Treatment of rat C6 meningeal dissemination model by intrathecal injection o frecomvinant soluble FasL

点击翻译按钮获取中文摘要

Fas (CD95) ligand (FasL) has the ability to induce apoptosis in Fas-expressing glioma cells by binding to with Fas: Several molecular species have been designed to be soluble Fas ligands for therapeutic purposes. Most of them possessing just only extracellular domain of Fas ligand (soluble FasL) cannot be used practically due to either insufficient biological activity or reduced productivity. We. successfully constructed a chimeric soluble. FasL by fusing a isoleucine zipper motif for se If-oligomerization and a FLAG sequence to the extracellular domain of the human Fas ligand (FIZ-shFasL). The cytotoxic effect of FIZ-shFasL on Jurkat cells was equivalent to that of membrane-bound FasL and approximately ten-fold stronger than that of agonistic anti-Fas antibody (CH-11). Expression of Fas and Bcl-2 on cell lines was determined using flow cytometry and compared with sensitivity to FIZ-shFasL. Flowcytometric analysis demonstrated that the differential Fas expression of human brain tumor cell lines partially correlated with levels of apoptosis through FIZ-shFasL. The intravenous administration of 1.0mg/kg of FIZ -shFasL resulted in a lethal effect in rats. A rat meningeal dissemination model with rat Fas-expressing C6 glioma cells can be treated successfully by intrathecal FIZ-shFasL administration without any apparent adverse effects. These results suggest that intrathecal administration of FIZ-shFasL maybe applied to the treatment of patients with leptomeningeal gliomatosis in the near future.