A novel ex vivo model system for evaluation of conditionally replicative adenoviruses therapeutic efficacy and toxicity

摘要: Purpose: Current animal tumor models are inadequate for the evaluation of toxicity and efficacy conditionally replicative adenoviruses. A novel model system is needed that will provide insight into anticipated therapeutic index adenoviruses preclinically. We endeavored to show a system, which involves ex vivo adenovirus in thin, precision-cut slices human primary liver. Experimental Design: The Krumdieck thin-slice tissue culture was used obtain xenografts ovarian cancer cell lines, tumors, determined viability over period 36 48 hours by ([3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxphenyl2-(4-sulfophenyl)-2H-tetrazolium, inner salt)]) (MTS) assay. In vitro Hey cells, xenografts, or liver were infected with 500vp/cell either replication competent wild-type (Ad5/3wt), (Ad5/3cox-2), deficient (Ad5/3luc1). At 12-, 24-, 36-hour intervals, these quantitative reverse transcription-PCR adenoviral E4 copy number. Results: Primary able maintain up after infection nonreplicative virus (Ad5luc1). Infection Ad5/ 3cox-2 showed consistent seen cells an setting. both Ad5/3wt Ad5/3cox time period. Human but relative reduction indicative conditional “liver off” phenotype, thus predicting lower toxicity. Conclusions: represents stringent method vectors allows assessment replication. This first study incorporate this specificity Also, valid means preclinical assay potential adenovirus-based hepatotoxicities, providing powerful tool determine clinical translation