MECHANISMS OF BRAIN TUMOR CELL DEATH AFTER GENE TRANSFER

基因转移后脑肿瘤细胞死亡的机制

• 批准号: 2735690
• 负责人: Harold David Shine
• 金额: $ 17.04万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-15 至 2000-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2735690
• 关键词: Adenoviridae; Alphaherpesvirinae; animal genetic material tag; brain neoplasms; cell death; colony stimulating factor; drug metabolism; enzyme activity; ganciclovir; gene therapy; interleukin 12; interleukin 2; laboratory rat; neoplasm /cancer genetics; neoplasm /cancer immunology; neoplasm /cancer therapy; nonhuman therapy evaluation; thymidine kinase; transfection; transfection /expression vector; tumor necrosis factor alpha; virus genetics

DESCRIPTION (Adapted from Applicant's Abstract): Patients with malignant brain tumors have poor prognoses even when treated with the best conventional therapy of surgical resection, radiation therapy, and chemotherapy. Hence, investigation of new therapeutic approaches for these neurological diseases is needed. One novel approach has been the introduction of genes into tumor cells that render them sensitive to cytotoxic drugs. Previous experiments demonstrated a robust tumoricidal activity against experimental brain using the herpes simplex virus thymidine kinase (HSVtk) gene that converts ganciclovir (GCV) to a form that is cytotoxic to rapidly dividing cells. The treatment was not as effective when tested with tumors generated from cell lines with lesser immunogenicity. These observations suggest that the tumoricidal activity results from two processes: (1) direct tumoricidal activity of HSV-tk conversion of GCV and (2) cellular immune responses. The applicant will test the hypothesis that cell death from HSV-tk/GCV treatment causes antigen presenting cells (APCS) to activate cytotoxic T lymphocyte (CTL) precursors which then destroy residual tumor and prohibit further cell growth. The presence of an immunological component can explain the weaker tumoricidal activity observed in models in which the hosts were immunoincompetent or in which the cell lines were less immunogenic. If this hypothesis is correct then (1) depending on their immunogenicity, different tumor cell lines will elicit different immune responses to HSV-tk/GCV-mediated cell death in vivo as measured by immunological analyses, and (2) neuroimmune modulation by cytokine gene transfer will elicit a heightened CTL response to the tumor cells. The objective of this project is to delineate the neuroimmunological mechanisms of cell death in experimental brain tumors following initial killing by HSV-tk/GCV treatment. The Specific Aims are to: (1) characterize the immunological response to HSV-tk/GCV-mediated death of syngeneic experimental tumors generated by 3 glial tumor cell lines with different degrees of immunogenic potential, (2) measure the tumoricidal effects of in situ immune modulation by adenovirus-mediated transduction of tumors with the genes for the cytokines IL-2, GM-CSF, TNFA. and IL-12 with and without HSV-tk/GCV treatment. and (3) characterize the immunological responses elicited by adenoviral-mediated cytokine immune modulation with and without HSV-tk/GCV treatment.

描述（改编自申请人的摘要）：恶性患者 即使用最好的治疗，脑肿瘤的预后也很差 传统的手术切除，放射治疗和 化学疗法。 因此，研究这些新的治疗方法 需要神经疾病。 一种新颖的方法是 将基因引入肿瘤细胞，使其对它们敏感 细胞毒性药物。 以前的实验证明了强大的肿瘤 使用单纯疱疹胸苷对实验大脑的活性 将Ganciclovir（GCV）转换为形式的激酶（HSVTK）基因 细胞毒性到快速分裂的细胞。 治疗不那么有效 用较少的细胞系产生的肿瘤测试 免疫原性。 这些观察结果表明肿瘤活性 来自两个过程的结果：（1）HSV-TK的直接肿瘤活性 GCV和（2）细胞免疫反应的转化。 申请人将 测试HSV-TK/GCV治疗的细胞死亡的假设会引起抗原 呈现细胞（APC）激活细胞毒性T淋巴细胞（CTL）前体 然后破坏残留的肿瘤并禁止进一步的细胞生长。 这 免疫学成分的存在可以解释较弱的肿瘤 在宿主具有免疫能力或在中的模型中观察到的活性 细胞系的免疫原性较低。 如果这个假设是正确的 然后（1）根据其免疫原性，不同的肿瘤细胞系将 在体内引起对HSV-TK/GCV介导的细胞死亡的不同免疫反应 通过免疫分析测量，（2）通过 细胞因子基因转移将引起对肿瘤的CTL反应增强 细胞。 该项目的目的是描述神经免疫学 初始脑肿瘤中细胞死亡的机制 通过HSV-TK/GCV治疗杀死。 具体目的是：（1） 表征对HSV-TK/GCV介导的死亡的免疫学反应 由3个神经胶质肿瘤细胞系产生的合成性实验肿瘤， 不同程度的免疫原性，（2）测量肿瘤性 腺病毒介导的原位免疫调节的影响 具有细胞因子IL-2，GM-CSF，TNFA的基因的肿瘤。 和IL-12 并且没有HSV-TK/GCV处理。 （3）特征免疫学 腺病毒介导的细胞因子免疫调节引起的反应 并且没有HSV-TK/GCV处理。