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

增强抗癌药物化学敏感性并改善治疗指数的基因治疗

• 批准号: 10470265
• 负责人: TANIGAWA Nobuhiko
• 金额: $ 4.1万
• 依托单位: Osaka Medical College
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B).
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-10470265/
• 关键词: gene therapy; augmentation of chemosensitivity to anticancer drugs; Fluoro-pyrimidine; Thymidine phosphorylase; PD-ECGF; retroviral vector; digestive cancer; angiogenesis; PD-GCGF; retroviral vcctor

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.

人们正在研究新的方法来改进人类癌症的治疗方法。我们发现，在人类胃癌或结肠癌中，对5-FU的敏感性与胸苷磷酸化酶(TP)和胸苷激酶(TK)的水平有很强的相关性。此外，用质粒载体成功地将TP/PD-ECGF基因导入PC9细胞后，部分阐明了该细胞对多西氟尿苷和5-氟尿嘧啶增敏的体外机制，并获得了该增敏中包含的一种细胞附着的旁观者效应的确证数据。我们的部分研究工作是与东京时经医科大学细菌学I教研室合作，首次成功地获得了携带TP/PD-ECGF基因的逆转录病毒载体，目前我们正在进行进一步研究，以进一步阐明氟嘧啶类药物的化疗增敏机制。同时，无论是在腹膜种子细胞还是在体外癌细胞中，血管生成多肽TP酶的水平都显著降低。综上所述，该逆转录病毒载体携带TP/PD-ECGF基因可用于肿瘤血管生成的研究。因此，像这样的病毒导向酶前药疗法的研究将有可能为改进癌症化疗提出宝贵的方法。

项目成果

M.Ohtani: "Impact of expression of cyclin-dependent kinase inhibitor p27k^<klrl> and apoptosis in tumor cells on overall survival of patients with non-early gastric carcimoma" Cancer. (in press).

M.Ohtani：“细胞周期蛋白依赖性激酶抑制剂 p27k^<klrl> 的表达和肿瘤细胞凋亡对非早期胃癌患者总体生存的影响”癌症。

M.Ohtani: "Impact of the expression of cyclin-dependent kinase inhibitor p27^<kip1> and apoptosis in tumor cells on the overall survival of patients with non-early stage gastric carcinoma"Cancer. 85(8). 1711-1718 (1999)

M.Ohtani：“细胞周期蛋白依赖性激酶抑制剂 p27^<kip1> 的表达和肿瘤细胞凋亡对非早期胃癌患者总体生存的影响”癌症。

T.Tenjyo: "Prognostic significance of p27^<kip1> protein expression and spontaneous apoptosis in patients with colorectal adenocarcinomas"Oncology. 58. 45-51 (2000)

T.Tenjyo：“结直肠腺癌患者中 p27^<kip1> 蛋白表达和自发性细胞凋亡的预后意义”肿瘤学。

C-D.Lu: "Expression of a novel antiapoptosis gene,survivin,correlated with tumor cell apoptosis and p53 accumulation in gastric carcinoma" Cancer Research. 58. 1808-1812 (1998)

C-D.Lu：“一种新型抗凋亡基因生存素的表达，与胃癌中肿瘤细胞凋亡和p53积累相关”癌症研究。

C-D.Lu: "Loss of p27^<kip1> expression independently predicts poor prognosis for resectable pancreatic adenocarcinomas"Cancer. 85. 1250-1260 (1999)

C-D.Lu：“p27^<kip1> 表达的缺失独立预测可切除胰腺腺癌的不良预后”癌症。