INTRACEREBRAL INJECTION OF ADENOVIRUS HARBORING THE HSVTK GENE COMBINED WITH GANCICLOVIR ADMINISTRATION - TOXICITY STUDY IN NONHUMAN-PRIMATES

A high dose (1-2.5x 10(10) infectious units) of recombinant gene (IG.A d.MLPI.TK) was injected into the white matter adenovirus harboring the herpes simplex thymidine kinase of the right frontal lobe in two rhes us monkeys (M. mulatta). injection of the vector was followed by syste mic ganciclovir administration (10 mg/kg per day) for 14 days. During treatment no clinical symptoms were observed. Histopathological analys is of the brain at day 18 showed a 5 mm necrotic area at the site of t he virus injection. This area was invaded and surrounded by inflammato ry cells and activated astrocytes (gliosis). Immunohistochemical analy sis of the infiltrates revealed the presence of predominantly mononucl ear cells. In the vicinity of the lesion perivascular cuffs were seen containing T lymphocytes and clusters of B lymphocytes. From this prec linical study we conclude that the toxicity of adenotk/GCV is acceptab le and treatment of patients with malignant gliomas using this kind of therapy is feasible. However, careful dose finding in clinical studie s is recommended.