Vesicular stomatitis virus G pseudotyped retrovector mediates effective in vivo suicide gene delivery in experimental brain cancer.

摘要: Direct in vivo tumor-targeting with “suicide” viral vectors is limited by either inefficient gene transfer ( i.e. , retroviral vectors) or indiscriminate of a conditionally toxic to surrounding nonmalignant tissue adenoviral vectors). Retrovectors pseudotyped the vesicular stomatitis virus G protein (VSVG) may serve as remedy this conundrum. These particles differ from standard murine retroviruses their very broad tropism and capacity be concentrated ultracentrifugation without loss activity. We propose that VSVG-typed retrovector can used for efficient tumor-specific herpes simplex thymidine kinase (TK) delivery . To test hypothesis, we developed bicistronic vector expresses TK green fluorescence (pTKiGFP). The 293GPG packaging cell line was generate vTKiGFP retroparticles. In cytotoxicity assays, vTKiGFP-transduced human glioma lines were sensitized cytotoxic effects gangciclovir (GCV) 10,000-fold. Subsequently, titer 2.3 × 10 cfu/ml. tested antitumor activity retroparticles rat C6 model brain cancer. Concentrated stock (9 μl volume) injected stereotactically preestablished intracerebral tumor. rats treated GCV days. Control (no GCV) had mean survival 38 days (range, 20–52 days). Sections performed on postmortem revealed large tumors evidence high efficiency expression (as assessed GFP fluorescence). Fluorescence restricted malignant tissue. experimental group (GCV treated), 8 12 remain alive well >120 after implantation. conclusion, at transducing vitro leads significant sensitization. Recombinant titers allow intratumoral doses. therapeutic reagent has been demonstrated preclinical