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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.

首先，我们研究了在裸鼠体内的人膀胱癌细胞系的基因治疗与凝溶胶蛋白基因的疗效。在该分析中，我们使用原位植入裸鼠中的人膀胱癌细胞。与接种对照载体相比，通过经尿道接种含有凝溶胶蛋白基因的腺病毒，人膀胱癌细胞系（UMUC-2、KU-7）的细胞生长受到强烈抑制。关于凝溶胶蛋白基因在人膀胱癌中表达的基本机制，凝溶胶蛋白基因的启动子损伤中的核组蛋白的脱乙酰化被证明是重要的，并且对人膀胱癌施用Trycostatin诱导了凝溶胶蛋白基因在人膀胱癌细胞中的增强表达。其通过用酪氨酸取代天冬酰胺-116而衍生自v-H-ras癌基因，也可以抑制人膀胱癌细胞系的生长。在该分析中，我们通过含N116 Y的腺病毒载体（AdCMV-N116 Y）在体内使用N116 Y ras突变体。使用这种腺病毒载体系统，我们研究了N116 Y对原位植入的膀胱癌细胞在体内的生长抑制作用。结果表明，AdCMV-N116 Y对膀胱癌细胞（UMUC-2，KU-7）的生长有明显的抑制作用，虽然目前尚处于临床前研究阶段，但经尿道接种AdCMV-N116 Y或AdCMV-Gelsolin的基因治疗有望成为膀胱癌的治疗手段。