Ovarian cancer gene therapy: repeated treatment with thymidine kinase in an adenovirus vector and ganciclovir improves survival in a novel immunocompetent murine model.
OBJECTIVE
Our purpose was to assess the effect of multiple injections of the system of herpes simplex virus thymidine kinase in an adenovirus vector and ganciclovir on survival in a murine model of human epithelial ovarian cancer.


METHODS
In this work we tested the ability of the system of thymidine kinase delivered by an adenovirus vector and ganciclovir to treat ovarian cancer in a novel murine model for epithelial ovarian cancer, SaskMouse. SaskMouse was developed by injecting LM-1 cells, a murine epithelial ovarian cancer cell line, intraperitoneally into a syngeneic C57BL/6N x C3H/He mouse strain. The cells developed into multiple cancer implants on different abdominal organs, leading to ascites and rapid death. The model has an intact immune system, as evidenced by the inability of different human cancer cells to develop into cancers when injected into the mice intraperitoneally.


RESULTS
The system of thymidine kinase delivered by an adenovirus vector and ganciclovir was applied to SaskMouse. Mice were either untreated (group 1), treated with one intraperitoneal injection of adenovirus- thymidine kinase at 250 plaque-forming units/cell (group 2), or treated with two intraperitoneal injections of adenovirus-thymidine kinase at 250 plaque-forming units/cell on days 0 and 23 (group 3). Survivals were 23 +/- 2, 27 +/- 2, and 35 +/- 4 days, respectively (P <.05). Antiadenoviral antibodies were assayed both in the serum and in the peritoneal fluid of treated mice. Despite high antibody titers in serum, there were no detectable antibodies in the peritoneal fluid.


CONCLUSIONS
Our data suggest that multiple intraperitoneal injections of the combination of thymidine kinase delivered by an adenovirus vector and ganciclovir are effective in prolonging survival in the presence of ovarian cancer. There are potential implications for other abdominal malignancies.
Al-Hendy
A
A
Departments of Obstetrics, Gynecology, and Reproductive Science and Pathology and the Cancer Center, University of Saskatchewan, Saskatoon,Saskatchewan, Canada.
Magliocco
A M
AM
Al-Tweigeri
T
T
Braileanu
G
G
Crellin
N
N
Li
H
H
Strong
T
T
Curiel
D
D
Chedrese
P J
PJ
D000256:Adenoviridae / Q000235:genetics / Q000276:immunology; D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D000998:Antiviral Agents / Q000627:therapeutic use; D001202:Ascitic Fluid / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D015774:Ganciclovir / Q000627:therapeutic use; D015316:Genetic Therapy; D005822:Genetic Vectors; D007121:Immunocompetence; D051379:Mice; D008815:Mice, Inbred Strains; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000097:blood / Q000188:drug therapy / Q000628:therapy*; D013937:Thymidine Kinase / Q000235:genetics* / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
D000914:Antibodies, Viral; D000998:Antiviral Agents; D013937:Thymidine Kinase; D015774:Ganciclovir