Intracranial administration of adenovirus expressing HSV-TK in combination with ganciclovir produces a dose-dependent, self-limiting inflammatory response.
Replication-defective adenovirus expressing the herpes simplex thymidine kinase gene (H5.010RSVtk) may be useful in treating human gliomas. To determine the toxicity of this therapeutic strategy, we injected H5.010RSVtk stereotactically into the normal brain of Wistar rats, cotton rats, and rhesus monkeys in conjunction with systemic ganciclovir (GCV) at 10 mg/kg per day. In the Wistar rat, 5.7 x 10(9) pfu resulted in histopathologic injury consisting of localized necrosis, mild gliosis, marked malacia, and focal astrocytosis; however, 1.0 x 10(8) pfu resulted in only mild gliosis and trace meningitis and approximates a "no toxic effect" dose. A dose of 1.0 x 10(9) pfu in both adenoviral immune and adenoviral naive cotton rats resulted in similar findings. In the rhesus monkey, doses ranging from 1.4 x 10(8) pfu to 1.5 x 10(11) pfu resulted in localized gliosis, necrosis, perivascular cuffing, meningitis, and roughly correlated in severity with increasing dose. No histologic evidence of toxicity was found in non-central nervous system (CNS) tissues, and no virus could be cultured from cerebrospinal fluid (CSF), blood, urine, and stool samples. All animals survived to prescribed end points without signs of general toxicity or neurologic symptoms, except for 2 of the rhesus monkeys, one of which became febrile and the other of which developed a grand mal seizure (both subsequently resolved). These toxicology studies define the parameters for developing a phase I clinical trial.
Smith
J G
JG
Department of Medicine, University of Pennsylvania Medical Center, Philadelphia 19104, USA.
Raper
S E
SE
Wheeldon
E B
EB
Hackney
D
D
Judy
K
K
Wilson
J M
JM
Eck
S L
SL
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use*; D001921:Brain / Q000821:virology; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D015774:Ganciclovir / Q000627:therapeutic use*; D005822:Genetic Vectors; D007249:Inflammation / Q000821:virology; D008253:Macaca mulatta; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D016205:Sigmodontinae; D018139:Simplexvirus / Q000235:genetics*; D013238:Stereotaxic Techniques; D013937:Thymidine Kinase / Q000235:genetics*
D000998:Antiviral Agents; D013937:Thymidine Kinase; D015774:Ganciclovir