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The purpose of this study was to examine the toxicity of combining oncolytic adenovirus-mediated cytotoxic and interleukin 12 (IL-12) gene therapy in a preclinical model to support future phase 1 trials. One hundred and twenty C57BL/6 male mice received an intraprostatic injection of saline ( n = 24) or an oncolytic adenovirus (Ad5-yCD/ mu TK SR39  rep -mIL12) expressing two suicide genes and mouse IL-12 ( n = 96). The adenovirus was administered at three dose levels (1.3 × 10 6 , 1.3 × 10 7 , 1.3 × 10 8 vp/kg) followed by 2 weeks of 5-flurocytosine (5-FC) and gancliclovir (GCV) prodrug therapy. There were no premature deaths. Daily observations of animals did not reveal any obvious clinical problems throughout the 78-day in-life phase of the study. Animals in the highest adenovirus dose group exhibited lymphopenia and transaminitis on day 3, both of which resolved by day 17. Except for mild inflammation of the prostate and seminal vesicles, histopathology of major organs was largely unremarkable. IL-12 and interferon-gamma levels in prostate and serum peaked on day 3 and were either undetectable or returned to baseline levels by day 17. No adenoviral DNA was detected in serum in any group at any time point. The results demonstrate that local administration of an oncolytic adenovirus expressing two suicide genes and IL-12 is well tolerated and support moving this investigational approach into human trials.

Preclinical toxicology of oncolytic adenovirus-mediated cytotoxic and interleukin-12 gene therapy for prostate cancer