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

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。

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.