Oncolysis of prostate cancers induced by vesicular stomatitis virus in PTEN knockout mice.
Vesicular stomatitis virus (VSV) is an oncolytic virus which selectively infects and kills cancer cells. The goal of the present study was to determine the safety and efficacy of VSV treatment of prostate tumors that arise in situ in immunocompetent, transgenic prostate-specific PTEN-null (PTEN(-/-)) mice. Interferon-sensitive VSV(AV3 strain), which expresses luciferase, was injected intraprostatically into tumor-bearing PTEN(-/-) and control mice and then monitored for tissue bioluminescence over 96 hours. Virus readily dispersed throughout the bodies of mice after only 3 hours; however, it persisted at high levels for >72 hours in PTEN(-/-) mice, but at relatively low levels and for only approximately 48 hours in controls. Plaque assays provided a similar pattern, with much higher concentrations of replicating virus in prostates of PTEN(-/-) mice than in controls. Transient, low levels of virus were detected in the spleens of both groups. Apoptotic analyses by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining revealed that VSV(AV3) is able to selectively infect and kill prostate cells in PTEN(-/-) mice, while sparing normal cells in control mice. The primary mechanism for cell kill is apparently apoptotic oncolysis as opposed to neutrophil invasion as has been reported using xenograft models. These results suggest that control of locally advanced human prostate cancer may be achievable through intraprostatic injection and amplification of a safe oncolytic virus, such as VSV(AV3).
Vancouver Prostate Centre, Department of Medicine, University of British Columbia, Vancouver, British Columbia V6H 3Z6, Canada.
Maryam
M
Moussavi
Ladan
L
Fazli
Howard
H
Tearle
Yubin
Y
Guo
Michael
M
Cox
John
J
Bell
Christopher
C
Ong
William
W
Jia
Paul S
PS
Rennie
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002277:Carcinoma / Q000235:genetics / Q000473:pathology / Q000628:therapy* / Q000821:virology; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000502:physiology; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000502:physiology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy* / Q000821:virology; D014709:Vero Cells; D014721:Vesicular stomatitis Indiana virus / Q000502:physiology*; D019562:Viral Load / Q000235:genetics / Q000502:physiology; D023041:Xenograft Model Antitumor Assays
D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse