Ram Z, Walbridge S, Heiss J D, Culver K W, Blaese R M, Oldfield E H
Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.
J Neurosurg. 1994 Mar;80(3):535-40. doi: 10.3171/jns.1994.80.3.0535.
The authors have recently shown the feasibility of eradicating brain tumors using in vivo retroviral-mediated transduction of tumors with the herpes simplex thymidine kinase (HStk) gene and ganciclovir therapy. However, thymidine kinase-transduced subcutaneous tumors in immunocompromised (athymic) mice were less responsive to this therapy than in immunocompetent animals, suggesting a role of the immune system in the process of tumor eradication. Broad suppression of humoral and cell-mediated immunity is found in patients with malignant gliomas. Interleukin-2 (IL-2) production and IL-2 receptor expression are decreased in gliomas patients. These findings and the proposed association between lymphocytic infiltration of brain tumors and survival suggest that immune response modifiers may be useful in treating glioma patients. To evaluate the role of local cytokine expression by tumor cells, alone or combined with HStk gene transfer and ganciclovir therapy, the authors investigated the efficacy of tumor (9L gliosarcoma) eradication in Fischer rats by in vitro and in vivo tumor transduction with the IL-2 gene alone or with a combined vector carrying both the HStk and IL-2 genes. Tumors injected with HStk vector-producer cells alone, with or without ganciclovir, and rats inoculated in the brain and subcutaneously with 9L cells that had previously been transduced in vitro served as controls. Murine vector-producer cells (3 x 10(6)/50 microliters) were injected into the brain tumors 7 days after tumor inoculation. Ganciclovir (15 mg/kg) was administered intraperitoneally twice daily for 10 days to animals that received HStk with or without IL-2 vector-producer cells, starting 5 days after producer-cell injection. The experiment was repeated with continuous daily treatment of all rats with oral dexamethasone (0.5 mg/kg). Rats were sacrificed 21 days after tumor inoculation, and the brains were removed for histological and immunohistochemical analysis for IL-2. Within each experimental group, tumors were found in a similar proportion in the dexamethasone-treated and untreated rats. Large brain tumors developed in all 10 rats that had been inoculated with 9L cells which had been pretransduced in vitro with the IL-2 gene, whereas only three of eight rats receiving subcutaneous inoculation of similar cells developed palpable tumors. No enhancement of tumor eradication was observed by adding the IL-2 gene in the HStk vector construct compared to the use of the vector with HStk alone. Lymphocytic infiltration was absent in all dexamethasone-treated rats but was observed in all treatment groups not receiving steroids.(ABSTRACT TRUNCATED AT 400 WORDS)
作者最近已证明,通过单纯疱疹病毒胸苷激酶(HStk)基因的体内逆转录病毒介导的肿瘤转导和更昔洛韦治疗来根除脑肿瘤是可行的。然而,免疫受损(无胸腺)小鼠中经胸苷激酶转导的皮下肿瘤对这种治疗的反应不如免疫健全动物,这表明免疫系统在肿瘤根除过程中发挥作用。恶性胶质瘤患者存在体液免疫和细胞介导免疫的广泛抑制。胶质瘤患者的白细胞介素-2(IL-2)产生和IL-2受体表达降低。这些发现以及脑肿瘤淋巴细胞浸润与生存之间的假定关联表明,免疫反应调节剂可能对治疗胶质瘤患者有用。为了评估肿瘤细胞局部细胞因子表达单独或与HStk基因转移及更昔洛韦治疗联合的作用,作者通过单独用IL-2基因或用携带HStk和IL-2基因的联合载体进行体外和体内肿瘤转导,研究了在Fischer大鼠中根除肿瘤(9L胶质肉瘤)的疗效。单独注射HStk载体产生细胞(无论有无更昔洛韦)的肿瘤,以及预先在体外转导过的9L细胞脑内接种和皮下接种的大鼠作为对照。肿瘤接种7天后,将鼠载体产生细胞(3×10⁶/50微升)注入脑肿瘤。从注射产生细胞5天后开始,对接受HStk(无论有无IL-2载体产生细胞)的动物每天腹腔注射两次更昔洛韦(15毫克/千克),共10天。对所有大鼠持续每日口服地塞米松(0.5毫克/千克)重复该实验。肿瘤接种21天后处死大鼠,取出大脑进行组织学和IL-2免疫组织化学分析。在每个实验组中,地塞米松治疗组和未治疗组中发现肿瘤的比例相似。在所有10只接种了体外预先用IL-2基因转导的9L细胞的大鼠中都出现了大的脑肿瘤,而在8只皮下接种类似细胞的大鼠中只有3只出现了可触及的肿瘤。与单独使用含HStk的载体相比,在HStk载体构建体中添加IL-2基因未观察到肿瘤根除增强。所有地塞米松治疗的大鼠均无淋巴细胞浸润,但在所有未接受类固醇治疗的组中均观察到淋巴细胞浸润。(摘要截至于400字)