In vivo transfer of the human interleukin-2 gene: negative tumoricidal results in experimental brain tumors.
In vivo transfer of the human interleukin-2 gene: negative tumoricidal results in experimental brain tumors.
复制标题
人白细胞介素 2 基因的体内转移：实验性脑肿瘤的阴性杀瘤结果。
作者：
Z. Ram;S. Walbridge;John D Heiss;K. Culver;R. Blaese;E. Oldfield
作者最近显示了使用体内逆转录病毒介导的单纯疱疹胸苷激酶（HStk）基因转导和更昔洛韦治疗根除脑肿瘤的可行性。然而，胸腺嘧啶核苷激酶转导的皮下肿瘤在免疫功能低下（无胸腺）的小鼠比在免疫功能正常的动物，这种治疗的反应较低，这表明在肿瘤根除的过程中的免疫系统的作用。在恶性胶质瘤患者中发现广泛的体液和细胞介导的免疫抑制。胶质瘤患者白细胞介素-2（IL-2）的产生和IL-2受体的表达减少。这些发现和脑肿瘤淋巴细胞浸润与生存率之间的相关性表明，免疫应答调节剂可能有助于治疗胶质瘤患者。为了评估肿瘤细胞局部细胞因子表达的作用，单独或与HStk基因转移和更昔洛韦治疗相结合，作者研究了通过单独或与携带HStk和IL-2基因的组合载体进行IL-2基因体外和体内肿瘤转导在Fischer大鼠中根除肿瘤（9 L胶质肉瘤）的功效。单独注射HStk载体生产细胞、加或不加更昔洛韦的肿瘤，以及在脑中和皮下接种先前在体外转导的9 L细胞的大鼠作为对照。肿瘤接种后7天，将小鼠载体生产细胞（3 × 10（6）/50微升）注射到脑肿瘤中。更昔洛韦（15 mg/kg）腹腔内给药，每天两次，持续10天的动物接受HStk与或不与IL-2载体生产细胞，生产细胞注射后5天开始。重复实验，每天连续给所有大鼠口服地塞米松（0.5 mg/kg）。在肿瘤接种后21天处死大鼠，取出脑进行组织学和IL-2的免疫组织化学分析。在每个实验组中，地塞米松治疗组和未治疗组大鼠的肿瘤比例相似。在所有10只接种了9 L细胞的大鼠中均发生了大的脑肿瘤，9 L细胞在体外预转导了IL-2基因，而接受皮下接种类似细胞的8只大鼠中只有3只发生了可触及的肿瘤。与单独使用具有HStk的载体相比，通过在HStk载体构建体中添加IL-2基因没有观察到肿瘤根除的增强。在所有地塞米松给药大鼠中均未观察到淋巴细胞浸润，但在所有未接受类固醇的给药组中均观察到淋巴细胞浸润。（400字处截断摘要）
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)
通过表达反义胰岛素样生长因子 I RNA 的免疫原性 C6 细胞治疗和预防大鼠胶质母细胞瘤。
DOI：
10.1126/science.8418502
发表时间：
1993
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Trojan,J;Johnson,TR;Rudin,SD;Ilan,J;Tykocinski,ML;Ilan,J
通讯作者：
Ilan,J
原发性颅内肿瘤患者淋巴细胞活化受损的细胞动力学基础。
DOI：
--
发表时间：
1984
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Elliott,LH;Brooks,WH;Roszman,TL
通讯作者：
Roszman,TL