluoromethylketone (z-IETD)-fmk, do not block CTS1-induced cell death. Ad-CTS1 synergizes with radiotherapy and CD95 ligand in killing glioma cells. In summary, Ad-CTS1 induces an unusual type of cell death that appears to be independent of BCL-2 family proteins, cytochrome c release, and caspases. CTS1 gene transfer is a promising strategy of somatic gene therapy for malignant glioma.
07.08.2001 10:11:29
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