Efficient gene transfer of VSV-G pseudotyped retroviral vector to human brain tumor.
A retroviral vector constructed from the murine leukemia virus (MLV) can only express transgenes in cells undergoing mitosis, indicating its suitability as a delivery vehicle for cancer gene therapy. However, the transduction efficiency (TE) of retroviruses embedding endogenous envelope proteins in human cancer cells was found to be unsatisfactory. Recently, several research groups have demonstrated the feasibility of a retroviral vector pseudotyped with a vesicular stomatitis virus G (VSV-G) protein. In this study, the potential of VSV-G pseudotyped MLV-based retrovirus was examined as a delivery vehicle in a variety of human cancer cells including brain tumor cells in vitro and in vivo. The transduction efficiency of the 293T/G/GP/LacZ retrovirus in cell culture was superior in most cancer cells, particularly in brain tumor cells, compared with that of other retroviruses, such as PA317- or PG13-derived. The relative growth rate and phosphatidylserine expression level on the plasma membrane of target cells mainly influenced the transduction efficiency of VSV-G pseudotyped retrovirus, which suggested that both the relative growth rate and phosphatidylserine expression level were major determinants of TE. Furthermore, 293T/G/GP/LacZ could efficiently transduce human cancer cells regardless of the presence of chemical additives, whereas in other retroviruses, cationic chemical additives such as polybrene or liposomes were essential during virus infection. Finally, an average of 10% gene expression was routinely obtained exclusively in the tumor mass when 293T/G/GP/LacZ concentrated by simple ultracentrifugation was directly administrated to pre-established brain tumors in animal models (U251-N nu/nu mice or C6 Wistar rats). All told, the present study suggests that the VSV-G pseudotyped retrovirus is a suitable vector for brain tumor gene therapy.
Lee
H
H
Department of Microbiology, University of Ulsan College of Medicine, Seoul, Korea.
Song
J J
JJ
Kim
E
E
Yun
C O
CO
Choi
J
J
Lee
B
B
Kim
J
J
Chang
J W
JW
Kim
J H
JH
D001932:Brain Neoplasms / Q000378:metabolism / Q000628:therapy*; D002411:Cation Exchange Resins / Q000494:pharmacology; D002462:Cell Membrane / Q000378:metabolism; D002784:Cholesterol / Q000031:analogs & derivatives / Q000494:pharmacology; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage*; D006583:Hexadimethrine Bromide / Q000494:pharmacology; D006801:Humans; D009052:Leukemia Virus, Murine / Q000235:genetics*; D008055:Lipids / Q000494:pharmacology; D010718:Phosphatidylserines / Q000378:metabolism; D011479:Protamines / Q000494:pharmacology; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured; D014721:Vesicular stomatitis Indiana virus
D002411:Cation Exchange Resins; D005229:Fatty Acids, Monounsaturated; D008055:Lipids; C086724:Lipofectamine; D010718:Phosphatidylserines; D011479:Protamines; D000644:Quaternary Ammonium Compounds; C070648:3-(N-(N',N'-dimethylaminoethane)carbamoyl)cholesterol; D006583:Hexadimethrine Bromide; D002784:Cholesterol; C070046:1,2-dioleoyloxy-3-(trimethylammonium)propane