TY - JOUR
T1 - Local inflammatory response and vector spread after direct intraprostatic injection of a recombinant adenovirus containing the herpes simplex virus thymidine kinase gene and ganciclovir therapy in mice
AU - Timme, Terry L.
AU - Hall, Simon J.
AU - Barrios, Roberto
AU - Woo, Savio L C
AU - Aguilar-Cordova, Estuardo
AU - Thompson, Timothy C.
N1 - Copyright:
Copyright 2005 Elsevier Science B.V., Amsterdam. All rights reserved.
PY - 1998
Y1 - 1998
N2 - We have evaluated the safety and potential toxicity of an adenoviral vector containing the herpes simplex virus thymidine kinase gene (adenovirus/Rous sarcoma virus thymidine kinase in a preclinical model for prostate cancer. Clinical grade vector prepared for human trials was injected directly into the dorsolateral prostate of C57BI/6 mice in a volume of 5 μL at doses of 2.5 × 106, 2.5 × 107, or 2.5 × 108. The mice received intraperitoneal injections of either ganciclovir or saline twice daily for 6 days, beginning 12 hours after vector injection. Representative tissues and fluids were collected for evaluation the day after the final dose. Microscopic pathologic evaluation revealed inflammatory infiltration without necrosis within the dorsolateral and ventral prostate, but no necrosis or leukocyte infiltration was observed in sample tissues from lung, liver, large intestine, bladder, seminal vesicle, testis, or epididymis. DNA was extracted from the above tissues as well as pelvic lymph nodes, blood, seminal fluid, urine, and sperm and analyzed by polymerase chain reaction for the presence of vector sequences. The vector was readily detected in the dorsolateral prostate, the site of injection. The amount of vector detected was reduced in some samples from ganciclovir-treated animals. At the highest dose, vector spread was observed in the ventral prostate, seminal vesicle, testis, pelvic lymph nodes, gut, and liver. Spread to the testis was observed in only one animal. Vector DNA was not detected in urine, seminal fluid, or sperm but was detected in the blood of one animal. This adenoviral vector, therefore, appears to have minimal spread to sites distant from the site of injection and no detectable pathological sequelae within this dose range in this preclinical model for prostate cancer, which may be generalizable to other solid tumors.
AB - We have evaluated the safety and potential toxicity of an adenoviral vector containing the herpes simplex virus thymidine kinase gene (adenovirus/Rous sarcoma virus thymidine kinase in a preclinical model for prostate cancer. Clinical grade vector prepared for human trials was injected directly into the dorsolateral prostate of C57BI/6 mice in a volume of 5 μL at doses of 2.5 × 106, 2.5 × 107, or 2.5 × 108. The mice received intraperitoneal injections of either ganciclovir or saline twice daily for 6 days, beginning 12 hours after vector injection. Representative tissues and fluids were collected for evaluation the day after the final dose. Microscopic pathologic evaluation revealed inflammatory infiltration without necrosis within the dorsolateral and ventral prostate, but no necrosis or leukocyte infiltration was observed in sample tissues from lung, liver, large intestine, bladder, seminal vesicle, testis, or epididymis. DNA was extracted from the above tissues as well as pelvic lymph nodes, blood, seminal fluid, urine, and sperm and analyzed by polymerase chain reaction for the presence of vector sequences. The vector was readily detected in the dorsolateral prostate, the site of injection. The amount of vector detected was reduced in some samples from ganciclovir-treated animals. At the highest dose, vector spread was observed in the ventral prostate, seminal vesicle, testis, pelvic lymph nodes, gut, and liver. Spread to the testis was observed in only one animal. Vector DNA was not detected in urine, seminal fluid, or sperm but was detected in the blood of one animal. This adenoviral vector, therefore, appears to have minimal spread to sites distant from the site of injection and no detectable pathological sequelae within this dose range in this preclinical model for prostate cancer, which may be generalizable to other solid tumors.
KW - Adenovirus
KW - Gene therapy
KW - Inflammation
KW - Prostate
KW - Safety
UR - http://www.scopus.com/inward/record.url?scp=0032020501&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0032020501&partnerID=8YFLogxK
M3 - Article
C2 - 9570298
AN - SCOPUS:0032020501
SN - 0929-1903
VL - 5
SP - 74
EP - 82
JO - Cancer Gene Therapy
JF - Cancer Gene Therapy
IS - 2
ER -