Bonnekoh B, Greenhalgh D A, Bundman D S, Eckhardt J N, Longley M A, Chen S H, Woo S L, Roop D R
Department of Cell Biology, Baylor College of Medicine, Houston, Texas 77030.
J Invest Dermatol. 1995 Mar;104(3):313-7. doi: 10.1111/1523-1747.ep12664614.
To assess the potential of an in vivo, adenovirus-mediated gene therapy approach for the treatment of malignant melanoma, the efficacy of adenovirus-mediated herpes simplex virus thymidine kinase gene (HSV-Ek) transfer and administration of ganciclovir (GCV) was investigated using a nude mouse model. Initially, B16 murine melanoma cells were efficiently transduced in vitro by a recombinant replication-defective adenovirus containing the HSV-tk gene (ADV/RSVtk), and rendered sensitive to cell killing by 10 micrograms/ml GCV. A significant "bystander effect" was observed at low multiplicity of infection in comparison of cell killing to control B16 transduction by adenovirus containing the beta-galactosidase gene (ADV/RSV-beta-gal). In vivo, melanomas established from subcutaneous injection of 4 x 10(5) B16 cells were injected after 14 d with 1 x 10(10) ADV/RSV-tk viral particles. Subsequent treatment for 6 d with GCV resulted in an inhibition of melanoma growth, with an approximately 40-50% reduction in melanoma volume in comparison to controls in repeated experiments. These data demonstrate that adenovirus-mediated gene transfer can function as an efficient delivery system to reduce established tumor burden in vivo. This result may hold significant promise for the development of effective in situ gene therapy for melanoma in humans.
为评估体内腺病毒介导的基因治疗方法用于治疗恶性黑色素瘤的潜力，利用裸鼠模型研究了腺病毒介导的单纯疱疹病毒胸苷激酶基因（HSV-tk）转移及给予更昔洛韦（GCV）的疗效。最初，含HSV-tk基因的重组复制缺陷型腺病毒（ADV/RSVtk）在体外高效转导B16鼠黑色素瘤细胞，并使其对10微克/毫升的GCV诱导的细胞杀伤敏感。与含β-半乳糖苷酶基因的腺病毒（ADV/RSV-β-gal）转导的对照B16细胞相比，在低感染复数时观察到显著的“旁观者效应”。在体内，皮下注射4×10⁵个B16细胞建立黑色素瘤，14天后注射1×10¹⁰个ADV/RSV-tk病毒颗粒。随后用GCV治疗6天导致黑色素瘤生长受到抑制，在重复实验中，与对照组相比，黑色素瘤体积减少约40 - 50%。这些数据表明腺病毒介导的基因转移可作为一种有效的递送系统，以减轻体内已形成的肿瘤负担。这一结果可能为人类黑色素瘤有效原位基因治疗的发展带来重大希望。
