Murine retroviral vector producer cells survival and toxicity in the peritoneal cavity of dogs.
Retroviral vector producer cells (VPC) can effectively transfer genes in vivo. To develop a safe method to target gene delivery into intraperitoneal tumors, we have examined the toxicity of intraperitoneal (i.p.) infusion of retroviral VPC in a xenogeneic canine model. Mongrel dogs were injected intraperitoneally (i.p.) with 2 x 10(9) murine LTKOSN.2 VPC. The animals did not demonstrate acute toxicity and tolerated the i.p. infusion of the cells without difficulty. Starting 7 days after i.p. injection, the dogs received intravenous injections of ganciclovir (GCV) twice daily (5 mg/kg) for 7 days. The treatment dogs underwent peritoneal washings on days 3, 7 and 14 after their initial infusion of cells to study the persistence of the VPC. GCV treatment did not cause significant toxicities. Dogs underwent serial blood tests to evaluate bone marrow, renal, liver and immunological function. Complete blood counts, electrolytes and renal function remained normal throughout the study. Although, transient mild elevations occurred of serum alkaline phosphate, the remaining hepatic enzymes remained normal. Histologic examination of tissues from animals sacrificed after the i.p. administration of the VPC revealed no tissue destruction of the normal peritoneal lining. The dogs mounted an antibody response to the murine VPC that was first observed 7 days post injection. PCR analysis of selected tissues after GCV administration did not reveal persistent vector sequences. These results demonstrated that the injection of xenogeneic VPC is not accompanied by significant adverse effects over a 1 month period following administration into the canine peritoneal cavity. These data support the potential clinical application of the VPC in Phase I clinical trials in humans.
Link
C J
CJ
Human Gene Therapy Research Institute, Central Iowa Health System, 1415 Woodland Ave., Des Moines, IA 50309, USA.
Moorman
D W
DW
Ackerman
M
M
Levy
J P
JP
Seregina
T
T
D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D002417:Cattle; D002470:Cell Survival / Q000187:drug effects; D004285:Dogs; D015774:Ganciclovir / Q000494:pharmacology; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006403:Hematologic Tests; D018259:Herpesvirus 1, Human / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D007677:Kidney Function Tests; D008111:Liver Function Tests; D051379:Mice; D023421:Models, Animal; D010529:Peritoneal Cavity / Q000166:cytology*; D010533:Peritoneal Lavage; D016133:Polymerase Chain Reaction; D013937:Thymidine Kinase / Q000235:genetics; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000276:immunology / Q000637:transplantation
D013937:Thymidine Kinase; D000469:Alkaline Phosphatase; D015774:Ganciclovir