INTRACRANIAL ADMINISTRATION OF ADENOVIRUS EXPRESSING HSV-TK IN COMBINATION WITH GANCICLOVIR PRODUCES A DOSE-DEPENDENT, SELF-LIMITING INFLAMMATORY RESPONSE
Jg. Smith et al., INTRACRANIAL ADMINISTRATION OF ADENOVIRUS EXPRESSING HSV-TK IN COMBINATION WITH GANCICLOVIR PRODUCES A DOSE-DEPENDENT, SELF-LIMITING INFLAMMATORY RESPONSE, Human gene therapy, 8(8), 1997, pp. 943-954
Replication-defective adenovirus expressing the herpes simplex thymidi
ne 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, cotto
n rats, and rhesus monkeys in conjunction with systemic ganciclovir (G
CV) at 10 mg/kg per day. In the Wistar rat, 5.7 x 10(9) pfu resulted i
n histopathologic injury consisting of localized necrosis, mild gliosi
s, marked malacia, and focal astrocytosis; however, 1.0 x 10(8) pfu re
sulted 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 i
mmune and adenoviral naive cotton rats resulted in similar findings. I
n the rhesus monkey, doses ranging from 1.4 x 10(8) pfn to 1.5 x 10(11
) pfu resulted in localized gliosis, necrosis, perivascular cuffing, m
eningitis, and roughly correlated in severity with increasing dose. No
histologic evidence of toxicity was found in non-central nervous syst
em (CNS) tissues, and no virus could be cultured from cerebrospinal fl
uid (CSF), blood, urine, and stool samples. All animals survived to pr
escribed end points without signs of general toxicity or neurologic sy
mptoms, except for 2 of the rhesus monkeys, one of which became febril
e and the other of which developed a grand mal seizure (both subsequen
tly resolved). These toxicology studies define the parameters for deve
loping a phase I clinical trial.