Treatment of Experimental Human Mesothelioma Using Adenovirus Transfer of the Herpes Simplex Thymidine Kinase Gene

ObjectiveThe authors demonstrate the ability of an adenovirus vector expressing the herpes simplex thymidine klnase (HSV tk) gene to treat human malignant mesothelioma growing within the peritoneal cavity of severe combined immunodeficient (SCID) mice. Background DataIntroduction of the HSV tk gene into tumor cells renders them sensitive to the antiviral drug ganciclovir (GCV). This approach has been used previously to treat experimental brain tumors. Although malignant mesothelioma is refractory to current therapies, its localized nature and the accessibility of the pleural space make it a potential target for a similar type of in vivo gene therapy using adenovirus. MethodsAn adenovirus containing the HSV tk gene (Ad.RSV tk) was used to transduce mesothelioma cells in vitro. These cells were then injected into the flanks of SCID mice. Ad.RSV tk was also injected directly into the peritoneal cavity of SCID mice with established human mesothelioma tumors. Mice were subsequently treated for 7 days with GCV at a dose of 5 mg/kg. ResultsMesothelioma cells transduced in vitro with Ad.RSV tk formed nodules when injected in the subcutaneous tissue. These tumors could be eliminated by the administration of GCV, even when as few as 10% of cells were transduced to express HSV tk (bystander effect). Administration of Ad.RSV tk into the peritoneal space of animals with established multifocal human mesothelioma followed by GCV therapy resulted in the eradication of macroscopic tumor in 90% of animals and microscopic tumor in 80% of animals when evaluated after 30 days. The median survival of animals treated with Ad.RSV tk/GCV was significantly longer than that of control animals treated with similar protocols.

目的：作者展示了一种表达单纯疱疹胸苷激酶（HSV - tk）基因的腺病毒载体治疗在重症联合免疫缺陷（SCID）小鼠腹腔内生长的人类恶性间皮瘤的能力。 背景资料：将HSV - tk基因导入肿瘤细胞使其对抗病毒药物更昔洛韦（GCV）敏感。这种方法先前已用于治疗实验性脑肿瘤。尽管恶性间皮瘤对当前的治疗方法有抵抗性，但其局部性以及胸膜腔的可及性使其成为使用腺病毒进行类似体内基因治疗的潜在靶点。 方法：含有HSV - tk基因的腺病毒（Ad.RSV - tk）用于在体外转导间皮瘤细胞。然后将这些细胞注射到SCID小鼠的侧腹。Ad.RSV - tk也被直接注射到患有已形成的人类间皮瘤肿瘤的SCID小鼠的腹腔内。随后小鼠以5mg/kg的剂量接受更昔洛韦治疗7天。 结果：用Ad.RSV - tk在体外转导的间皮瘤细胞在皮下组织注射时形成结节。即使只有10%的细胞被转导表达HSV - tk（旁观者效应），通过给予更昔洛韦也能消除这些肿瘤。在患有已形成的多灶性人类间皮瘤的动物腹腔内给予Ad.RSV - tk，接着进行更昔洛韦治疗，30天后评估时，90%的动物宏观肿瘤被根除，80%的动物微观肿瘤被根除。用Ad.RSV - tk/GCV治疗的动物的中位生存期明显长于用类似方案治疗的对照动物。