Adenoviral-Mediated Herpes Simplex Virus-Thymidine Kinase Gene Transfer in Vivo for Treatment of Experimental Human Melanoma
| Autor: | Dennis R. Roop, Savio L. C. Woo, David A. Greenhalgh, Ken-ichiro Kosai, Milton J. Finegold, Bernd Bonnekoh, Thomas Krieg, Donnie S. Bundman, Shu-Hsia Chen |
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| Rok vydání: | 1996 |
| Předmět: |
Ganciclovir
viruses Genetic enhancement Genetic Vectors Mice Nude Dermatology Biology Gene delivery Thymidine Kinase Biochemistry Adenoviridae Mice Genes Reporter Transduction Genetic In vivo Tumor Cells Cultured medicine cancer Animals Humans Simplexvirus Cytotoxic T cell Melanoma Molecular Biology Reporter gene Gene Transfer Techniques adenovirus Cell Biology beta-Galactosidase medicine.disease gene therapy Molecular biology nude mice Thymidine kinase Cell Division Injections Intraperitoneal medicine.drug |
| Zdroj: | Journal of Investigative Dermatology. 106:1163-1168 |
| ISSN: | 0022-202X |
| Popis: | To assess the efficacy of an in vivo adenoviral-mediated cytotoxic gene therapy, human melanomas were established in nude mice and transduced with herpes simplex virus-thymidine kinase (tk) followed by treatment with ganciclovir (GCV). In initial experiments, adenovirus (adv) containing the beta-galactosidase reporter gene was employed to determine melanoma cell infectivity in vitro. In comparison to murine melanoma cell lines B16 and K1735-M2, human A375-SM cells exhibited up to a 10-fold greater susceptibility to adenoviral transduction, similar to the degree of infectivity found for human epidermal HaCaT cells. In addition, human A375-SM melanoma cells exhibited a greater sensitivity in vitro to the cytotoxic effects of transduction with tk-adv and treatment with GCV, which was mediated by a strong bystander effect. In vivo, intratumoral injection of relatively large human melanomas (160 mm3) with 1.2 X 109 pfu of tk-adv, followed by intraperitoneal GCV treatment (60 mg/kg twice daily) over 4 days, typically resulted in a 50% reduction in melanoma growth rate compared to mock or untreated controls. Moreover, histometrical analysis employing a rigorous computerized imaging system revealed that the residual viable tumor area in the tk-adv/GCV-treated group was only one-fifth that of solvent controls. These data show that adv is a highly efficient in vivo gene delivery system to treat experimental human melanomas. In comparison to a previous murine melanoma study, human melanomas appeared to exhibit a greater sensitivity to this cytotoxic treatment in vivo, which may hold significant promise for development of effective gene therapy modalities to treat melanoma in humans. |
| Databáze: | OpenAIRE |
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