Brain malignancies are a significant source of morbidity and mortality. Glioblastoma multiforme (GBM) is the most common and the most malignant tumor occurring in the central nerwous system and is notorious for its highly infiltrative and invasive behaviour.

Despite surgery, radiotherapy and chemotherapy, about 40% of patients with GBM die within ca 6-8 months after diagnosis. Establishment of a curative treatment for glioblastoma will require better understanding of the molecular mechanisms underlying the proliferation, migration, and invasion of the tumor cells.

Several lines of evidence have been accumulated regarding signal transduction pathways in glioma cells. Amplification of the epidermal growth factor receptor (EGFR) gene occurs in ca 50% of glioblastomas, and the tumor cells usually show overexpression of EGFR. It stimulates the activation of phosphatidylinositol-3-0H kinase (PIK3). Loss of a tumor suppressor gene called phosphatase/tensin homolog on chromosome 10 (PTEN) is also frequently detected in glioblastoma as well as breast, prostate and endometrial carcinomas and melanoma. Recently it has been shown that tenascin-C (TN-C) is strongly expressed in human malignant gliomas and can stimulate glioma cell proliferation and angiogenesis. TN-C is a dominant epitope in GBM.

Disappointing results in the therapy of GBM have fuelled a search for new treatment modalities.

RNA interference (RNAi) is a eukaryotic regulatory mechanism that uses double stranded DNA (dsRNA) molecules as triggers to direct sequence homology-dependent, post-transcriptional gene silencing. RNAi represents a particularly powerful method which includes the RNAi-mediated targeting in vitro and in vivo for functional studies of various genes whose expression is known to be up regulated as well as the development of novel therapeutic approaches based on gene targeting.

RNAi phenomenon relies on a multistep intracellular pathway which can be roughly divided into two phases. In the first one, endogenous or exogenous dsRNA molecules present within the cell are processed through the cleavage activity of RNase III-type activity (Dicer) into short 20-30 nucleotide fragments called siRNAs. In the second step, siRNAs as well as many proteins including nucleases and helicase form RNA-induced silencing complex (RISC). Through unwinding of double stranded siRNA, the complex becomes activated with single–stranded, noncoding siRNA which guides the RISC complex to its complementary target RNA causing its endonucleolytic cleavage.

We used double stranded interfering RNAs (dsRNAs) to reduce tenascin-C expression in brain tumor cells. RNAi was injected into postoperative area of 46 patients. The follow up study with MRI and CT clearly show increased survival at better quality of life. The technology we called interference RNA intervention (iRNAi).

Acknowledgements: This work was supported by the network "Synthesis,  structure and therapeutic properties of compounds and organic substances".

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