Mechanism of resistance to cisplatin by metastatic renal cell carcinoma

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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.