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DRUG TRANSFER AND EXPRESSION OF P-GLYCOPROTEIN IN THE RAT 9L GLIOMA

大鼠 9L 胶质瘤中的药物转移和 P-糖蛋白的表达

基本信息

批准号：
03454347
负责人：
YAMASHIMA Tetsumori
金额：
$ 4.1万
依托单位：
KANAZAWA 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：
1991
资助国家：
日本
起止时间：
1991 至 1992
项目状态：
已结题

项目摘要

Two weeks after the inoculation of 1.5x10^5 of 9L glioma cells into the rat brain, the transfer of radiolabelled drugs into the brain and the experimental 9L glioma during the first cerebral circulation,was measured with a liquid scintilation counter and analyzed by the method of Oldendorf. The expression of P-glycoprotein, which is known to be associated with the efflux of drugs, was also studied, using anti-P-glycoprotein monoclonal antibody: C-219. Furthermore, the ultrastructure of brain capillaries, tumor vessels and glioma cells was studied by conventional and immuno-electron microscopy. Sucrose (control), the transport of which through the blood-brain barrier is known to be saturable, accumulated to 5 fold higher levels in the tumor relative to brain. MCNU (ranimustine: methyl 6-[3-(2-chloroethyl-3-nitrosoureido]-6-deoxy-alpha-D-glucopyranoside), 5-FU (5-fluorouracil) and doxorubicin (Adriamycin) showed quite little accumulation into the normal brain, whereas ACNU (nimustine: 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride) showed an increased accumulation. MCNU and doxorubicin showed negligible accumulation in the glioma cells despite diffusion into the tumor interstitial space. In contrast, ACNU and 5-FU showed an increased accumulation in tumor cells. The transfer of 5-FU into the cultured 9L glioma cells was decreased by ATP inhibitors or by low temperature. Although both brain capillary endothelial cells and glioma cell membranes were immunohistochemically positive for P-glycoprotein, the tumor vasculature showed low expression of P-glycoprotein. The endothelial cells of tumor vessels ultrastructurally showed increased fenestrations, swelling and disrupted junctions. Accordingly, it is suggested that hydrophilic drugs such as doxorubicin, being pumped out by P-glycoprotein, do not accumulate in 9L glioma as do other lipophilic drugs such as ACNU, or 5-FU associated with the carrier-mediated mechanism.

将1.5x10^5个9 L胶质瘤细胞接种到大鼠脑中后两周，用液体膨胀计数器测量放射性标记药物在第一次脑循环期间向脑和实验性9 L胶质瘤中的转移，并通过Oldendorf方法进行分析。还使用抗P-糖蛋白单克隆抗体C-219研究了已知与药物外排相关的P-糖蛋白的表达。并应用常规电镜和免疫电镜观察脑毛细血管、肿瘤血管和胶质瘤细胞的超微结构。蔗糖（对照），其通过血脑屏障的转运已知是可饱和的，在肿瘤中积累到相对于脑高5倍的水平。MCNU（雷莫司汀：甲基6-[3-（2-氯乙基-3-亚硝基脲基]-6-脱氧-α-D-吡喃葡萄糖苷）、5-FU（5-氟尿嘧啶）和阿霉素（阿霉素）在正常脑中的蓄积相当少，而ACNU（尼莫司汀：1-（4-氨基-2-甲基-5-嘧啶基）甲基-3-（2-氯乙基）-3-亚硝基脲盐酸盐）的蓄积增加。MCNU和阿霉素在胶质瘤细胞中的蓄积可忽略不计，尽管它们扩散到肿瘤间质中。相反，ACNU和5-FU显示在肿瘤细胞中的积累增加。ATP抑制剂和低温可抑制5-FU向9 L胶质瘤细胞的转运。尽管脑毛细血管内皮细胞和胶质瘤细胞膜均呈P-糖蛋白免疫组化阳性，但肿瘤血管系统显示P-糖蛋白低表达。肿瘤血管内皮细胞超微结构表现为穿孔增多、肿胀和连接中断。因此，这表明亲水性药物如阿霉素，被P-糖蛋白泵出，不像其他亲脂性药物如ACNU或与载体介导机制相关的5-FU那样在9 L胶质瘤中积累。