Combination gene therapy using multidrug resistance (MDR1) gene shRNA and herpes simplex virus-thymidine kinase.
The current study was designed to evaluate the anti-tumor effects of MDR1 shRNA in combination with herpes simplex virus-thymidine kinase/ganciclovir (HSV-tk/GCV) suicide gene therapy system. Introduction of an MDR1-targeted small hairpin RNA (shMDR) markedly enhanced the intracellular accumulation of and increased sensitivity to drugs transported by P-glycoprotein. Functional TK-eGFP fusion protein expression was confirmed by Western blot analysis and ganciclovir uptake assay. Compared with GCV or doxorubicin alone, the combination of anti-cancer drug chemotherapy with GCV administration displays additive cytotoxicity in shMDR1-TK-eGFP expressing cells. These results for the first time suggest the potential of combination gene therapy using suicide gene therapy and RNAi-based gene therapy in vitro.
Park
Seung-Yoon
SY
Department of Biochemistry, School of Medicine, Dongguk University, Kyungju 780-714, Republic of Korea.
Lee
Wan
W
Lee
Jaetae
J
Kim
In-San
IS
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D003131:Combined Modality Therapy; D017931:DNA Primers; D004317:Doxorubicin / Q000494:pharmacology; D015774:Ganciclovir / Q000494:pharmacology; D015316:Genetic Therapy / Q000379:methods*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D018259:Herpesvirus 1, Human / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D010957:Plasmids; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013937:Thymidine Kinase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D017931:DNA Primers; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D004317:Doxorubicin; D013937:Thymidine Kinase; D015774:Ganciclovir