PRODRUG-ACTIVATING GENE THERAPY FOR EXPERIMENTAL GLIOMAS USING THE ESCHERICHIA COLI GPT GENE AND 6-THIOXANTHINE.

使用大肠杆菌 GPT 基因和 6-硫代黄嘌呤对实验性神经胶质瘤进行前药激活基因治疗。

• 批准号: 07671519
• 负责人: TAMIYA Takashi
• 金额: $ 1.47万
• 依托单位: OKAYAMA UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1995
• 资助国家: 日本
• 起止时间: 1995 至 1996
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07671519/
• 关键词: E.coli gpt gene; 6-thioxanthine; retrovirus vector; C6 glioma cell; prodrug-activating gene; gene therapy

A recently described strategy for the tretment of brain tumors involves the trasfer and expression of an exogenous prodrug-activating gene into the neoplastic cell, thereby rendering it capable to convert an inactive agent into an oncolytic metabolite. A gene/drug combination employs the Esherichia coli gpt gene, which encodes xanthine-guanine phosphoribosyl transferase (XGPRT) and can convert the inactive prodrug, such as 6-thioxanthine (6-TX), into the toxic metabolites.In the present study, we have investigated the usefulness of the 6-TX/gpt gene therapy paradigm for gliomas. Our in vitro results show that the prodrug, 6-TX successfully ablates C6 glioma cells that express the gpt transgene at concentrations that have little or no effect on parental C6 cells. In subcutaneous and intracerebral models of rat C6 gliomas in athymic mice, the 6-TX/gpt gene therapy strategy was found to retard tumor growth. These findings demonstrate the potential therapeutic selectivity of the 6TX/gpt gene therapy strategy and suggest the value of further studies of this modality.

最近描述的治疗脑肿瘤的策略涉及将外源性前药活化基因转移和表达到肿瘤细胞中，从而使其能够将无活性剂转化为溶瘤代谢物。大肠杆菌gpt基因编码黄嘌呤-鸟嘌呤磷酸核糖转移酶（XGPRT），可将6-硫代黄嘌呤（6-TX）等非活性前体药物转化为毒性代谢产物。我们的体外结果表明，前药6-TX成功地消融了表达gpt转基因的C6神经胶质瘤细胞，其浓度对亲本C6细胞几乎没有影响或没有影响。在裸鼠皮下和脑内大鼠C6胶质瘤模型中，发现6-TX/gpt基因治疗策略延缓肿瘤生长。这些发现表明了6 TX/gpt基因治疗策略的潜在治疗选择性，并建议进一步研究这种模式的价值。

项目成果

Tamiya T,Ono Y,Wei MX,Mroz PJ,Moolten FL,Chiocca EA: "Escherichia coli gpt gene sensitizes rat glioma cells to killing by 6-thioxanthine or 6-thioguanine." Cancer Gene Terapy. 3. 155-162 (1996)

Tamiya T、Ono Y、Wei MX、Mroz PJ、Moolten FL、Chiocca EA：“大肠杆菌 gpt 基因使大鼠神经胶质瘤细胞对 6-硫代黄嘌呤或 6-硫鸟嘌呤的杀伤敏感。”

Takashi Tamiya: "Escherichia coli gpt gene sensitizes rat glioma cells to killing by 6 thioxanthine or 6-thioguanine" Cancer Gene Therapy. 3・3. 155-162 (1996)

Takashi Tamiya：“大肠杆菌 gpt 基因使大鼠神经胶质瘤细胞对 6 硫黄嘌呤或 6-硫鸟嘌呤的杀伤敏感”，癌症基因治疗 3・3 (1996)。

Takashi Tamiya: "Transgene inheritance and retroviral infection contribute to the efficiency of gene expression in solid tumors inoculated with retroviral vector producer cells." Gene Therapy. 2. 531-538 (1995)

Takashi Tamiya：“转基因遗传和逆转录病毒感染有助于提高接种逆转录病毒载体生产细胞的实体瘤中的基因表达效率。”

Takashi Tamiya: "Escherichia coli gpt gene sensitizes rat glioma cells to killing by 6 thioxanthine or 6-thioguanine" Cancer Gene Therapy. 3. 155-162 (1996)

Takashi Tamiya：“大肠杆菌 gpt 基因使大鼠神经胶质瘤细胞对 6 硫黄嘌呤或 6-硫鸟嘌呤的杀伤敏感”癌症基因疗法。

Yasuhiro Ono: "Malignant astrocytomas with homozygous CDKN2/p16 gene delctions have higher Ki-67 proliferation indicesi" Journal of Neuropathology and Experimental Neurology!. 55. 1026-1031 (1996)

Yasuhiro Ono：“具有纯合 CDKN2/p16 基因缺失的恶性星形细胞瘤具有更高的 Ki-67 增殖指数”《神经病理学和实验神经学杂志》！