Intracerebral injection of adenovirus harboring the HSVtk gene combined with ganciclovir administration: toxicity study in nonhuman primates.
A high dose (1-2.5 x 10(10) infectious units) of recombinant adenovirus harboring the herpes simplex thymidine kinase gene (IG.Ad.MLPI.TK) was injected into the white matter of the right frontal lobe in two rhesus monkeys (M. mulatta). Injection of the vector was followed by systemic ganciclovir administration (10 mg/kg per day) for 14 days. During treatment no clinical symptoms were observed. Histopathological analysis of the brain at day 18 showed a 5 mm necrotic area at the site of the virus injection. This area was invaded and surrounded by inflammatory cells and activated astrocytes (gliosis). Immunohistochemical analysis of the infiltrates revealed the presence of predominantly mononuclear cells. In the vicinity of the lesion perivascular cuffs were seen containing T lymphocytes and clusters of B lymphocytes. From this preclinical study we conclude that the toxicity of adenotk/GCV is acceptable and treatment of patients with malignant gliomas using this kind of therapy is feasible. However, careful dose finding in clinical studies is recommended.
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage*; D001402:B-Lymphocytes; D001921:Brain / Q000276:immunology / Q000473:pathology; D001932:Brain Neoplasms / Q000628:therapy; D003131:Combined Modality Therapy; D015774:Ganciclovir / Q000008:administration & dosage*; D015316:Genetic Therapy / Q000009:adverse effects* / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage / Q000633:toxicity*; D005910:Glioma / Q000628:therapy; D007267:Injections; D008253:Macaca mulatta; D008297:Male; D018139:Simplexvirus / Q000201:enzymology; D013601:T-Lymphocytes; D013937:Thymidine Kinase / Q000235:genetics*