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Free keywords:
GENE-THERAPY; CARCINOEMBRYONIC ANTIGEN; HEPATOCELLULAR-CARCINOMA;
GLIOBLASTOMA-MULTIFORME; CYTOSINE DEAMINASE; BREAST-CANCER;
5-FLUOROURACIL; FUSION; STRAIN; PHOSPHORIBOSYLTRANSFERASEHepatocellular carcinoma; oncolytic measles virus; suicide gene therapy;
cytosine deaminase; apoptosis;
Abstract:
Due to late diagnosis and a pronounced chemoresistance, Most patients with hepatocellular carcinoma (HCC) have an overall poor prognosis. Measles vaccine viruses (MeV) have been shown to possess anti-tumor properties and their efficacy has been enhanced by arming with suicide genes. To test armed MeV for the treatment of HCC, we equipped it with the suicide gene Super-cytosine deaminase (SCD) and tested the efficacy in cell culture and in a mouse xenograft model of human HCC. Prodrug conversion was investigated in cell culture and quantified by high-performance liquid chromatography. We observed a strong oncolytic activity of MeV-SCD against human HCC in vitro and in vivo. The prodrug was efficiently converted in infected cells leading to a significant enhancement of the cytotoxic effect. Treatment of HCC xenografts with MeV caused long-term virus replication in tumor tissue. We show that the suicide gene therapy induces an apoptosis-like cell death but is not dependent on intact apoptosis pathways. These results demonstrate that MeV-based suicide gene therapy is a promising novel therapy regimen for HCC overcoming resistance towards conventional therapy. The independence from apoptosis raises hopes for the treatment of patients whose tumor cells exert defects in this cell death mechanism.
