Mechanism of resistance to cisplatin by metastatic renal cell carcinoma

转移性肾细胞癌对顺铂耐药的机制

基本信息

批准号：
02670725
负责人：
AKIMOTO Masao
金额：
$ 1.34万
依托单位：
Nippon Medical School
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1990
资助国家：
日本
起止时间：
1990 至 1991
项目状态：
已结题

项目摘要

Mechanism of resistance to cisplatin by metastatic renal cell carcinomaCDDP (Cisplatin), a platinum complex drug, is the most potent known anticancer agent and shows a broad spectrum of activity against human neoplasia. However, it does not have any effect on renal cell carcinoma.Methods: We established four renal cell carcinoma cell lines derived from a patient with advanced RCC; i. e., a primary tumor line (HANKS-Pr) and metastases to the lungs (HANKS-Lu), liver (HANKS-Li), and lymph nodes (HANKS-LN). We also studied the mechanism of resistance to CDDP using a renal cell carcinoma (NM-R-5) line established in our department. Metallothionein is a cysteine-rich protein of low molecular weight and has a high affinity for various heavy metals. It is well known that induction of metallothionein is effective in preventing the death of mice treated with cisplatin. It has been reported that the prevention of lethality and renal toxicity due to cisplatin can be achieved in mice by the induction of metallothionein synthesis without compromising its antitumor activity. Glutathion (GSH) is a major nonprotein with SH groups that is suggested to decrease the activity of CDDP by conjugation to form GSHCDDP. The sensitivity of tumor cells to CDDP was determined by the MTT assay. Cellular MT levels were determined by the 203Hg-binding assay, and GSH levels were determined by chromatography.Results: A correlation between the MT concentration and a decreased effect of CDDP was recognized, but no correlation with GSH was recognized.Conclusion: In renal cell carcinoma, MT is suggested to participate in the mechanism of resistance to CDDP.

转移性肾细胞癌（Cisplatin）对顺铂的抗性机制（一种铂络合物）是最有效的已知抗癌剂，并且显示出针对人类肿瘤的广泛活性。但是，它对肾细胞癌没有任何影响。方法：我们建立了源自患有晚期RCC患者的四个肾细胞癌细胞系；我。例如，对肺（Hanks-Lu），肝脏（Hanks-LI）和淋巴结（Hanks-LN）的原发性肿瘤线（Hanks-PR）和转移。我们还使用在我们的部门中建立的肾细胞癌（NM-R-5）线研究了对CDDP的耐药机制。金属硫蛋白是一种低分子量的富含半胱氨酸的蛋白质，对各种重金属具有高亲和力。众所周知，金属硫蛋白的诱导有效防止用顺铂治疗的小鼠死亡。据报道，通过诱导金属硫蛋白合成而不会损害其抗肿瘤活性，可以在小鼠中预防因顺铂引起的杀伤力和肾脏毒性。谷胱甘肽（GSH）是一种主要的非蛋白质，具有SH基团，建议通过结合形成GSHCDP来降低CDDP的活性。肿瘤细胞对CDDP的敏感性由MTT分析确定。细胞MT水平由203HG结合测定法确定，GSH水平通过色谱法确定：识别MT浓度与CDDP效应降低之间的相关性，但已识别与GSH的相关性。结论：结论：在肾细胞癌中，MT建议在CDDP中参与CDDP。