Mechanism of acquired drug resistance and reversing resist

获得性耐药及逆转耐药机制

• 批准号: 05671914
• 负责人: FUNATO Tadao
• 金额: $ 1.47万
• 依托单位: Tohoku University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1993
• 资助国家: 日本
• 起止时间: 1993 至 1995
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-05671914/
• 关键词: Anti-Cancer-drug; Drug-resistance; Antisense; Ribozyme; Colon cancer; Leukemia; Cisplatin; Cytosine arabinoside; サイトシン・アラビノシド; 結腸癌

Our previous work has focused on implicating fos in the cellular resistance to cancer chemotherapy agents. Our hypothesis, simply standed, is that fos is resposible for directing the cellular respose to DNA damage by activating transcription of genes encoding enzymes involved in DNA synthesis and repair. Inthis study, we have investigated the cisplatin resistance in vitro and in vivo. A hammerhead ribozyme for fos was disigned to cleave selectively only expresed fos RNA the efficacy of an anti-fos ribozyme in reversing this resistant cell lines. The c-fos ribozyme was suppressed fos mRNA in cultured resistant cell line. We demonstrated that expresion of the fos ribozyme sensitivity of A2780DDP cells to antineoplastic agents. On the other hand, the reversal of this resistance is associated with down-regulation of dTMP synthase, DNA polymerase, topoisomerase I and hMT,genes linked to DNA synthesis and repair. Moreover, this fos ribozyme supresed expresion of c-fos gene on implanted tumors in an athymic mice and reversed sensitivity for cisplatin, but not inhibition.

我们以前的工作集中在牵连fos在细胞耐药性癌症化疗药物。我们的假设，简单地说，是fos是负责指导细胞对DNA损伤的反应，通过激活基因编码的酶参与DNA合成和修复的转录。在本研究中，我们研究了顺铂耐药的体外和体内。设计了一种锤头状核酶，它能选择性地切割表达fos的RNA，并观察了抗fos核酶逆转耐药细胞系的效果。c-fos核酶在培养的抗性细胞系中抑制fos mRNA的表达。本实验证实了A2780 DDP细胞对化疗药物的敏感性。另一方面，这种耐药性的逆转与dTMP合酶、DNA聚合酶、拓扑异构酶I和hMT的下调有关，这些基因与DNA合成和修复有关。此外，该fos核酶抑制c-fos基因在裸鼠移植瘤中的表达，并逆转顺铂的敏感性，但不抑制。

项目成果

船渡忠男,他: "アンチセンス・リボザイムによる遺伝子発現抑制作用の電気泳動的分析" 生物物理化学. 38. 237-241 (1994)

Tadao Funato等人：“反义核酶的基因表达抑制效应的电泳分析”生物物理化学38.237-241(1994)。

Tone,T,Kashani-Sabet,M,Funato,T.et al.: "Suppression of EJ cells tumorigenicity." in vivo. 7. 471-476 (1993)

Tone,T,Kashani-Sabet,M,Funato,T.et al.：“EJ 细胞致瘤性的抑制。”

Funato, T.: "Suppression of H-ras-mediated transformation on NIII313 cells by a rasnibes" Biochemical Pharmacology. 48. 1471-1475 (1994)

Funato, T.：“rasnibes 抑制 H-ras 介导的 NIII313 细胞转化”生物化学药理学。

Ohta, T.: "H-ras ribozyme-mediated alteration of the human melanoma phenotype." Annals of the New York Academy ofSciences. 716. 242-256 (1994)

Ohta, T.：“H-ras 核酶介导的人类黑色素瘤表型的改变。”

Funato, T.: "Suppression of H-ras mediated transformation in NIH3T3 cells by a ras ribozyme." Biochemical Pharmacology. 48. 1471-1475 (1994)

Funato, T.：“ras 核酶抑制 NIH3T3 细胞中 H-ras 介导的转化。”