Suicide gene therapy using AAV-HSVtk/ganciclovir in combination with irradiation results in regression of human head and neck cancer xenografts in nude mice.
The application of adeno-associated virus (AAV) vectors to cancers is limited by their low transduction efficiency. Previously, we reported that gamma-ray enhanced the second-strand synthesis, leading to the improvement of the transgene expression, and cytocidal effect of the herpes simplex virus type-1 thymidine kinase (HSVtk) and ganciclovir (GCV) system. In this study, we extended this in vitro findings to in vivo. First, the laryngeal cancer cell line (HEp-2) and HeLa were treated with AAVtk/GCV, the number of surviving cells was reduced as the concentration of GCV increased. Furthermore, the 4 Gy irradiation enhanced the killing effects of AAVtk/GCV by four-fold on HeLa cells and 15-fold on HEp-2 cells. Following the in vitro experiments, we evaluated the transgene expression and the antitumor activity of the AAV vectors in combination with gamma-ray in nude mice inoculated with HEp-2 subcutaneously. The LacZ expression was observed in the xenografted tumors and significantly increased by gamma-ray. The AAVtk/GCV system suppressed the tumors growth, and gamma-ray augmented the antitumor activity by five-fold. These findings suggest that the combination of AAVtk/GCV system with radiotherapy is significantly effective in the treatment of cancers and may lead to reduction of the potential toxicity of both AAVtk/GCV and gamma-ray.
Kanazawa
T
T
Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical School, Tochigi, Japan.
Mizukami
H
H
Okada
T
T
Hanazono
Y
Y
Kume
A
A
Nishino
H
H
Takeuchi
K
K
Kitamura
K
K
Ichimura
K
K
Ozawa
K
K
D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D003131:Combined Modality Therapy; D000229:Dependovirus / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D015774:Ganciclovir / Q000008:administration & dosage* / Q000627:therapeutic use; D015870:Gene Expression / Q000528:radiation effects; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000235:genetics; D006367:HeLa Cells; D006258:Head and Neck Neoplasms / Q000532:radiotherapy* / Q000628:therapy*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D011879:Radiotherapy Dosage; D018139:Simplexvirus / Q000201:enzymology; D013937:Thymidine Kinase / Q000235:genetics; D014161:Transduction, Genetic / Q000379:methods*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D001616:beta-Galactosidase / Q000235:genetics
D000998:Antiviral Agents; D013937:Thymidine Kinase; D001616:beta-Galactosidase; D015774:Ganciclovir