Identifying the safety profile of a novel infectivity-enhanced conditionally replicative adenovirus, Ad5-delta24-RGD, in anticipation of a phase I trial for recurrent ovarian cancer.
OBJECTIVE
The purpose of this study was to evaluate the biodistribution and toxicity of the tropism-modified infectivity-enhanced conditionally replicative adenovirus, Ad5-delta24-arginine-glycine-aspartate (RGD).


METHODS
Cohorts of cotton rats were treated intravenously or intraperitoneally for 3 consecutive days with 5 x 10(8) to 5 x 10(11) particles/kg of Ad5-delta24-RGD or controls and killed on day 8, 17, or 56. For biodistribution studies, tissue samples from 14 organ sites and serum samples were evaluated for the presence of virus with the use of quantitative polymerase chain reaction analysis. For toxicity experiments, tissue samples from more than 30 organ sites and serum samples were obtained for the assessment of vector-related tissue or laboratory effects.


RESULTS
Ad5-delta24-RGD was noted in tested samples at days 8 and 17 in animals that were treated intravenously and intraperitoneally with clearance by day 56. There were lower copies of vector noted in the blood and liver specimens of intraperitoneally treated animals. Mild peritonitis histopathologic findings were noted in rats that were treated intraperitoneally with Ad5-delta24-RGD; pathologic findings did not vary significantly with dose, over time, or in comparison to that noted in animals that were treated with Ad5-delta24.


CONCLUSIONS
These studies provide critical insights regarding Ad5-delta24-RGD dosing and anticipated toxicity for a planned clinical trial for ovarian cancer.
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John G
JG
Southern Research Institute, Birmingham, AL, USA.
Tian
Baohong
B
Schweikart
Karen
K
Tomaszewski
Joseph
J
Harris
Ray
R
Broadt
Trevor
T
Polley-Nelson
Judith
J
Noker
Patricia E
PE
Wang
Minghui
M
Makhija
Sharmila
S
Aurigemma
Rose
R
Curiel
David T
DT
Alvarez
Ronald D
RD
D000256:Adenoviridae; D000704:Analysis of Variance; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis / Q000401:mortality / Q000628:therapy*; D009842:Oligopeptides / Q000494:pharmacology*; D050130:Oncolytic Virotherapy / Q000379:methods*; D010051:Ovarian Neoplasms / Q000401:mortality / Q000628:therapy*; D016133:Polymerase Chain Reaction; D011336:Probability; D011897:Random Allocation; D051381:Rats; D011919:Rats, Inbred Strains; D012016:Reference Values; D012680:Sensitivity and Specificity; D016205:Sigmodontinae; D016019:Survival Analysis
D009842:Oligopeptides; C047981:arginyl-glycyl-aspartic acid