Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.
Clin Cancer Res. 2010 Aug 15;16(16):4198-206. doi: 10.1158/1078-0432.CCR-10-0949. Epub 2010 Jul 2.
This study aimed to test the influence of functional renal organic cation transporters (OCT2 in humans, Oct1 and Oct2 in mice) on biomarkers of cisplatin nephrotoxicity, such as urinary activity of N-acetyl-beta-D-glucosaminidase (NAG).
Temporal cisplatin-induced nephrotoxicity was assessed by histopathology and biomarkers. Cisplatin-mediated NAG changes and survival were determined in wild-type and Oct1/2(-/-) mice. Identification of OCT2 inhibitors was done in transfected 293Flp-In cells, and the NCI(60) cell line panel was used to assess contribution of OCT2 to cisplatin uptake in cancer cells.
Classical biomarkers such as blood urea nitrogen and serum creatinine were not elevated until 72 hours after cisplatin administration and substantial kidney damage had occurred. Oct1/2(-/-) mice had 2.9-fold lower NAG by 4 hours (P < 0.0001) and 2.3-fold increased survival (P = 0.0097). Among 16 agents, cimetidine strongly inhibited uptake of tetraethylammonium bromide (P = 0.0006) and cisplatin (P < 0.0001), but did not have an influence on cisplatin uptake in SK-OV-3 cells, the cancer line with the highest OCT2 mRNA levels. In wild-type mice, cimetidine inhibited cisplatin-induced NAG changes (P = 0.016 versus cisplatin alone) to a degree similar to that seen in Oct1/2(-/-) mice receiving cisplatin (P = 0.91). Cumulative NAG activity of >0.4 absorbance units (AU) was associated with 21-fold increased odds for severe nephrotoxicity (P = 0.0017), which was linked with overall survival (hazard ratio, 8.1; 95% confidence interval, 2.1-31; P = 0.0078).
Cimetidine is able to inhibit OCT2-mediated uptake of cisplatin in the kidney, and subsequently ameliorate nephrotoxicity likely with minimal effect on uptake in tumor cells.
本研究旨在测试功能性肾有机阳离子转运体（人类中的有机阳离子转运体 2[OCT2]，小鼠中的有机阳离子转运体 1[Oct1]和有机阳离子转运体 2[Oct2]）对顺铂肾毒性生物标志物的影响，如尿 N-乙酰-β-D-氨基葡萄糖苷酶（NAG）活性。
通过组织病理学和生物标志物评估顺铂诱导的肾毒性的时间进程。在野生型和 Oct1/2(-/-)小鼠中确定顺铂介导的 NAG 变化和存活率。在转染的 293Flp-In 细胞中鉴定 OCT2 抑制剂，并使用 NCI(60)细胞系面板评估 OCT2 对癌细胞中顺铂摄取的贡献。
直到顺铂给药后 72 小时，经典生物标志物如血尿素氮和血清肌酐才升高，并且已经发生了实质性的肾脏损伤。Oct1/2(-/-) 小鼠在 4 小时时 NAG 降低 2.9 倍（P < 0.0001），存活率提高 2.3 倍（P = 0.0097）。在 16 种药物中，西咪替丁强烈抑制了溴化四乙铵（P = 0.0006）和顺铂（P < 0.0001）的摄取，但对 SK-OV-3 细胞（具有最高 OCT2 mRNA 水平的癌细胞系）中的顺铂摄取没有影响。在野生型小鼠中，西咪替丁抑制了顺铂诱导的 NAG 变化（P = 0.016 与单独使用顺铂相比），程度与接受顺铂的 Oct1/2(-/-) 小鼠相似（P = 0.91）。累积 NAG 活性>0.4 吸光度单位（AU）与严重肾毒性的 21 倍odds 相关（P = 0.0017），这与总生存期相关（风险比，8.1；95%置信区间，2.1-31；P = 0.0078）。
西咪替丁能够抑制肾脏中 OCT2 介导的顺铂摄取，随后改善肾毒性，而对肿瘤细胞中的摄取影响很小。
