Gene therapy for augmentation chemosentivities to anticancer drugs with improvement of therapeutic index

人们正在研究改进人类癌症治疗的新方法。我们已经发现，在胃癌或结肠癌患者中，对5-FU的敏感性与胸腺嘧啶磷酸化酶（TP）和胸腺嘧啶激酶（TK）水平之间存在很强的关联。此外，利用质粒载体将TP/PD-ECGF cDNA成功转染到PC9细胞后，利用转染的细胞部分阐明了多西氟定和5-FU敏感性增强的体外机制，并获得了增强中包含的一种细胞附着体的旁观者效应的验证数据。我们的一部分研究工作是与东京继科医科大学细菌学一系合作，首次成功地产生了一种含有TP/PD-ECGF cDNA的逆转录病毒载体，我们现在正在进行研究，以进一步阐明对氟嘧啶化学敏感性的增强机制。与此同时，血管生成肽之一的TP酶在腹膜播种细胞和体外癌细胞中的水平急剧下降。综上所述，我们可以认为这个新开发的含有TP/PD-ECGF cDNA的逆转录病毒载体可能对肿瘤血管生成的研究有很大的帮助。因此，像这样的病毒导向酶前药物治疗的研究将有可能为改善癌症化疗提供宝贵的方法。

Novel approaches are being investigated for improvement of therapies of human cancers. We have identified a strong association between sensitivity to 5-FU and levels of thymidine phosphorylase (TP) and thymidine kinase (TK) in either human gastric or colon cancer. In addition, after TP/PD-ECGF cDNA was successfully transfected into PC9 cells with use of a plasmid vector, the in vitro mechanism of augmentation of sensitivities to Doxifluridine and 5-FU was partly clarified, by use of the transfected cells, with obtaining confirmatory data of a bystander effect of a type of cell attachment included in the augmentation. A part of our research works, collaborating with the Department of Bacteriology I in Tokyo Jikeikai Medical College, firstly succeeded in yielding a retroviral vector involving TP/PD-ECGF cDNA and we are now conducting the investigation for further clarification of augmentation mechanism of chemosensitivities to Fluoro-pyrimidines. In the mean time, the level of TP enzyme, one of angiogenic peptides, is drastically decreased in both peritoneal seeding cells and in vitro cancer cells. Taken together, it can be considered that this newly developed retroviral vector involving TP/PD-ECGF cDNA may be substantially useful for study of tumor angiogenesis. Thus, the study of a virally directed enzyme prodrug therapy like this would have potential to propose invaluable methods for improvement of cancer chemotherapies.