Influence of Oct1/Oct2-deficiency on cisplatin-induced changes in urinary N-acetyl-beta-D-glucosaminidase.
Influence of Oct1/Oct2-deficiency on cisplatin-induced changes in urinary N-acetyl-beta-D-glucosaminidase.
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DOI：
10.1158/1078-0432.ccr-10-0949
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发表时间：
2010-08-15
期刊：
影响因子：
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通讯作者：
Sparreboom A
中科院分区：
文献类型：
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作者：
Franke RM;Kosloske AM;Lancaster CS;Filipski KK;Hu C;Zolk O;Mathijssen RH;Sparreboom A
有机阳离子转运体先前与顺铂肾毒性有关。在这项研究中，我们发现在缺乏Oct1和Oct2转运体的小鼠[Oct1/2（−/−）小鼠]中，顺铂的肾小管分泌被消除，这些小鼠受到保护，不会遭受严重的顺铂诱导的肾损伤。与野生型小鼠相比，Oct1/2（−/−）小鼠在顺铂给药后尿n -乙酰-β- d -氨基葡萄糖酶（NAG）活性的变化也显著降低（~4倍，P=0.0016）。累积尿NAG活性的截止值为b> 0.4 AU，与严重肾毒性的风险增加21倍相关（P=0.0017），而严重肾毒性又与总生存率相关[风险比（95%CI） 8.1 (2.1-31)， P=0.0078]。接下来，我们使用转染的293flip - in细胞，筛选了16种不同浓度的药物对人类同源转运体OCT2的抑制潜力。我们进一步关注了西咪替丁作为OCT2抑制剂的可能效用，因为它具有很强的效力（抑制率为95%），并且该药物不与顺铂常规共给药。在小鼠中，我们发现西咪替丁对顺铂诱导的尿NAG活性变化的抑制程度与对照组小鼠显著不同（P=0.016），但与Oct1/2（−/−）小鼠相似（P=0.91）。有趣的是，西咪替丁不影响SKOV-3细胞对顺铂的摄取，SKOV-3细胞是OCT2表达最高的NCI60细胞系。综上所述，本研究表明，OCT2抑制剂可以完全抑制转运蛋白介导的顺铂在肾近端小管细胞中的摄取，从而改善顺铂的肾毒性，而不影响肿瘤细胞中的积累。
Organic cation transporters have previously been implicated in cisplatin nephrotoxicity. In this study, we found that renal tubular secretion of cisplatin is abolished in mice lacking the Oct1 and Oct2 transporters [Oct1/2(−/−) mice], and these mice are protected from experiencing severe cisplatin-induced renal damage. Compared to wildtype mice, Oct1/2(−/−) mice also experienced a significantly decreased change in urinary activity of N-acetyl-β-D-glucosaminidase (NAG) following cisplatin administration (~4-fold, P=0.0016). A cutoff for cumulative urinary NAG activity of >0.4 AU was associated with a 21-fold increased odds for severe nephrotoxicity (P=0.0017), which in turn was linked with overall survival [hazard ratio (95%CI), 8.1 (2.1–31), P=0.0078]. Next, we screened 16 agents at varying concentrations for inhibitory potential against the human homolog transporter, OCT2, using transfected 293Flp-In cells. We focused further on the possible utility of cimetidine as an OCT2 inhibitor because of its strong potency (>95% inhibition), and because this agent is not routinely co-administered with cisplatin. In mice, we found that cimetidine inhibited cisplatin-induced urinary NAG activity changes to a degree significantly different from vehicle-control treated mice (P=0.016), but similar to that seen in Oct1/2(−/−) mice (P=0.91). Interestingly, cimetidine did not affect the uptake of cisplatin into SKOV-3 cells, the NCI60 cell line with the highest OCT2 expression. Collectively, this study suggests that OCT2 inhibitors can completely inhibit transporter-mediated uptake of cisplatin in renal proximal tubular cells, and subsequently ameliorate cisplatin nephrotoxicity without affecting the accumulation in tumor cells.