Cationic liposomes conjugation to recombinant adenoviral vectors containing herpes simplex virus thymidine kinase gene followed by ganciclovir treatment reduces viral antigenicity and maintains antitumor activity in mouse experimental glioma models.
Gene therapy using adenoviral (Ad) vector containing herpes simplex virus thymidine kinase (AxCAHSV-tk) followed by the administration of ganciclovir (GCV) has been a promising therapy for cancer including malignant gliomas. However, there remain numerous problems to overcome, such as the high immunogenicity and toxicity of Ad vector. To optimize the therapy, we investigated whether a conjugation of our original cationic liposomes and Ad vectors reduces viral antigenicity and maintains the antitumor activity in mouse experimental (subcutaneous and intracranial) glioma models. Our original liposomes consist of N-(alpha-trimethylammonioacetyl)-didodecyl-D-glutamate chloride, dilauroyl phosphatidylcholine, and dioleoyl phosphatidyl-ethanolamine in a molar ratio of 1:2:2. AxCAHSV-tk and GCV showed a remarkable inhibition of experimental glioma growth. The growth-inhibitory effect decreased in mice previously immunized with another Ad vector (AxCALacZ). In contrast, the conjugation of AxCAHSV-tk and liposomes did not diminish the growth-inhibitory effect. Furthermore, the conjugation reduced antigenicity for Ad vector in vivo. These findings suggest that suicide gene therapy, using a conjugation of AxCAHSV-tk and our liposomes, is a feasible approach for human cancer gene therapy, especially malignant gliomas.
Mizuno
Masaaki
M
Department of Molecular Neurosurgery, Nagoya University, Graduate School of Medicine, Nagoya, Japan. mmizuno@med.nagoya-u.ac.jp
Ryuke
Yasushi
Y
Yoshida
Jun
J
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D000956:Antigens, Viral / Q000276:immunology / Q000378:metabolism; D000998:Antiviral Agents / Q000627:therapeutic use*; D017209:Apoptosis; D001932:Brain Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D002412:Cations; D004274:DNA, Recombinant / Q000737:chemistry; D004195:Disease Models, Animal; D005260:Female; D015774:Ganciclovir / Q000627:therapeutic use*; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D005910:Glioma / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D007263:Infusions, Parenteral; D008081:Liposomes; D051379:Mice; D008810:Mice, Inbred C57BL; D018139:Simplexvirus / Q000201:enzymology*; D013937:Thymidine Kinase / Q000235:genetics*; D014407:Tumor Cells, Cultured; D001616:beta-Galactosidase / Q000235:genetics
D000956:Antigens, Viral; D000998:Antiviral Agents; D002412:Cations; D004274:DNA, Recombinant; D008081:Liposomes; D013937:Thymidine Kinase; D001616:beta-Galactosidase; D015774:Ganciclovir