Mechanism of resistance to cisplatin by metastatic renal cell carcinoma

Research Project

Project/Area Number	02670725
Research Category	Grant-in-Aid for General Scientific Research (C)
Allocation Type	Single-year Grants
Research Field	Urology
Research Institution	Nippon Medical School
Principal Investigator	AKIMOTO Masao Nippon Medical School Department of urology, Medical Professor, 医学部, 教授 (50089752)
Co-Investigator(Kenkyū-buntansha)	HATTORI Tomotaka Nippon Medical School, Department of urology Chinical Fellow, 医学部, 助手 (60228492) NISHIMURA Taiji Nippon Medical School, Department of urology, Associate Professor, 医学部, 助教授 (00104026) KAWAMURA Naoki Ebina general Hospital Department of urology, chief, 泌尿器科, 医長 (40161369) 堀内和孝日本医科大学, 医学部・泌尿器科学教室, 助手 (00173625)
Project Period (FY)	1990 – 1991
Project Status	Completed (Fiscal Year 1991)
Budget Amount *help	¥2,100,000 (Direct Cost: ¥2,100,000) Fiscal Year 1991: ¥1,100,000 (Direct Cost: ¥1,100,000) Fiscal Year 1990: ¥1,000,000 (Direct Cost: ¥1,000,000)
Keywords	reual tumor / drug resistance / metallothionein / glutathion / cisplatin / cell line / 腎細胞癌 / シスプラチン耐性 / メタロサイオネイン / 腎癌 / 転移性腎癌 / CDDP(Pt濃度) / 組織適合抗原 / mdr / GSTーπ
Research Abstract	Mechanism of resistance to cisplatin by metastatic renal cell carcinoma CDDP (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.