Safety of intrapleurally administered recombinant adenovirus carrying herpes simplex thymidine kinase DNA followed by ganciclovir therapy in nonhuman primates.
Preclinical safety and toxicity studies of intrapleural administration of recombinant adenovirus carrying the herpes simplex thymidine kinase gene (H5.010RSVtk) were performed. Previously reported experimental evidence has demonstrated the efficacy of this approach in animal models of a localized thoracic cancer, malignant mesothelioma. H5.010RSVtk was delivered at high dose (10(12) pfu) into the pleural cavity of three non-human primates followed by systemic administration of ganciclovir. No clinical toxicity was noted. Although an inflammatory reaction observable by microscopy was noted in the serosal spaces of the chest cavity, these changes were reversible and were not associated with radiographic sequelae. Extrathoracic viral dissemination was minimal and detectable only by sensitive polymerase chain reaction techniques. This low level of viral dissemination was not associated with detectable clinical, biochemical, or pathologic abnormalities.
Kucharczuk
J C
JC
Department of Surgery, University of Pennsylvania Medical Center, Philadelphia 19104, USA.
Raper
S
S
Elshami
A A
AA
Amin
K M
KM
Sterman
D H
DH
Wheeldon
E B
EB
Wilson
J M
JM
Litzky
L A
LA
Kaiser
L R
LR
Albelda
S M
SM
D000256:Adenoviridae / Q000235:genetics* / Q000276:immunology; D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D000963:Antimetabolites / Q000008:administration & dosage*; D004274:DNA, Recombinant / Q000009:adverse effects / Q000032:analysis; D004279:DNA, Viral / Q000009:adverse effects / Q000032:analysis; D004333:Drug Administration Routes; D005260:Female; D015774:Ganciclovir / Q000008:administration & dosage*; D018014:Gene Transfer Techniques / Q000009:adverse effects*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000009:adverse effects*; D008099:Liver / Q000473:pathology; D008168:Lung / Q000473:pathology; D008297:Male; D009500:Neutralization Tests; D009928:Organ Specificity; D010215:Papio; D010994:Pleura / Q000473:pathology; D012449:Safety; D018139:Simplexvirus / Q000201:enzymology / Q000235:genetics; D013937:Thymidine Kinase / Q000235:genetics*; D019076:Transgenes; D017201:Virus Shedding
D000914:Antibodies, Viral; D000963:Antimetabolites; D004274:DNA, Recombinant; D004279:DNA, Viral; D013937:Thymidine Kinase; D015774:Ganciclovir