ADENOVIRAL-MEDIATED THYMIDINE KINASE GENE-TRANSFER INTO THE PRIMATE BRAIN FOLLOWED BY SYSTEMIC GANCICLOVIR - PATHOLOGICAL, RADIOLOGIC, AND MOLECULAR STUDIES

Transduction of experimental gliomas with the herpes simplex virus thy midine kinase gene (HSV-tk) using a replication-defective adenoviral v ector (ADV/RSV-tk) confers sensitivity to ganciclovir (GCV) leading to tumor destruction and prolonged host survival in rodents, To determin e treatment tolerance prior to clinical trials, we conducted toxicity studies in 6 adult baboons (Papio sp,), The animals received intracere bral injections of either a high dose of ADV/RSV-tk [1.5 x 10(9) plaqu e-forming units (pfu)] with or without GCV, or a low dose of ADV/RSV-t k (7.5 x 10(7) pfu) with GCV. The low dose corresponded to the anticip ated therapeutic dose; the high dose was expected to be toxic, Magneti c resonance imaging (MRI) of the brain was obtained before treatment a nd at 3 and 6 weeks after treatment, Animals receiving the high-dose v ector and GCV either died or became moribund and required euthanasia d uring the first 8 days of treatment, Necropsies revealed cavities of c oagulative necrosis at the injection sites, Animals receiving only the high-dose vector were clinically normal; however, lesions were detect ed with MRI at the injection sites corresponding to cystic cavities at necropsy, Animals receiving the low-dose vector and GCV were clinical ly normal, exhibited small MRI abnormalities, and, although no gross l esions were present at necropsy, microscopic foci of necrosis were pre sent, The vector sequence was detected by polymerase chain reaction (P CR) at the injection sites and in nonadjacent central nervous system t issue in all animals, Recombinant DNA sequence was detected outside of the nervous system in some animals, and persisted up to 6 weeks, The viral vector injections stimulated the production of neutralizing anti bodies in the animals, No shedding of the vector was found in urine, f eces, or serum 7 days after intracerebral injection, This study sugges ts that further investigations including clinical toxicity trials of t his form of brain tumor therapy are warranted.