Mechanism of resistance to cisplatin by metastatic renal cell carcinoma

转移性肾细胞癌对顺铂的耐药机制顺铂(CDDP)是目前已知的最有效的抗癌药物，具有广泛的抗肿瘤活性。方法：我们建立了四种肾癌细胞系，即原发肿瘤系(Hanks-Pr)、肺转移瘤(Hanks-Lu)、肝转移瘤(Hanks-Li)和淋巴结转移瘤(Hanks-LN)。我们还利用我室建立的肾癌细胞株(NM-R-5)研究了顺铂耐药的机制。金属硫蛋白是一种富含半胱氨酸的低分子蛋白质，对多种重金属具有很高的亲和力。众所周知，金属硫蛋白的诱导在预防顺铂治疗的小鼠死亡方面是有效的。有报道称，在不影响顺铂抗肿瘤活性的情况下，可通过诱导金属硫蛋白的合成来预防顺铂对小鼠的致死性和肾脏毒性。谷胱甘肽(GSH)是一种主要的含SH基团的非蛋白质，建议通过结合来降低CDDP的活性，形成GSHCDDP。用四甲基偶氮唑盐比色法测定肿瘤细胞对顺铂的敏感性。结果：MT浓度与CDDP的作用呈正相关，与GSH无相关性。结论：在肾癌中，MT可能参与了CDDP的耐药机制。

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.