Establishment of gene therapy against bladder cancer utilizing gelsolin gene and a dominant negative ras mutant

利用凝溶胶蛋白基因和显性失活ras突变体建立针对膀胱癌的基因治疗

基本信息

批准号：
12470326
负责人：
SHINOHARA Nobuo
金额：
$ 4.03万
依托单位：
Hokkaido University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12470326/
关键词：
Human bladder cancer cell lines Gelsolin Gene Therapy ras suppressor mutant Regulation of expression intravesical administration enhanced effect 同所移植腫瘍 Ras抑制変異体アデノウィルスベクタ

项目摘要

Initially, we investigated the in vivo efficacy of gene therapy with the gelsolin gene in nude mice with human bladder cancer cell lines. In this analysis, we used orthotopically-implanted human bladder cancer cells in nude mice. By transurethral inoculation of adenovirus-containing Gelsolin gene, cellular growth was strongly suppressed in human bladder cancer cell lines (UMUC-2, KU-7), compared to the inoculation of control vector. With regard to the basic mechanism of the expression of gelsolin gene in human bladder cancer, deacethylation of the nuclear histone in the promoter lesion of the gelsolin gene is shown to be important and administration of trycostatin to the human bladder cancer induced the enhanced expression of gelsolin gene in human bladder cancer cells.We also examined whether N116Y, which derived from the v-H-ras oncogene by substituting the asparagine-116 with tyrosine, can also inhibit the growth of human bladder cancer cell lines. In this analysis, we used the N116Y ras mutant in vivo via an N116Y-containing adenoviral vector (AdCMV-N116Y). Using this adenoviral vector system, we investigated the growth suppressive effects of N116Y on orthotopically implanted bladder cancer cells in vivo. The results demonstrated that inoculation of AdCMV-N116Y caused significant growth suppression of orthotopically implanted bladder cancer cells (UMUC-2, KU-7).Although this is still in preclinical stage, gene therapy via transurethral inoculation of AdCMV-N116Y or AdCMV-Gelsolin might hold promise for the treatment of human bladdder cancer.

最初，我们研究了与人膀胱癌细胞系中凝胶蛋白基因基因疗法的体内疗效。在此分析中，我们在裸鼠中使用了原始植入的人膀胱癌细胞。通过对含有腺病毒的凝胶蛋白基因的经尿道接种，与对照载体接种相比，人类膀胱癌细胞系（UMUC-2，KU-7）在人膀胱癌细胞系（UMUC-2，KU-7）中受到了强烈抑制。关于在人膀胱癌中凝醇蛋白基因表达的基本机制，核组织蛋白在启动子病变中的脱甲基化被证明很重要，并且对人膀胱癌的施用至关重要，对人类膀胱癌的表达诱导了N116y的凝胶蛋白基因的增强。用酪氨酸代替天冬酰胺-116，还可以抑制人膀胱癌细胞系的生长。在此分析中，我们通过含N116Y的腺病毒载体（ADCMV-N116Y）在体内使用N116Y RAS突变体。使用这种腺病毒载体系统，我们研究了N116Y对原始植入的膀胱癌细胞的生长抑制作用。结果表明，接种ADCMV-N116Y导致原位植入的膀胱癌细胞的显着生长抑制（UMUC-2，KU-7）。虽然这仍然处于临床前阶段，通过临床上的基因治疗，通过对ADCMV-N116Y或ADCMV-GELSOLIN进行过尿中的基因治疗可能会对人类Bladdder Cancer进行治疗。