Gene therapy for hepatocellular carcinoma.

概要

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The α-fetoprotein (AFP) gene is reexpressed in hepatoma cells. We have previously shown that the retrovirus vector (LNAF0.3TK) carrying the herpes simplex virus thymidine kinase (HSVTK) gene regulated by the 0.3-kb human AFP promoter provides ganciclovir (GCV)-mediated cytotoxicity in AFP-producing hepatoma cells in parallel with the ability of AFP production. Since the recent reports have revealed that a G to A substitution in the human AFP promoter region is relevant to the hereditary persistence of human AFP, the same substitution was generated in LNAF0.3TK to construct LNAFM0.3TK. LNAFM0.3TK infection into intermediate and low AFP-producing human hepatoma cells, PLC/PRF/5 and huH1/cl. 2, respectively, resulted in more pronounced growth inhibition by GCV treatment than LNAF0.3TK infection. In addition, to improve the efficacy of retrovirus-mediated gene therapy for the intermediate or low AFP-producing hepatoma cells, human AFP domain B enhancer region was linked to 5'-end of the 0.3-kb AFP promoter region. The infections with sense and reverse-oriented retrovirus vectors, LNAFE0.3TK and LN (AFE0.3TK) R, respectively, sensitized PLC/PRF/5 and huH1/cl.2 cells to GCV, in which LN (AFE0.3TK) R infection showed more pronounced tumoricidal effect. These results suggest that modifications of the AFP promoter ensure the therapeutic gene expression in gene therapy for the low AFP-producing hepatoma cells.
日本電気泳動学会の論文