(优选)顺铂肾毒性研究进展最新

●基础研究●维生素E对顺铂所致的小鼠肾毒性的影响及其机制研究张　林1，刘伏友2，彭佑铭2，李大伟1，曾　妮1，武　蓉1，刘沧桑1（1长沙市四医院肾内科，湖南　长沙，410006；2中南大学湘雅二医院肾脏病研究所，湖南　长沙，410008）摘要：目的　观察维生素E对抗癌药物顺铂致小鼠肾毒性的影响及其可能机制。

方法　采用10 mg・kg-1顺铂腹腔注射诱导小鼠肾脏损伤，48小时后分别予维生素E 250 mg・kg-1和500 mg・kg-1口服灌胃，顺铂诱导72小时后通过检测小鼠血清尿素氮和肌酐水平评价肾功能的变化，检测肾组织中丙二醛（malonaldehyde，MDA）含量，过氧化物歧化酶（superoxide dismutase，SOD）、过氧化氢酶（catalase，CAT）、还原型谷胱甘肽（reduced glutathione，GSH）和谷胱甘肽过氧化物酶（glutathion peroxidase，GPX）活性的变化，以评价小鼠肾组织氧化应激水平。

结果　与正常小鼠相比，10 mg・kg-1顺铂诱导的小鼠血清尿素氮、肌酐水平和肾组织MDA水平均显著升高（P<0.01），而肾组织SOD、CAT、GSH、GPX的活性均显著降低（P<0.01）；与10 mg・kg-1顺铂诱导的小鼠相比，250 mg・kg-1和500 mg・kg-1维生素E灌胃的小鼠血清尿素氮、肌酐水平和肾组织MDA水平均显著降低（P<0.01），250 mg・kg-1维生素E灌胃的小鼠肾组织GPX的活性显著升高（P<0.01），500 mg・kg-1维生素E灌胃的小鼠肾组织CAT和GPX的活性均显著升高（P<0.01），而三组之间肾组织SOD活性的差异无统计学意义（P>0.05）。

结论　高剂量的维生素E可以有效改善顺铂诱导的小鼠肾功能，可能与其降低肾组织的氧化应激有关。

关键词：维生素E；氧化应激；肾毒性；顺铂中图分类号：R730.53　文献标识码：A　文章编号：2095-1264（2012）05-0343-05d oi：10.3969/j.issn.2095-1264.2012.05.004The Effect of Vitamin E on Cisplatin Induced Nephrotoxicity in Mice and its Mechanism Zhang Lin1, Liu Fuyou2, Peng Youming2, Li Dawei1, Zeng Ni1, Wu Rong1, Liu Cangsang1 (1The Forth Hospital of Changsha, Changsha, Hunan, 410006, China; 2The Second Xiangya Hospital of Central SouthUniversity, Changsha, Hunan, 410008, China)Abstract:Objective To investigate the effects of vitamin E on cisplatin induced nephrotoxicity in mice and its mechanism. Methods 10 mg・kg-1 cisplatin was used to induce nephrotoxicity in mice by intraperitoneal injection, and 48 h later, 250 mg・kg-1 and 500 mg・kg-1 vitamin E were respectively used. Then at 72 h after cisplatin treatment, the serum level of urea nitrogen and creatinine were detected to evaluate the change of renal function, and the activities of malonaldehyde (MDA), superoxide dis-mutase (SOD), catalase (CAT), reduced glutathione (GSH) and glutathion peroxidase (GPX) in renal tissue were detected to evaluate the change of oxidative stress. Results Compared with normal mice, the serum level of urea nitrogen and creatinine as well as MDA in renal tissue significantly increased in 10 mg・kg-1 cisplatin-induced mice (P<0.01), while the activity of SOD, CAT, GSH and GPX in renal tissue were significantly reduced (P<0.01). Compared with 10 mg・kg-1 cisplatin-induced mice, serum level of urea nitrogen and creatinine as well as MDA in renal tissue of 250 mg・kg-1 and 500 mg・kg-1 vitamin E induced mice significantly reduced (P<0.01), and the activity of GPX in renal tissue of 250 mg・kg-1 vitamin E induced mice significantly increased (P<0.01), and so did the activity of GPX and CAT in renal tissue of 500 mg・kg-1 vitamin E induced mice (P<0.01), but no significant difference of the activity of SOD in renal tissue between the three groups was found (P>0.05). Conclusions High dose of vitamin E was effective to improve the renal function of cisplatin induced mice, and the decrease of oxidative stress may be involved.Keywords: Vitamin E; Antioxidant; Nephrotoxicity作者简介：张林，男，主治医生，研究方向：肾脏疾病和血液净化，E-mail: ssdlf@。

顺铂的肾脏毒性及其预防
丁大成;周际昌
【期刊名称】《肿瘤防治研究》
【年(卷),期】1990(17)3
【摘要】顺铂(Cisplatin DDP)是当前最有效的化疗药物之一,但是它也有许多不良反应,常见的有重度消化道反应、耳毒性、肾脏毒性、骨髓抑制、末梢神经病、离子紊乱等。

【总页数】2页(P185-186)
【关键词】顺铂;肾脏毒性;毒性;预防
【作者】丁大成;周际昌
【作者单位】
【正文语种】中文
【中图分类】R730.53
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化疗BEP方案的最新研究进展化疗在癌症治疗中一直扮演着重要的角色，其中 BEP 方案（博来霉素、依托泊苷、顺铂）是一种常用于治疗多种恶性肿瘤的化疗方案。

随着医学研究的不断深入，BEP 方案在近年来也取得了诸多新的研究进展，为癌症患者带来了更多的希望。

BEP 方案最初主要应用于生殖细胞肿瘤的治疗，如睾丸癌、卵巢癌等。

其作用机制是通过不同的途径干扰肿瘤细胞的生长和分裂，从而达到抑制肿瘤的目的。

博来霉素通过破坏肿瘤细胞的 DNA 结构发挥作用；依托泊苷则主要抑制肿瘤细胞的有丝分裂；顺铂则通过与 DNA 结合形成交叉联结，从而阻止 DNA 的复制和转录。

在最新的研究中，对于 BEP 方案的用药剂量和时间间隔进行了更精细的探索。

研究人员发现，根据患者的个体差异，如年龄、身体状况、肿瘤的分期和类型等，优化用药剂量和时间间隔，可以在保证疗效的同时，降低药物的毒副作用。

例如，对于年龄较大、身体较为虚弱的患者，适当减少药物剂量或延长用药间隔，能够减少骨髓抑制、胃肠道反应等不良反应的发生，提高患者的耐受性和生活质量。

同时，新的研究也在关注 BEP 方案与其他治疗手段的联合应用。

免疫治疗是当前癌症治疗领域的热点，将 BEP 方案与免疫治疗药物联合使用，显示出了协同增效的作用。

免疫治疗药物可以激活患者自身的免疫系统，增强对肿瘤细胞的识别和攻击能力，与 BEP 方案的化疗作用相结合，能够更有效地控制肿瘤的生长和转移。

此外，靶向治疗药物与 BEP 方案的联合应用也在研究之中。

靶向治疗药物能够针对肿瘤细胞特定的靶点发挥作用，精准地抑制肿瘤细胞的生长。

与 BEP 方案联合使用，有望进一步提高治疗效果，为患者带来更好的预后。

在药物不良反应的管理方面，也有了新的进展。

针对博来霉素可能引起的肺毒性，研究人员通过密切监测患者的肺功能指标，提前采取预防措施，如使用抗氧化剂、限制累积剂量等，有效地降低了肺毒性的发生率和严重程度。

对于依托泊苷可能导致的骨髓抑制，新的支持治疗方法，如使用造血生长因子等，能够促进骨髓造血功能的恢复，减少贫血、白细胞减少和血小板减少等并发症的发生。

顺铂致肾损伤中炎症介质作用机制的研究进展张启龙;聂克【摘要】炎症介质可以通过介导氧化应激、细胞凋亡、炎症反应、线粒体功能障碍等多种作用机制在顺铂致肾损伤的过程发挥重要作用,其中主要的炎症介质有血管活性胺、前列腺素、溶酶体成分、细胞因子、一氧化氮、神经肽、激肽、补体等.【期刊名称】《山东医药》【年(卷),期】2016(056)011【总页数】3页(P90-92)【关键词】顺铂;肾损伤;炎症介质【作者】张启龙;聂克【作者单位】山东中医药大学,济南250355;山东中医药大学,济南250355【正文语种】中文【中图分类】R453·综述·顺铂是目前临床上最常用的一线化疗药物，其抗肿瘤机制是抑制肿瘤细胞DNA的合成、转录，损伤细胞膜的正常结构，但是它在杀死肿瘤细胞的同时对人体正常组织细胞有很强的毒副作用，包括肾毒性、耳毒性、胃肠道反应、骨髓抑制、神经毒性、过敏反应等。

其中以肾毒性最为常见和严重，临床上约有三分之一的患者在接受化疗后出现不同程度的肾损伤。

顺铂的肾毒性成为限制其临床用药剂量的最主要原因。

顺铂导致的肾损伤与氧化应激、细胞凋亡、炎症反应、线粒体功能障碍等多种机制有关[1]。

炎症介质是炎症过程中产生的并介导炎症反应的化学物质，根据产生炎症介质位置的不同将其分为组织源性与血浆源性。

多种炎症介质在肾损伤的发生机制中起重要作用。

现就顺铂致肾损伤中炎症介质的作用机制研究进展进行综述。

1.1 血管活性胺类5-羟色胺(5-HT)是一种常见的血管活性胺，它能刺激血管的收缩，增加血管壁的通透性，而多巴胺(DA)在低浓度的情况下对血管有舒张作用。

实验[2]表明，5-HT与DA含量的动态平衡可以调节肾脏血管的压力，顺铂可以刺激胃肠道嗜铬细胞释放5-HT，大幅升高血液中5-HT的含量，破坏5-HT与DA之间的动态平衡，导致肾脏血压升高，入球小动脉血管收缩，肾血流量减少，肾小球损伤。

应用5-HT2A拮抗剂，如沙格雷酯可以有效降低肾脏的血压，改善肾脏慢性缺血，同时可以很好地抑制肾成纤维细胞纤维化，缓解肾损伤[3]。

顺铂作用机制ethods: In order to culture A549 cells in vitro, use hemocytometer to test gro216，全称为顺式-二氯-反式-乙酸（氨环已胺）合铂（Ⅳ），是第一个进入临床试验的口服铂（Ⅳ）药物。

由美国施贵宝公司、英国Johnson Matthey公司和癌症研究所共同开发。

与顺铂无交叉耐药，与鬼臼素有协同抗癌作用，毒性为骨髓抑制，Ⅱ期单药临床研究表明，该药对小细胞肺癌、顽固性前列腺癌有效，对其它一些癌种的临床试验正在进行之中。

此外，在28个进入临床的铂类抗癌药物中,因疗效欠佳或毒副作用大而被淘汰的药物有近20个.如顺铂类化合物的环戊胺铂、铂蓝、环丙胺铂、乙二胺丙二酸铂等；卡铂类化合物的恩络铂、僧尼铂、NK-121等；环已二胺类化合物的环硫铂、DACCP等，四价铂类化合物的奥玛铂等。

目前，全世界的科学家们仍在继续寻找综合评价优于顺铂和卡铂的新一代药物。

同时，还在进一步研究顺铂和卡铂的联合用药方案，以扩大它们在癌症治疗中的适应证和提高疗效。

篇三：顺铂肾毒性机制及其防护的研究进展顺铂肾毒性机制及其防护的研究进展顺铂(CDDP)是一种高效广谱的抗肿瘤药，容易引起胃肠道反应、骨髓抑制、耳毒性等不良反应。

尤其是它在肾脏中高聚集、高排泄、高代谢，其肾毒性作用尤为突出。

统计显示[1]，临床顺铂化疗肾损害发生率为25%_35%，如何降低其肾毒性，是目前急需解决的课题。

1 顺铂肾毒性机制顺铂在高氯环境下活性低，但当其进入低氯的细胞内液后活性增高，很快发生水合解离，生成带正电荷的水合配离子，受DNA静电引力的作用，向细胞核迁移，形成 cis-［Pt(NH3)2］2/DNA加合物。

加合作用改变了DNA 正常复制模版的功能，引起DNA复制障碍，从而抑制肿瘤细胞的分裂[2]。

顺铂的肾毒性是否与这一机制有关尚未明确。

研究表明，氧化性损伤是顺铂肾毒性的机制之一。

1 Springer14 February 2012/Published online: 1 March 2012 Arch Toxicol (2012) 86:1233-1250 DOI 10.1007/s00204-012-0821-7RE VI EW AR TIC LECisplatin-induced nephrotoxicity and targets of nephroprotection: an updateNeife Aparecida Guinaim dos Santos • Maria Augusta Carvalho Rodrigues •Nadia Maria Martins • Antonio Cardozo dos SantosReceived: 26 January 2012/Accepted: © Springer-Verlag 2012Abstract Cisplatin is a highly effective antitumor agent whose clinical application is limited by the inherent nephrotoxicity. The current measures of nephroprotection used in patients receiving cisplatin are not satisfactory, and studies have focused on the investigation of new possible protective strategies. Many pathways involved in cisplatin nephrotoxicity have been delineated and proposed as targets for nephroprotection, and many new potentially protective agents have been reported. The multiple pathways which lead to renal damage and renal cell death have points of convergence and share some common modulators. The most frequent event among all the described pathways is the oxidative stress that acts as both a trigger and a result. The most exploited pathways, the proposed protective strategies, the achievements obtained so far as well as conflicting data are summarized and discussed in this review, providing a general view of the knowledge accu-mulated with past and recent research on this subject. Keywords Cisplatin - Nephrotoxicity - Nephroprotection - Oxidative stress - Apoptosis - Molecular mechanisms - Mitochondria CisplatinCisplatin (cisplatinum or cis-diamminedichloroplatinum (II), CDDP) is a highly effective chemotherapeutic drugN. A. G. dos Santos - M. A. Carvalho Rodrigues - N. M. Martins - A. C. dos Santos (&)Department of Clinical, Toxicological Analyses and Food Sciences of School of Pharmaceutical Sciences of Ribeirao Preto, University of Siio Paulo, Ribeiriio Preto, SP, Brazil e-mail: acsantos@p.brwhose anticancer activity was accidentally discovered by the physicist-biologist Barnett Rosenberg, during his studies addressing the effect of a platinum electrode-generated electric field on the division processes of Escherichia coli. He observed that the cellular division was inhibited and a filamentous growth was induced by electrolysis products thatwere afterward identified as platinum compounds. Based on this observation, he and his colleagues investigated the antitumor activity of platinum compounds in leukemia L1210- and Sarcoma 180-bearing mice. The antitumor efficacy of cisplatin was then discovered (Rosenberg et al. 1965, 1967, 1969).The clinical use of cisplatin was approved by the FDA in December 1978 (FDA database). Since then, the application of cisplatin has been broadened to several types of cancer and it has been used both alone or combined with other drugs: as first-line treatment, as adjuvant, or even as neoadjuvant therapy of other procedures such as surgery or radiotherapy. Currently, the use of cisplatin is approved to treat bladder cancer, cervical cancer, malignant mesothelioma, non-small cell lung cancer, ovarian cancer, squamous cell carcinoma of the head and neck, and testicular cancer (National Cancer Institute database). Additionally, cisplatin has been used to treat other types of cancer when the first-line treatment has failed or yet in specific situations that preclude the standard treatment (Candelaria et al. 2006; Helm and States 2009; Goffin et al. 2010; Campbell and Kindler 2011; Ismaili et al. 2011a, b).Cisplatin chemotherapy is limited by tumor cells resistance and severe side effects such as nephrotoxicity, neurotoxicity, ototoxicity, and emetogenicity (Wang and Lippard 2005; Pabla and Dong 2008). Among these factors, nephrotoxicity has been reported as the major limiter in cisplatin therapy (Arany and Safirstein 2003).The susceptibility of kidneys to cisplatin toxicityKidneys are particularly affected by cisplatin, and this has been attributed mainly to (a) high concentration of cisplatin in the kidneys and (b) the renal transport systems. Cisplatin is eliminated predominantly by the kidneys; the biliary and the intestinal excretion of this drug are minimal. During the excretion process, the drug is concentrated and even nontoxic blood levels of cisplatin might reach toxic levels in kidneys. In fact, it has been reported that the concentration of cisplatin in epithelial tubular cells is fivefold higher than in blood (Rosenberg 1985; Bajorin et al. 1986; Gordon and Gattone 1986; Kuhlmann et al. 1997; Schenellmann 2001). The nephrotoxicity induced by cisplatin is dose-dependent and therefore limits the increase of doses, compromising the efficacy of the therapy (Hanigan and Devarajan 2003). The toxic effects occur primarily in the renal proximal tubules, particularly in the epithelial tubular cells of S-3 segment (Werner et al. 1995). Glomeruli and distal tubules are also affected afterward. Impairment of the renal function is found in approximately 25-35% of patients treated with a single dose of cisplatin (Han et al. 2009). Decrease of 2040% of glomerular filtration, increased BUN (blood urea nitrogen), and increased serum creatinine concentrations as well as reduced serum magnesium and potassium levels are frequent in patients treated with cisplatin (Ries and Klastersky 1986; Kintzel 2001; Han et al. 2009).The high concentration of cisplatin in kidneys favors its cellular uptake by passive diffusion (Gale et al. 1973; Gately and Howell 1993), and this was once considered the main process through which cisplatin entered and accumulated in cells. More recently, active transport systems have gained importance and have been associated with tumor cells resistance as well as the toxicity of cisplatin (Ishida et al. 2002; Pabla et al. 2009; Burger et al. 2011). The facilitated transport systems which have been associated with cisplatin nephrotoxicity are those mediated by the organic cation transporter OCT2 and more recently, the copper transporter Ctr1. In 2002, Ishida and colleagues proposed that cisplatin uptake was mediated by the copper transporter Ctr1 in yeast and mammals (Ishida et al. 2002). Although Ctr1 is highly expressed in kidney (Sharp 2003), it was first associated with cisplatin uptake by non-renal cells and only recently a study associated Ctr1 with cis- platin uptake in renal cells and therefore nephrotoxicity (Pabla et al. 2009). OCT2 is highly expressed in the basolateral membrane of proximal tubules and has been reported to participate in the renal accumulation of cisplatin (Ludwig et al. 2004; Ciarimboli et al. 2005; Yonezawa et al. 2005).It has been reported that OCT1/2 double-knockout mice treated with cisplatin presented only a mild nephrotoxicity as well as reduced renal platinum accumulation when compared to wild-type mice (Ciarimboli et al. 2005). Additionally, it was reported that the concomitant administration of imatinib, a cationic anticancer agent, with cis- platin prevented cisplatin-induced nephrotoxicity by inhibiting the OCT2-mediated renal accumulation of cis- platin (Tanihara et al. 2009). In vivo and in vitro studies have shown that cimetidine inhibits cisplatin renal damage without affecting its antitumor activity (Katsuda et al. 2010). However, in another study with cimetidine in vivo, only a partial protection against cisplatin-induced nephrotoxicity was observed. The nephroprotective action of cimetidine has been attributed to (i) a competitive inhibition of cisplatin transport by OCT2, since cimetidine is an organic cation and therefore an OCT substrate (Ciarimboli et al. 2005); and (ii) inhibition of cytochrome P450 with blockade of iron release and consequently inhibition of hydroxyl radicals generation (Baliga et al. 1998). The protective effect of cimetidine has also been shown in a clinical trial with nine patients treated with cisplatin, verapamil, and cimetidine (Sleijfer et al. 1987). Another strategy to blockade cisplatin uptake in renal cells is the inhibition of Ctr1. In fact, it has been reported that CTR1- deficient cells accumulate less platinum in their DNA and are more resistant to the cytotoxic effect of cisplatin than the CTR1-replete cells (Lin et al. 2002). The antitumor mechanism versus the nephrotoxic mechanismThe molecule of cisplatin is formed by a central platinum ion linked to 2 chloride ions and 2 ammonia molecules. Neither the antitumor activity nor the nephrotoxicity of cisplatin results from the heavy metal platinum itself, since both effects are stereospecific to the cis isomer, not occurring with the trans isomer (Goldstein and Mayor 1983). Instead, the cytotoxicity of cisplatin is related to highly reactive aquated metabolites, whose formation is determined by the concentration of chloride ions. As the intracellular concentration of chloride (20 mM) is lower than the blood concentration (100 mM), cisplatin remains unaltered in the bloodstream, but undergoes hydrolysis in the intracellular environment, originating positively charged molecules in which one or two chloride ions have been replaced by water. These aquated forms easily react with the nuclear DNA, forming covalent bonds with purine bases, primarily at the N7position, resulting in 1,2-intrastrand crosslinks, which are the main responsible for the genotoxic effects of cisplatin. These crosslinks between DNA and cisplatin lead to the impairment of replication and transcription, resulting in cell cycle arrest and eventually apoptosis (Jamieson and Lippard 1999; Wong and Giandomenico 1999; Cohen and Lippard 2001; Wang and1 SpringerLippard 2005). The apoptosis triggered by DNA damage is mediated by the tumor suppressor gene p53 that activates pro-apoptotic genes and repress anti-apoptotic genes (Jiang et al. 2004; Norbury and Zhivotovsky 2004; Jiang and Dong 2008). The dividing tumor cells are particularly susceptible to DNA damage, and the anticancer activity of cisplatin has been mainly attributed to DNA adducts formation (Eastman 1999; Hanigan and Devarajan 2003). However, some studies have suggested that nuclear DNA adducts formation may not be the only determinant of cisplatin pharmacological effect and that mitochondrial DNA (mtDNA) might be a more common target of cis- platin binding, due to its weaker repair (Olivero et al. 1997; Gonzalez et al. 2001; Yang et al. 2006; Cullen et al. 2007).In adult humans, proximal tubular cells are non-dividing; therefore, the formation of adducts with DNA might not play a key role in cisplatin nephrotoxicity (Wainford et al. 2008). Besides nuclear and mitochondrial DNA, cisplatin targets other cellular components such as RNA, proteins, and phospholipids and distinct mechanisms have been associated with the toxic effects of cisplatin on healthy renal cells. Oxidative damage and inflammatory events might explain the effects on other cellular constituents and have been associated with cisplatin-induced nephrotoxicity (Cvitkovic 1998; Ali and Al Moundhri 2006; Yao et al. 2007; Pabla and Dong 2008). Several lines of evidence indicate that cisplatin nephrotoxicity is mainly associated with mitochondria-generated oxygen reactive species (ROS) (Matsushima et al. 1998; Somani et al. 2000; Chang et al. 2002; Wang and Lippard 2005; Santos et al. 2007; Santos et al. 2008). Alterations in renal hemodynamic modulators have also been associated with the toxic effects of cisplatin on kidneys (Hye Khan et al.2007).It has been suggested that cisplatin is conjugated with reduced glutathione (GSH) in the liver and reaches the kidney as a cisplatin-GSH conjugate, which is cleaved to a nephrotoxic metabolite mainly by the action of gamma- glutamyl transpeptidase (GGT), an enzyme primarily located in the brush border of the proximal convoluted tubule of the kidney. The metabolite formed is a highly reactive thiol/platinum compound that interacts with macromolecules leading eventually to renal cell death (Ward 1975; Wainford et al. 2008). The interference in this biotransformation pathway has been proposed as an approach to prevent the formation of the nephrotoxic metabolite and therefore, minimizing cisplatin nephrotoxicity. It has been demonstrated that GGT-deficient mice are resistant to the nephrotoxic effects of cisplatin (Hanigan et al. 2001). Additionally, studies have demonstrated that inhibition of GGT with acivicin, both in mice and in rats, protected against the nephrotoxicity of cisplatin (Hanigan et al. 1994; Townsend and Hanigan 2002). The participation of other enzymes such as aminopeptidase N (AP-N), renal dipeptidase (RDP), and cysteine-S-conjugate beta-lyase (C-S lyase) in this toxificant pathway has been reported. The following sequence has been proposed: after cisplatin-GSH conjugates are secreted into the proximal tubule lumen and cleaved by GGT, a cysteine-glycine conjugate is formed and then cleaved by the cell surface aminopeptidases, AP-N, or RDP, to a cysteine conjugate, which is then reabsorbed into proximal tubular cells and finally metabolized by C-S lyase to toxic reactive thiols resulting in nephrotoxicity (Hanigan et al. 1994; Townsend and Hani- gan 2002; Townsend et al. 2003; Zhang and Hanigan 2003). The inhibition of C-S lyase with amino oxyacetic acid was protective in mice treated with 15 mg/kg cisplatin (Town-send and Hanigan 2002); however, opposing data have been reported. According to a more recent study, AP-N, RDP, and CS-lyase inhibition were non-protective against nephrotoxicity in mice treated with 10 mg/kg cisplatin and/or in rats treated with 6 mg/kg cisplatin (Wainford et al. 2008).A second-generation platinum-protecting disulfide drug named BNP7787 (disodium 2,2-dithio-bis-ethane sulfonate, dimesna, Tavocept TM) was developed to specifically inactivate the toxic platinum species found in normal organs in order to reduce or prevent common toxicities of platinum chemotherapeutic drugs (Hausheer et al. 1998). BNP7787 is selectively taken up by the kidneys where it is converted into mesna (Ormstad and Uehara 1982). BNP7787 may accumulate in renal tubular cells, where it can exert its protective effects against cisplatin-induced nephrotoxicity by direct covalent conjugation of mesna with cisplatin (Hausheer et al. 2011a). Besides the formation of this inactive adduct with cisplatin, other mechanisms might be involved in the protection: (a) inhibition of GGT, (b) inhibition of AP-N, and (c) inhibition of C-S lyase (Hausheer et al. 2010, 2011b). Additionally, it was reported that BNP7787 does not interfere in the antitumor activity of cisplatin in human ovarian cancer cell lines in vitro or in nude mice bearing human ovarian cancer xenografts (Boven et al. 2002). The drug is currently undergoing global Phase III studies (Hausheer et al. 2011a).Mechanisms of cell death in cisplatin-induced nephrotoxicity1 Springerinvolved in cisplatin-induced nephrotoxicityCisplatin induces two models of cell death: apoptosis and necrosis. Initially, only necrosis was associated with the renal damage induced by cisplatin (Goldstein and Mayor 1983); afterward, the induction of apoptosis was also demonstrated. A study published in 1996 demonstrated that high concentrations of cisplatin (800 (iM) induced necrosis in primary cultures of mouse proximal tubular cells, while lower concentrations (8 (iM) led to apoptosis(Lieberthal1 Springeret al. 1996). More recently, several studies have demonstrated that both the mechanisms of cell death are induced by cisplatin in vivo (Baek et al. 2003; Tsuruya et al. 2003; Wang and Lippard 2005). The relative contribution of both types of cell death, apoptosis, and necrosis, to cisplatin nephrotoxicity has not been established yet (Bonegio and Lieberthal 2002; Faubel et al. 2004). However, apoptosis has been in the spotlight in the last years. Necrosis has been mainly associated with high doses of cisplatin, severe mitochondrial damage, and ATP depletion, whereas apoptosis is a process dependent on ATP energy and therefore associated with the milder mitochondrial alterations resulting from therapeutic doses (Lieberthal et al. 1998; Ueda et al. 2000; Hanigan and Devarajan 2003; Wang and Lippard 2005).Different apoptotic pathways are triggered by cisplatin in renal tubular epithelial cells (RTEC). The main reported pathways are (a) the intrinsic pathway, which is triggered by mitochondria and (b) the extrinsic pathway, which is mediated by TNF (tumor necrosis factor) receptor/ligand and Fas (APO — 1 or CD95)/Fas ligand systems (Ramesh and Reeves 2002). Additionally, the endoplasmic reticulum stress (ER stress) pathway has also been demonstrated in cisplatin-induced apoptosis in RTEC (Liu and Baliga 2005). The mechanisms of nephrotoxicity induced by cisplatin are summarized in Fig. 1, and the potential cytoprotectors which interfere in these pathways are summarized in Table 1.Intrinsic or mitochondrial apoptotic pathway Mitochondrial injury in RTEC leads to the release of apoptogenic factors, including cytochrome c, Smac/DIA- BLO, Omi/HtrA2, and apoptosis-inducing factor or AIF (Daugas et al. 2000a; Servais et al. 2008). The migration of cytochrome c to cytosol is a key event in caspases activation, and the following sequence of events has been described: formation of Apaf-1/cytochrome c apoptosome, caspase-9 activation, and ultimately the activation of the executioner caspase-3 (Lee et al. 2001; Park et al. 2002; Cullen et al. 2007). Smac/DIABLO and Omi/HtrA2 inhibit the suppressors of apoptosis, IAPs (inhibitor of apoptosis proteins), which interfere in the cytochrome c/Apaf-1/ caspase-9 activating pathway. Omi/HtrA2 can also promote apoptosis through its serine protease activity, a mechanism independent of caspases (Du et al. 2000; Cil- enti et al. 2005). AIF is a protein that translocates to the nucleus and promotes apoptosis without the activation of caspases (Daugas et al. 2000a).12n1 Springer1 Does not change cisplatin-antitumor action in the experimental model 12n1240Arch Toxicol (2012) 86:1233-125012nCisplatin can trigger the mitochondrial apoptotic pathway through different stimuli such as increased ROS generation and the activation of pro-apoptotic proteins (Hanigan and Devarajan 2003), which permeabilize the outer mitochondrial membrane and induce the release of cytochrome c (Lee et al. 2001; Park et al. 2002), AIF (Seth et al. 2005) and Omi/HtrA2 (Cilenti et al. 2005).Mitochondrial dysfunction is considered a key event in cisplatin-induced renal damage. Decline in membrane electrochemical potential, disturbance in calcium homeostasis, reduced ATP synthesis, and impaired mitochondrial respiration have been demonstrated in kidneys of rats treated with cisplatin (Santos et al. 2007; Rodrigues et al. 2010).It is known that cisplatin can damage complexes I, II, III, and IV of the mitochondrial respiratory chain, increasing the generation of superoxide anions at complexes I, II, and III. Superoxide anions might originate hydroxyl radicals by partial reduction catalyzed by transition metals, mainly iron (Fenton reaction) (Kruidering et al. 1994, 1997; Turrens 2003; Yao et al. 2007). Hydroxyl radicals are very strong oxidants, and their induction has been demonstrated in kidneys of rats treated with cisplatin (Matsushima et al. 1998; Santos et al. 2008). The oxidative damage induced by cisplatin has been associated with depletion of the non-enzymatic (GSH and NADPH) and the enzymatic antioxidant defense system (superoxide dismu- tase, catalase, glutathione peroxidase, glutathione transferase, and glutathione reductase) in rat kidneys (Hannemann et al. 1991; Sadzuka et al. 1992; Antunes et al. 2000; Kadikoylu et al. 2004). Lipoperoxidation, oxidation of cardiolipin, oxidation of sulfhydryl protein, increased carbonylated proteins levels, decreased activity of aconitase, cytochrome c release, increased activity of caspase-9, and caspase-3 have also been associated with the renal damage induced by cisplatin (Kaushal et al. 2001; Park et al. 2002; Santos et al. 2007). Cytochrome c is attached to the inner mitochondrial membrane (IMM), and its release occurs due to the loss of the mitochondrial membrane integrity. The mitochondrial membrane is a target of the oxidative species that attack proteins and lipids, particularly the anionic phospholipid cardiolipin, located in IMM. As cardiolipin holds cytochrome c attached to IMM, its oxidation contributes to cytochrome c release to cytosol (Petrosillo et al. 2003). Cardiolipin is also a target of caspase-2 and Bid, a pro-apoptotic protein from the Bcl 2 family, which promotes a link between the extrinsic and intrinsic apoptotic pathways, since it is activated by caspase-8 (extrinsic pathway) and acts on mitochondria promoting the apoptotic intrinsic pathway (Enoksson et al. 2004; Campbell et al. 2008; El Sabbahy and Vaidya 2011). Besides increasing mitochondrial ROS generation, cisplatin activates the pro-apoptotic proteins Bax and Bak, upstream mitochondrial injury. These proteins induce the permeabilization of the outer mitochondrial membrane and therefore, cytochrome c release and caspases activation (Lee et al. 2001; Park et al. 2002; Cullen et al. 2007). The nephrotoxicity induced by cisplatin is attenuated in Bax/Bak-knockout cells and in Bax-deficient mice (Jiang et al. 2006; Wei et al. 2007a). Erythropoietin (EPO), a renal cytokine which regulates hematopoiesis, has been shown to reduce apoptosis during cisplatin nephrotoxicity by the up-regulation of anti-apop- totic proteins expression, down-regulation of pro-apoptotic protein levels, and reduction of caspase-3 activity (Rjiba- Touati et al. 2012). Besides the apoptosis dependent of caspases activation, cisplatin can also trigger a mitochondrial mediated and caspase-independent apoptotic pathway through the apop- tosis-inducing factor (AIF), a protein located in the mito-chondrial intermembrane space and present in renal epithelium. When the outer mitochondrial membrane is damaged, AIFtranslocates to the nucleus inducing chromatin condensation and large-scale DNA fragmentation. The anti-apoptotic Bcl-2 protein preserves the mitochondrial membrane integrity, preventing both the release of cytochrome c and translocationof AIF to the nucleus (Daugas et al. 2000b; Adams and Cory 2001). The release of AIF has been reported to be dependent on caspase-2, which is activated by PIDD, a p53-induced protein with death domain. Caspase-2 permeabilizes the outer mito-chondrial membrane and damages anionic phospholipids, causing release of pro-apoptotic factors such as cytochrome c and AIF. Inhibition of caspase-2 and inhibition of AIF have been reported as protective against cisplatin- induced renal damage (Daugas et al. 2000b; Enoksson et al. 2004; Seth et al. 2005; Jiang and Dong 2008; Servais et al. 2008).The transcriptional factor p53 activates pro-apoptotic genes encoding Bax, Bak, PUMA-a, PIDD, and the ER- iPLA2 (Ca 2?-independent phospholipase A2) and down- regulates the anti-apoptotic proteins Bcl-2 and Bcl-xL, leading to the mitochondrial apoptotic pathway (Seth et al. 2005; Jiang et al. 2006; Jiang and Dong 2008; Servais et al.2008) . The involvement of ROS, particularly hydroxyl radicals, in p53 activation during cisplatin nephrotoxicity has been suggested (Jiang et al. 2007), and the crucial role of hydroxyl radicals in cisplatin nephrotoxicity has been demonstrated (Santos et al. 2008).Due to the importance of ROS and oxidative stress in the induction of apoptotic cell death, particularly of the intrinsic pathway, one of the most studied approaches to protect against cisplatin nephrotoxicity is the use of natural and synthetic antioxidants. Experimental studies have reported the protective effects of natural compounds such as vitamins C (Tarladacalisir et al. 2008), E (Ajith et al.2009) , and A (Dillioglugil et al. 2005); resveratrol (Do Amaral et al. 2008), quercetin (Francescato et al. 2004), and caffeic acid phenethyl ester (Ozen et al. 2004); naringenin (Badary et al. 2005) and lycopene (Atessahin et al. 2005), as well as synthetic compounds such as DMTU (Santos et al. 2008), DMSO (Jones et al. 1991), carvedilol (Rodrigues et al. 2010), allopurinol plus ebselem (Lynch et al. 2005), edaravone (Satoh et al. 2003; Iguchi et al. 2004), desferrioxamine (DFO) (Kadikoylu et al.2004) , and many others. Antioxidants protect kidneys from cisplatin damage mainly by free radical scavenging or iron chelation (Koyner et al. 2008). As ROS plays a role in the inflammatory pathway, antioxidants may also interfere positively in the inflammatory process. The nephroprotec- tive effect of quercetin, for example, seems to be related with its antioxidant activity as well as with its capacity to inhibit renal inflammation and tubular cell apoptosis. Quercetin has been shown to inhibit lipopolysaccharide- induced TNF-a and NO- production through attenuation of NF-kB activity in macrophages, microglia cells, and mast cells. Quercetin prevents the renal damage of cisplatin without affecting the antitumor activity of cisplatin in tumor-bearing rats (Sanchez-Gonzalez et al. 2011b).Some of the antioxidants which successfully protected against cisplatin nephrotoxicity in experimental studies cannot be clinically applied due to their intrinsic toxicity. One example is DMTU, an interesting small and highly diffusible molecule, which effectively scavenges hydroxyl radicals and prevents oxidative injury in different biological systems, but has been associated with fetotoxicity and lung damage (Milner et al. 1993; Beehler et al. 1994; Santos et al. 2008). The importance of these kinds of compounds is that (a) they help to delineate mechanisms and specific events involved in the toxicity/protection and (b) might be used as models for the development of new protective drugs with less intrinsictoxicity. In this context, compounds which have been proved safe in a different clinical application and also possess antioxidant properties, such as the antihypertensive carvedilol (Rodrigues et al.2010)and the antihyperuricemic allopurinol (Lynch et al. 2005), might be interesting alternatives.The dietary antioxidants such as vitamins A, C, and E and some flavonoids might act as pro-oxidants under some specific conditions; vitamin C and quercetin, for example, induce free radical production in the presence of transition metals (Laughton et al. 1989; Tirosh et al. 1996; Schmal- hausen et al. 2007; Santos 2012). Some studies have shown that the pro-oxidant activity of some flavonoids potentiate the antitumor activity of cisplatin. The flavonoids, 20,50- dihydroxychalcone (20,50-DHC, 20 (iM), and chrysin (20 (iM) potentiated the cytotoxicity of cisplatin in human lung adenocarcinoma (A549) cells and the mechanism of action was attributed to GSH depletion (Kachadourian et al. 2007). Cytotoxicity of quercetin in human leukemia cells HL-60 has been attributed to its pro-oxidant action (Sergediene et al. 1999). Additionally, it has been demonstrated that quercetin increases the efficacy of cisplatin in nude mice implanted with human tumor xenografts (Hofmann et al. 1990), in human non-small cell lung carcinoma H-520 cells (Kuhar et al. 2006), and in human head and neck cancer (Sharma et al. 2005). Therefore, while antioxidants have been shown to effectively prevent the nephrotoxicity of cisplatin, some of them might also be pro-oxidant and exacerbate the oxidative damage to healthy tissues or on the hand, interfere positively, sensitizing tumor cells to the action of cisplatin. The delicate balance among these effects determines the final outcome of the adjuvant therapy with antioxidants during cisplatin che-motherapy. Besides that, although the antitumor and toxic mechanisms induced by cisplatin seem to be distinct, there is a general concern that the antioxidant therapy might interfere in the antitumor efficacy. Further clinical studies are needed to establish the real role of antioxidants in cisplatin chemotherapy.Sulfhydryl compounds constitute a particular group of antioxidants that have also been reported to decrease the toxicity of platinum compounds. Their action includes restoration of thiol enzymes function, free radical scavenging, formation of non-toxic adducts, reduction in cis- platin uptake by renal cells, and increase in the urinary excretion of cisplatin (Santos 2012). The nephroprotective effect of diethyldithiocarbamate (DDTC), GSH, D-methi- onine, amifostine, sodium thiosulphate (STS), N-acetyl- cysteine (NAC), and lipoic acid has been demonstrated (Cvitkovic 1998; Wu et al. 2005; Bae et al. 2009); however, studies indicate that the thiol moiety react with cisplatin resulting in the formation of an inactive platinum- thiol conjugate (Hausheer et al. 1998). Different from the antioxidants that act as reducing agents, GSH, NAC, and STS are nucleophiles, and therefore can covalently bind to the electrophilic intermediates of cisplatin reducing the antitumor efficacy (Conklin 2004). A recent in vitro study demonstrated that tumor growth was statistically significantly increased when STS were administered simulta-neously with cisplatin or 4-hours after cisplatin (Yee et al. 2008). It was also demonstrated that STS, GSH, and NAC can prevent, and moreover, revert (only NAC and STS) the formation of cisplatin-DNA adducts in whole blood (Brouwers et al. 2008). In order to overcome the interaction between sulfhydryl agents and cisplatin, the administration by two different routes, for example, intravenous and intraperitoneal, respectively, has been proposed (Guastalla et al. 1994).Like other antioxidants, thiols might also have prooxidant action. It has been reported that thiols produce superoxide radicals causing low-density lipoproteins (LDL) oxidation (Heinecke et al. 1993; Tirosh et al. 1996).The thiophosphate amifostine (WR 2721) is approved by the FDA for minimizing renal toxicity in patients receiving cisplatin. It is a pro-drug which is converted to the active free thiol WR 1065, a scavenger of ROS (Cvitkovic 1998). The limitation factors of the use of amifostine include: high costs, side effects, and concerns that it might interfere in the antitumor efficacy of cisplatin (Koyner et al. 2008), although some studies suggest it does not. An in vitro study demonstrated that amifostine inhibits DNA platination and is also able to reverse part of the cisplatin-DNA adducts formed, but different from the other thiols tested (DDTC and STS), and amifostine does not interfere in the antitumor efficacy of cisplatin. Additionally, clinical studies with amifostine have not provide the evidence of impairment of antitumor activity (Block and Gyllenhaal 2005). The relative success of amifostine has been attributed to the selective formation, uptake, and accumulation of the active metabolite WR1065 in normal tissues (Treskes et al. 1992; Block and Gyllenhaal 2005).There are also reports of ineffectiveness of amifostine. Severe nephrotoxicity, among other toxicities, has been reported in some patients treated with cisplatin despite the use of the drug (Sastry and Kellie 2005; Katzenstein et al. 2009). The side effects of amifostine might be serious and include severe hypotension, ototoxicity, nausea, dizziness, vomiting, transient decrease in serum calcium levels, infusion-related flushing, and skin reactions (Gandara et al. 1990; Kemp et al. 1996; Block and Gyllenhaal 2005; Hausheer et al. 2011b). Subcutaneous administration seems to reduce its toxicity (Block and Gyllenhaal 2005).Extrinsic pathway, dependent on caspase-8The extrinsic apoptotic pathway is activated when a ligand binds to death receptors on the cytoplasmic membrane of cells, recruiting, and activating caspase-8, which in turn activates the effector caspase-3 (Strasser et al. 2000).12n。

铂类抗肿瘤药物相关肾损伤作用机制的研究进展闫菲菲(综述);段建春;王洁(审校)【期刊名称】《中国肺癌杂志》【年(卷),期】2015(18)9【摘要】Platinum derivatives are the most widely used chemotherapeutic agents to treat solid tumors including ovarian, head and neck, and testicular germ cell tumors, lung cancer, and colorectal cancer. Two major problems exist, however, in the clinic use of platinum derivatives. One is the development of tumor resistance to the drug during therapy, leading to treatment failure. hTe other is the drug’s toxicity such as the cisplatin’s n ephrotoxicity, which limits the dose that can be admin-istered. hTis paper describes the mechanism of platinum derivatives induced kidney injury.%铂类药物是目前应用最广泛的抗肿瘤药物之一，广泛应用于卵巢癌、睾丸肿瘤、头颈部肿瘤、肺癌和结直肠癌等恶性实体瘤中，然而，其严重的不良反应以及耐药问题限制了其临床应用。

同时该类药物可引起较严重的不良反应，从而限制了铂类药物的临床应用范围。

其中，限制顺铂使用的最主要因素是肾脏毒性。

本文就不同铂类药物引起肾损伤的作用机制进行综述。