Regulation for multidrug resistant cancer and cancer stem cells by ABC transporter-targeted virus

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The purpose of current study was to examine the specificity and efficacy of targeted therapeutic molecule for EGFR-overexpressing cancer cells, in stead of ABCG2-positive cancer stem cells due to technical difficulty in culture.1) Comparison for targeting ligand of single chain of antibody against EGFR versus EGFWe constructed two types of adapters comprising of nectin1-V-domain fused to a single chain of antibody (scFv) against EGFR or a natural ligand, EGF. The efficacy of adapter-mediated HSV infection was significantly higher when HSV was challenged with the scFv-adapters than EGF-adapters. The potential factors for the differential entry efficiency seem to be the followings.a) The scFv-adapter had a higher affinity to HSV-gD than EGF-adapter although the affinity to EGFR was similar.b) The scFv-adapter did not induce the activation of EGFR so much as the EGF-adapter.c) The EGF-adapter was rapidly degraded in endosome-lysosome pathway, whereas the scFv-adapter was resistant at the … More same time points by 30 min post-binding.The scFv-adapter is superior to the EGF-adapter as a targeting ligand for EGFR-mediated HSV infection. (Under manuscript preparation)2) Efficacy of EGFR-targeted suicide gene therapyWe constructed the expression plasmid for EGFR scFv-fused to E. coli PNP suicide gene and CA19-9 scFv-fused to E. coli PNP as the control, and then established colon cancer cell lines stably expressing the suicide genes. The efficacy of targeted suicide gene therapy for EGFR-overexpressing cancer was compared between the two targeting ligands. Tumor growth was more inhibited by the both suicide gene therapies compared with the saline control. EGFR scFv-fused to PNP suicide gene therapy induced a complete regression in some of mice harboring subcutaneous EGFR-overexpressing colon cancer and exhibited higher therapeutic efficacy than the control of CA19-9 scFv-fused suicide gene therapy. Immnofluorescence staining showed the co-localization of suicide gene expression and tumor vessels when provided with EGFR scFv-fused suicide gene but not much with CA 19-9 scFv-fused suicide gene (Biotherapy 21; 229-34, 2007) Less