Smythe W R, Hwang H C, Amin K M, Eck S L, Davidson B L, Wilson J M, Kaiser L R, Albelda S M
Department of Surgery, University of Pennsylvania, Philadelphia.
Cancer Res. 1994 Apr 15;54(8):2055-9.
Transfer of the herpes simplex virus thymidine kinase (HSVtk) gene into tumor cells using retroviral vectors followed by administration of ganciclovir provides a potential strategy for the treatment of malignancy. Because of the limitations of using retroviral vectors for clinical application, the feasibility of using a recombinant adenovirus containing HSVtk was examined. Cell lines derived from human malignant mesotheliomas and non-small cell lung cancers infected with a recombinant adenovirus containing HSVtk showed strong expression of HSVtk protein as determined by immunohistochemical staining. Infection with a recombinant adenovirus containing HSVtk rendered cells sensitive to doses of ganciclovir that were 2-3 logs lower than uninfected cells or those infected with a control virus. A strong "bystander effect" was noted in mesothelioma lines; there was no diminution in the efficacy of ganciclovir treatment until the ratio of infected:uninfected cells fell below 1:10. This study thus demonstrates in vitro efficacy of an adenovirus-transduced HSVtk drug sensitization gene therapy system in thoracic malignancies. Recombinant adenovirus transfer of the HSVtk gene followed by ganciclovir may have promise as an in situ treatment for tumors.
使用逆转录病毒载体将单纯疱疹病毒胸苷激酶（HSVtk）基因导入肿瘤细胞，随后给予更昔洛韦，为恶性肿瘤的治疗提供了一种潜在策略。由于将逆转录病毒载体用于临床应用存在局限性，因此研究了使用含HSVtk的重组腺病毒的可行性。通过免疫组织化学染色测定，源自人恶性间皮瘤和非小细胞肺癌的细胞系在感染含HSVtk的重组腺病毒后，显示出HSVtk蛋白的强表达。感染含HSVtk的重组腺病毒使细胞对更昔洛韦的敏感性增强，所需剂量比未感染细胞或感染对照病毒的细胞低2 - 3个对数。在间皮瘤细胞系中观察到强烈的“旁观者效应”；直到感染细胞与未感染细胞的比例降至1:10以下，更昔洛韦治疗的疗效才会降低。因此，本研究证明了腺病毒转导的HSVtk药物致敏基因治疗系统在胸部恶性肿瘤中的体外疗效。HSVtk基因的重组腺病毒转移后给予更昔洛韦可能有望作为肿瘤的原位治疗方法。
