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Basic study to establish molecular diagnosis and gene therapy for anticancer drug-resistant cancer cells

建立抗癌耐药癌细胞分子诊断和基因治疗的基础研究

基本信息

批准号：
13470353
负责人：
TANAKA Tetsuji
金额：
$ 3.52万
依托单位：
Wakayama Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470353/
关键词：
Uterine Cancer Ovarian Cancer Multidrug-resistance gene Anti-cancer drug-resistance

项目摘要

(1)Cellular and molecular characterization of anticancer drug-resistant cancer cells : Using more than 100 anticancer drug-resistant subclones derived from human uterine and ovarian carcinomas, their drug-sensitivities were quantitatively evaluated and compared to the results of mRNA expression profiling of the resistant subclones. In this study, we have first found some relationships of death-associated protein kinase (DAPK) and anticancer-drug sensitivities of cancer cells. Demethylation of uterine cancer cells induced DAPK expression and restored their SN38-sensitivity. Demethylation of SN38-resistant cells restored SN38-sensitivity while demethylation of CDDP-resistant cells did not affect their CDDP-sensitivities.(2)mRNA expression profiling of the drug-resistant subclones : cDNA microarray analyses revealed mRNA expression profiling of the drug-resistant subclones. Especially, c-myc mRNA expressions were significantly suppressed in many anti-cancer drug-resistant subclones.(3)Suppression of mRNA expression may disclose candidate genes of drug-sensitivity-regulating molecules : By using siRNA procedure, we have been discovering candidate genes of drug-sensitivity-regulating molecules. Relationship of STAT3 expression and anticancer drug-sensitivity has been investigated.(4)Basic study on gene therapy for drug-resistant cancer cells : Recently we have identified that growth-inhibitory signals of TGF-beta1 can be completely inhibited by activin A, indicating increased activin-A in endometrial adenocarcinoma indirectly enhance cell proliferation of the cancer cells. As targets for gene therapy, therefore ; we are investigating the regulatory factors that stimulate activin A production in cancer tissues.(5)Basic study for concurrent chemoradiation : In in vitro experiments with cervical SCC cells, we have found optimal combination of anticancer drugs with radiotherapy.

(1)抗癌耐药癌细胞的细胞和分子特征：利用100多个来自人子宫和卵巢癌的抗癌耐药亚克隆，定量评估其药物敏感性，并与耐药亚克隆的mRNA表达谱结果进行比较。在本研究中，我们首次发现了死亡相关蛋白激酶(DAPK)与癌细胞的抗癌药物敏感性之间的一些关系。子宫癌细胞去甲基化诱导DAPK表达，恢复其对SN38的敏感性。SN38耐药细胞去甲基化恢复对SN38的敏感性，而CDDP耐药细胞去甲基化不影响其对顺铂的敏感性。(2)耐药亚克隆的mRNA表达谱：基因芯片分析显示耐药亚克隆的mRNA表达谱。尤其是c-myc基因在许多抗癌耐药亚克隆中的表达明显下调。(3)抑制基因表达可能揭示药物敏感性调控分子的候选基因：通过siRNA程序，我们一直在寻找药物敏感性调控分子的候选基因。研究STAT3的表达与抗癌药物敏感性的关系。(4)耐药癌细胞基因治疗的基础研究：最近我们发现激活素A可以完全抑制转化生长因子-β1的生长抑制信号，提示激活素-A在子宫内膜腺癌中的增加间接促进了癌细胞的增殖。因此，作为基因治疗的靶点，我们正在研究刺激肿瘤组织中激活素A产生的调节因素。(5)同步放化疗的基础研究：在宫颈鳞癌细胞的体外实验中，我们找到了抗癌药物与放射治疗的最佳组合。