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Study of multidrug-resistance mechanism and its overcoming in cutaneous mesenchymal malignant tumor

皮肤间质恶性肿瘤多药耐药机制及其克服的研究

基本信息

批准号：
10670814
负责人：
KUSAKABE Hidenari
金额：
$ 1.73万
依托单位：
Osaka Medical College
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670814/
关键词：
mesenchymal tumor epithelioid sarcoma multidurg resistance lung resistance protein sensitivity test anticancer drug LRP 抗癌剤感受性検査間葉性悪性腫瘍多剤耐性 actinomycin D

项目摘要

The incidence of epithelioid sarcoma among cases with malignant soft tissue tumors is small, however, the rates of recurrence and metastasis of this type of sarcoma are high. To date, effective chemotherapy for advanced epithelioid sarcoma has not been established, furthermore, epithelioid sarcoma is known to exhibit multidrug resistance (MDR). The chemosensitivities of two cell lines established from epithelioid sarcoma to anticancer agents are examined in this study. The results showed that the ES-OMC-MN and SFT-8606 cell lines were resistant to vincristine (IC_<50>=1,190 nM and 872 nM, respectively) and adriamycin (IC_<50>=921 nM and 650 nM, respectively), but sensitive to actinomycin D (IC_<50><10 nM). The p-glycoprotein (p-Gp) and multidrug resistance gene 1 (MDRI) were not expressed in these cell lines, however, a high expression level of the lung resistance protein (LRP) was observed. The original tumor tissues from which the two cell lines were established were also found to be LRP-positive but not to express p- Gp. Their chemosensitivities to adriamycin of the cell lines, ES-OMC-MN and SFT- 8606, pretreated with 2.5 μg/ml anti-LRP antibody (LRP-56) were not significantly altered, however, the IC_<50> of vincristine became much smaller (IC_<50>=128 nM and 27 nM, respectively) than that in a non-pretreated cell line. It is thus suggested that the vincristine resistance in the two cell lines is LRP-mediated. Since cyclosporin A, known to be a modifier of p-Gp, also induced reversal of vincristine resistance in the ES-OMC- MN and SFT-8606 cell lines (IC_<50>=6.2 nM and 17 nM, respectively), it is suggested that cyclosporin A acts as a modifier against LRP.

上皮样肉瘤在恶性软组织肿瘤中的发生率很低，但复发转移率高。迄今为止，晚期上皮样肉瘤的有效化疗尚未建立，而且已知上皮样肉瘤表现出多药耐药（MDR）。本研究检测了两种上皮样肉瘤细胞系对抗癌药物的化疗敏感性。结果表明，ES-OMC-MN和SFT-8606细胞对长春新碱和阿霉素耐药（IC<50>分别为1,190 nM和872 nM，IC<50>分别为921 nM和650 nM），对放线菌素D敏感（IC <50><10 nM）。P-糖蛋白（p-Gp）和多药耐药基因1（MDRI）在这些细胞系中不表达，但观察到肺耐药蛋白（LRP）的高表达水平。还发现建立两种细胞系的原始肿瘤组织是LRP阳性的，但不表达p-GP。用2.5 μg/ml抗LRP抗体（LRP-56）预处理的ES-OMC-MN和SFT- 8606细胞对阿霉素的敏感性无明显改变，但<50>长春新碱的<50>IC_（分别为128 nM和27 nM）明显低于未预处理的细胞。因此，这两种细胞系中的长春新碱耐药性是LRP介导的。由于环孢菌素A（已知是p-Gp的修饰剂）也可诱导ES-OMC- MN和SFT-8606细胞系中长春新碱耐药性的逆转（IC_<50>分别为6.2 nM和17 nM），因此表明环孢菌素A可作为抗LRP的修饰剂。