Effect of anti-sense P-glycoprotein oligomer on P-glycoprotein-positive multidrug-resistant cancers

反义P-糖蛋白寡聚体对P-糖蛋白阳性多重耐药癌症的作用

• 批准号: 05454287
• 负责人: SAKURAI Minoru
• 金额: $ 3.97万
• 依托单位: MIE UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (B)
• 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-05454287/
• 关键词: Multidrug-resistant cancers; P-glycoprotein; Anti-sense oligonucleotide; アンチセンス; P-glycoprotein; Antisense; multidrug resistance

Multidrug resistance (mdr) genes encode P-glycoprotein (P-gp), an active transporter that pumps cytotoxic drugs out of cells. Thus, its overexpression is associated with the anticancer drug resistance. Disrupting P-gp/mdr function might, therefore, form the basis of a strategy for overcoming the multidrug resistance of cancer cells. To overcome multidrug resistance in a P-gp-overexpressing P388/ADR murine leukemia cell line, antisense mdrl phosphorothioate-oligodeoxynucleotide (AS-oligomer) was constructed. AS-oligomer inhibited P-glycoprotein expression and mdrl mRNA in vitro in a dose-dependent manner, whereas sense mdrl oligomer (SE-oligomer) had no effect at the doses used. When P388/ADR was treated in vitro with AS-oligomer and doxorubicin (ADR), ADR-resistance was reduced by approximately 2 logs. Furthermore, a single injection of AS-oligomer plus ADR intraperitoneally into B6D2 F1 mice with P388/ADR significantly prolonged mean survival time in a dose-dependent fashion. Again, sense mdrl oligomer had no effect in vivo. No side eddects, either acute or chronic, were found with this treatment during the observation period. These results show that antisense mdrl oligomer could be a useful tool to overcome multidrug resistance.

多药耐药（MDR）基因编码P-糖蛋白（P-gp），一种将细胞毒性药物泵出细胞的活性转运蛋白。因此，其过表达与抗癌药物抗性相关。因此，破坏P-gp/mdr功能可能成为克服癌细胞多药耐药性的策略的基础。为克服P-gp过表达的P388/ADR小鼠白血病细胞系的多药耐药，构建了反义多药耐药基因（mdr 1）硫代磷酸寡脱氧核苷酸（AS-oligomer）。AS-寡聚体在体外以剂量依赖性方式抑制P-糖蛋白表达和mdrl mRNA，而正义mdrl寡聚体（SE-寡聚体）在所用剂量下无影响。当P388/ADR在体外用AS-寡聚体和阿霉素（ADR）处理时，ADR抗性降低约2个对数。此外，单次腹腔注射AS寡聚体加ADR可显著延长P388/ADR的B6 D2 F1小鼠的平均生存时间，并呈剂量依赖性。同样，正义mdrl寡聚体在体内没有影响。在观察期间，未发现该治疗的急性或慢性副作用。这些结果表明反义mdrl寡聚体可能是克服多药耐药的有用工具。

项目成果

Hiratake S,Azuma E,Sakurai M.et al.: "Treatment of multidrug-resistant murine leukemia with antisense mdrl oligodeoxynucleotides." Biomedicine and Pharmacotherapy(受理).

Hiratake S、Azuma E、Sakurai M. 等人：“用反义 mdrl 寡脱氧核苷酸治疗多重耐药小鼠白血病”。

Azuma E,Sakurai M et al.: "In vivo treatment of multidrug-resistant murine leukemia with antisense MDRI oligodeoxynucleotides." Blood. 84. 43-43 (1994)

Azuma E、Sakurai M 等人：“用反义 MDRI 寡脱氧核苷酸体内治疗多重耐药小鼠白血病。”

Azuma E,Sakurai M.et al.: "Cytotoxic T-lymphocyte recognizing P-glycoprotein in murine multidrug-resistant leukemias" Eur.J.Haematology. (印刷中).

Azuma E、Sakurai M. 等人：“细胞毒性 T 淋巴细胞识别小鼠多重耐药白血病中的 P 糖蛋白”Eur.J.Haematology（出版中）。

Azuma,E.et al.: "Cytotoxic T-lymphocyte recognizing P-glycoprotein in murine multidrug-resistant leukemias" Eur. J. Haematology. (印刷中).

Azuma, E. 等人：“细胞毒性 T 淋巴细胞识别小鼠多重耐药白血病中的 P 糖蛋白”，Eur. J. Haematology（正在出版）。

Eiichi Azuma: "Successful abrogation of P-glycoprotein expression of a murine multidrug-resistant leukemia cell line with anti-sense mdr oligomer" Blood. 82. 1014-1014 (1993)

Eiichi Azuma：“用反义 mdr 寡聚物成功废除了小鼠多重耐药白血病细胞系的 P 糖蛋白表达”血液。