顺铂肾毒性研究进展最新

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一氧化氮在顺铂耳、肾毒性中的作用

ｒａｉｎｎｈｅｅｌｏｔｃｔｏｌｅｃｔｏｉｔｏｓｃｌｓｆｈｅｏｎｒｇｒｏｕｐ．Ｃｏｌｉｓ：Ｎｉｒｃｎｃｕｓｏｎｔｉｏｘｄｅｉｍａｅｐａａｎｍｐｔｔｏｌｉｙｂｌｙｉｏｒａｎｒｅｎ
ｏｔｔｉｉｙａｎｐｏｏｘｉｉｙｏｉｐｌｔｎ．ｏｏｘｃｔｄｎｅｈｒｔｃｔｆｃｓａｉ
ＫＥＹｏＲＤＳＷ
ＮｉｉｏｉｅｐａｍａｏｏｙＣｉｐａｉ／ｄｅｓｆｅｔＥａｉｅｓｓｉｔｃｘｄ／ｈｒｃｌｇｒｓｌｔｎａｖｒｅｅｆｃｒｄｓａｅ／ｍｍｕｏｏｙｎｌｇ
损害最为严重。
一
本研究通过建立顺铂中毒的动物模型，用免疫应
组织化学的研究方法观察内耳及肾脏中ｉＮＯＳ表达活
ｓａｎｉｏｉｕｃｂｌｉｒｃｏｄｅｓｎｔｓｎｉｅｉｅｌｄｏｕｅｒｈａｒｃｌｓｏｆｔｏｃｅｎｄｔｅｌｆｔｉｎｇｔｎｄｉｅｎｔｉｘｉｙｈａｅｉｎｎｒｈａｒｃｌｓａｎｔｉｅｌｈｅｃｈｌａａｈｅｃｌｓｏｐｒｉａｏｏｌｅｕｂｕｌｓａｎｓａｏｏｘｍｌｃｎｖｕｔｄｔｅｄｄｉｔｌｃｎｖｏｕｅｄｔｕｌｓｏｈｅｅｅｉｅａｏｕｐｌｔｕｂｅｆｔｘｐｒｍｎｔｌｇｒｗｈｉｅｈｅｅｗａｇａｉｌｔｒｓｎｅｔｖｅ
（ｈｉｘｕｎ５Ｏ０Ｓｉａｈａｇ０Ｏ０）ＱｉａｇＬｕＹａｘｎＬｎｅｌＪＸｉｎｉｎｉｇｕＨｏｇｔａ

复合氨基酸缓解顺铂治疗肺癌患者肾毒性临床观察

ｏｅａｙａｎ．ｈＵ（ｌｄｕｅｉｏｅ）ｓＲ（ｅｕｒａｎｅ，Ｃｃａｎｅｌａｎｅ，ＳｕｉｅｔｒｐｏｅＴｅＢＮｂｏｒａｎｔｇｎ，Ｃｈｌｏｒｓｒｍｃｅｔｉ）ｃｒ（ｒｔｉｃｒｃ）ｕＧ（ｒｉｎｅｉｎｅａｎｓｅｉｃａｉ）ｎｐｕｎｏｅｏｙｒｇｎｅｅｍｎｔｅｙａｉｌａｄｆｒｔｉｅｐｉｔ．ｅｕｔｐｃｖｙａｄｕＨ（ｒｅｐｗｒｆｄｏｅ）ｗｒｏｉｒｄｎｃｙｔｉｅｅｍｏｓＲｓｌｉｒｆｇｔｉｈｏｄｍａｆｎｔｌｎｓ
ＷＮＡＧ ‘ ＨＵＳｉｉｎ，Ａａ—ｉ（．ｎｕｒｖｃｌｏｉｌＨｆｉ３０１Ｃｉ；．ａｒＷｒ，ｅ，ｈ—ａＴＮＧＨｉｎ１Ａｈｉｏｉｉｓｔ，ｅ００，ｈｎ２ＣｄｅａｄｔｌｑＰｎａＨｐａｅ２ａｈＦｒｆｌｔｏｉｌｆＡｈｉｄｃｌｎｖｒｔ）ｉｔｆｉｅＨｓｔｎｕｉｉｓｙｓＡａｄｐａｏｉＭｅａＵｅｉ
王峰胡世莲唐海沁，，
（．１安徽医科大学附属省立医院、安徽省立医院，合肥２００；．３０１２安徽医科大学第一附属医院干部病房）
［摘要］目的毒性的疗效。方法
观察９复合氨基酸（．Ａ）９Ａ缓解非小细胞肺癌（ＳＬ患者含顺铂（Ｄ）ＮＣＣ）ＤＰ方案化疗肾６０例肾功能正常的ＮＣＣ化疗患者随机分为治疗组与对照组，态检测血肌酐（Ｃ）ＳＬ动ｓｒ、

顺铂作用机制

顺铂作用机制篇一：抗肿瘤药物顺铂对人肺癌A549细胞生抗肿瘤药物顺铂对人肺癌A549细胞生长的影响[摘要]目的：以体外培养的人肺腺癌A549细胞为研究对象，了解A549细胞不同生长发育时期的特性。

并观察经不同浓度顺铂、不同时间长度处理后，对A549生长的抑制作用，观察这种抑制作用的性质，为顺铂对人肺腺癌的分子生物学治疗提供理论依据。

方法：体外培养A549 细胞，以血球计数板检测不同时期A549细胞生长情况，观察其形态变化，并绘制生长曲线；用呈浓度梯度的顺铂处理人肺癌A549细胞,观察顺铂对A549细胞生长的影响；再用特定浓度的顺铂处理A549细胞不同时间，检测顺铂对A549细胞生长的影响。

结果：正常生长的A549细胞，细胞数目增长最快的时间段为96~108h，倍增时间为27.6小时。

用浓度为1μg/ml、2μg/ml、5μg/ml、10μg/ml、15μg/ml、20μg/ml的顺铂溶液处理A549细胞48小时后，A549细胞数目从8*10降至2.7*10，用2μg/ml、5μg/ml 的顺铂浓度分别处理A549细胞不同时间，2μg/ml浓度下，抑制率从3.57%上升至24.59%；5μg/ml时，抑制率从8.32%升至42.24%。

结论：顺铂对A549细胞生长的抑制作用随着浓度的升高而变强。

当顺铂浓度为2、5μg/ml时，对肺腺癌细胞A549的抑制最为显著。

随着顺铂处理时间的增长，其对A549细胞生长的抑制率逐步变高。

用5μg/ml 顺铂作用于A549细胞时，作用12h~24h时的抑制最为显著。

[主题词]:人肺癌A549细胞；顺铂；生长抑制 55ABSTRACTObjective: To culture human lung adenocarcinoma cell A549 in vitro, and study growingdevelopment in different growth stage. Investigate the influences on A549 cells at vary Cisplatin concentration and in various time quantum.Methods: In order to culture A549 cells in vitro, use hemocytometer to test growthism of A549 cells at different growth period. Observe its morphological changes and draw growth curve of A549 cells. Use Cisplatin in concentration gradient to stimulate A549 cells, and examine its effect onA549 cells; use Cisplatin to stimulate A549 cells in various time quantum, and investigate its influences.Results: The fastest growing period of A549 cells cultured in normal condition was 96 to 108 hours, and the double time was 27.6 hours. After 48 hours of stimulation of cisplatin at 1~20μg/ml, the amount decreased from8*105/ml to 2.7*105/ml. Use 2μg/ml、5μg/ml cisplatin to stimulate A549 cells in various time quantum, under 2μg/ml, the inhib ition rate rise from 3.57% to 24.59%;5μg/ml, it was from 8.32% to 42.24%.Conclusion:The inhibition rate of A549 cells stimulated by cispltin grew along with the concentration of Cisplatin and reaction time quantum. At 2、5μg/ml, cisplatin’s inhibition is the most markable; At 2、5μg/ml，there’s the most notable impact on A549 cells in 12 to 24 hours.[Key Words] Human Lung Cancer Cell A549; Cisplatin(DDP); Growth inhibition.目录综述 ........................................................................... .. (1)1. 癌症 ........................................................................... .. (1)1.1.1.2. 癌症概述 ........................................................................... ............................. 1 癌症的治疗 ........................................................................... . (2)2. 致癌药物――顺铂简介............................................................................ . (2)2.1．顺铂的发现 ........................................................................... .. (3)2.2．顺铂的作用机制 ........................................................................... .. (3)2.3．顺铂的耐药性 ........................................................................... .. (4)3．肿瘤和细胞周期 ........................................................................... ........................ 4 实验设计 ........................................................................... (6)1．研究目的 ........................................................................... .. (6)2．实验方案设计 ........................................................................... . (6)3．研究意义 ........................................................................... .. (7)4．材料与方法 ........................................................................... (7)4.1．材料 ........................................................................... .. (7)4.2．主要仪器 ........................................................................... .. (7)4.3．主要试剂与耗材 ........................................................................... (7)4.4．主要试剂配制 ........................................................................... .. (9)5．实验步骤 ........................................................................... .. (10)5.1．冻存细胞的复苏 ........................................................................... . (10)5.2．细胞的传代 ........................................................................... . (10)5.3. 细胞的计数 ........................................................................... . (11)5.4. A549细胞生长曲线特征 (11)5.5．用不同浓度顺铂对A549细胞生长的影响 (11)5.6．用顺铂处理不同时间，顺铂对A549细胞生长抑制率的影响 (12)5.7．统计学分析 ........................................................................... (12)6. 实验结果 ........................................................................... .. (12)6.1．人肺腺癌A549细胞生长曲线特征 (12)6.2．不同浓度顺铂对A549细胞生长的影响 (14)6.3．用顺铂处理不同时间，顺铂对A549细胞生长抑制率的影响 (16)7. 讨论 ........................................................................... (18)8. 结果与展望 ........................................................................... ................................ 20 翻译 ........................................................................... .................................................................. 21 参考文献 ........................................................................... ....................................................... 33 致谢 ........................................................................... .................................. 错误！未定义书签。

茶多酚对顺铂所致肾损伤保护作用的实验研究

茶多酚对顺铂所致肾损伤保护作用的实验研究原丽欣;张晓虹;尹龙赞【期刊名称】《实用药物与临床》【年(卷),期】2004(007)003【摘要】目的研究茶多酚(TP)对顺铂(DDP)所致肾毒性的保护作用及其机制.方法将小鼠随机分为4组:对照组、DDP组、DDP+低剂量TP组、DDP+高剂量TP组,分别腹腔注射生理盐水、顺铂2 mg/kg,喂饲TP0.5 g/kg,1.0 g/kg,测定血清中尿素氮(BUN)、肌酐(Cr)和肾组织匀浆中超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-Px)活性及丙二醛(MDA)含量,观察肾脏病理结构的变化.结果DDP组小鼠血清中BUN及Cr值升高,与对照组比较差异有极显著意义(P＜0.01),加入高剂量TP后,BUN及Cr值明显低于DDP组(P＜0.05).给予DDP后,肾组织中SOD、GSH-Px活性降低,MDA含量升高,与对照组比较,差异有显著性(P＜0.05,P＜0.01).喂饲TP后SOD、GSH-Px值有所上升,MDA下降,DDP+低剂量TP组与DDP组比较,SOD、MDA两项指标差异有显著性(P＜0.05),但与对照组比较,3项指标均存在显著差异(P＜0.05);DDP+高剂量TP组SOD、GSH-Px值升高,MDA含量降低较明显,与DDP组比较差异有显著性(P＜0.05,P＜0.01).光镜下肾组织超微结构亦见改善.结论TP在一定程度上可缓解DDP所致的肾损伤,其机制可能与抗氧化功能有关.【总页数】2页(P15-16)【作者】原丽欣;张晓虹;尹龙赞【作者单位】沈阳市第九人民医院,辽宁,沈阳,110024;沈阳军区总医院药剂科,辽宁,沈阳,110016;沈阳市劳动卫生职业病研究所,辽宁,沈阳,110024【正文语种】中文【中图分类】R965【相关文献】1.茶多酚对顺铂所致肾脏损伤的保护作用 [J], 姚林;刘桂香;李清钊2.五加双参片对顺铂所致大鼠肾损伤保护作用的实验研究 [J], 李新田;林昱;朱学莉;杨喜民3.维吾尔药复方待比地力对顺铂所致小鼠肾损伤的保护作用 [J], 舒广文;阿尔斯拉·玉苏甫;邱韵涵;戴晨曦;邓旭坤4.金水宝片对顺铂所致大鼠急性肾损伤的保护作用及机制 [J], 刘学武;周志敏;姜德建;龙利5.茶多酚对顺铂所致肾损伤的作用及其可能机制探讨 [J], 刘桂香;李清钊;姚林;蔚德敏因版权原因，仅展示原文概要，查看原文内容请购买。

氨磷汀对顺铂所致大鼠肾毒性的防护作用

，
杜佳新②，小红① 朱
随机将３６只大鼠分成３组，即对照
氨磷
研究氨磷汀对顺铂所致肾损害的防护作用，并探讨其可能机制。方法
组（氯化钠注射液４ｍ１、）顺铂组（．Ｏｇｍ，ｍ）０Ｏ６ｍ／ｌ１和氨磷汀组（．ｇｍ＋．０ｇｎ；ｍ）４０２ｍ／ｌ００６ｍ／￣４１。分别测定体质量、肾脏ｓｇｔｔｅｐｏｃｉｆｃｏｍｆｔｅｏｉｌｉｉｕｅｅｈｏｘｃｙｉＡｂｔｃ］ｂｅｔｏｉｅｔａｈｒｔｔｅｅｅｔｆａｉｓｎｎｃｓａｎ— ｄｃｄｎｐｒｏｉｔｎｒｖｎｉｅｅｖｏｉｐｔｎｔｉ
血清生化指标、蛋白含量及Ｎ乙酰卢一一葡萄糖苷酶、性磷酸酶、－氨酰转肽酶活性，做肾组织病理学检查。结果尿一Ｄ氨基碱ｒ谷并
汀组大鼠体质量较对照组低，但显著高于顺铂组。顺铂组大鼠的血清总蛋白、白蛋白均明显低于对照组，而尿素氮、肌酐均明显高于对照组，氨磷汀组与顺铂组相比有明显改善，更接近正常大鼠。氨磷汀组肾脏脏器系数较顺铂组明显下降，肾脏病理学检查显示氨磷汀可明显改善顺铂引起的肾小球充血、肾小管浊肿及管型的病理改变。结论
［键词］氨磷汀；铂；关顺肾毒性
氨磷汀对顺铂的肾毒性损伤有保护作用。
［中图分类号］Ｒ６９５
［文献标志码］Ａ
［文章编号］１０－９６２１）２１７００８９２（０００－１－３０
［Ｏ］１．９９ｊｉｎ１０－２．０００．８ＤＩ０３６／．ｓ．０８９６２１．２０ｓ９

饮绿茶预防顺铂所致肾毒性的临床观察

两组化疗前后各项指标比较，表１见。
３讨论
３１血、微量蛋白变化及意义．尿生理情况下，中ａ一尿ＭＧ含量极微（２ｇ ≤ ０／ｍ１，由肾小球滤过并在肾小管重吸收。当肾小球）它
小细胞肺癌２５例，小细胞肺癌５非７例。初次化疗３８
维普资讯
护理学杂志２００６年３月第２１卷第５期（合版）综
・
３５・
・
中医护理・
饮绿茶预防顺铂所致肾毒性的临床观察
田同荣
ＣｉｉｌｓｒａｉｆｒｅｅｅＰｅｅｔｎｏｅａｏｉｔＣｕｅｙＣｓｌｔ／ｌｎｒｎｌｃｅｖｔｎｏｅｎＴａｉｔｒｖｎｉｆｎｌｘｃｙａｓｄｂｉａｉ／ＴＡＮＴｏｇｏｇｎａＯｂｏＧｎｈｏＲＴｉｐｎ摘要：目的探讨饮用绿茶对顺铂化疗致急性肾损害的保护作用方法将８２例应用顺铂化疗的肺癌患者随机分为对照组与观察组各４１例，察组于应用顺铂化疗的同时饮用绿茶１５０ｍｌ，照组饮等量温开水。观察化疗前及化观０／对ｄ
疗后第１５１、１天两组血＆一、、Ｏ２ＭＧ、ａ — 尿ｌＭＧ、Ｂ血ＵＮ、Ｃ值的变化。结果对照组尿ａ — 血ｒｌＭＧ化疗后显著升高，与
化疗前比较，异有显著性意义（差Ｐｄ００，ｄ００）血Ｂ一．１Ｐ．５，２ＭＧ第５１、Ｏ天亦显著高于化疗前（＜００，Ｐ．１Ｐｄ００）观．５；

顺铂耳毒性机制及抗氧化药物局部应用的预防作用

顺铂耳毒性机制及抗氧化药物局部应用的预防作用於得红;汪雪玲;陈聿名;吴皓【摘要】Cisplatin is a widely used and effective drug for the treatment of various solid tumors.Unfortunately, its severe side-effects have also impacted patients,especially its often bilateral,progressive,irreversible and dose-depen-dent ototoxicity.Current evidence indicates that cisplatin triggers the production of reactive oxygen species(ROS)in tar-get tissues in the inner ear.A large number of agents that protect against cisplatin-induced ototoxicity have been success-fully tested in cell culture and animal models.However,many of them interfere with the therapeutic effects of cisplatin, and therefore are not suitable for systemic administration in clinical practice. Until now, none of them has been ap-proved by the FDA.Consequently,local administration strategies,namely intratympanic administration,have been de-veloped to achieve otoprotection,without reducing the antitumoral effects of cisplatin.This review summarizes the clini-cal and experimental studies of ciaplatin ototoxicity,including details of the molecular mechanisms of action,to gain in-sight for future drug development in this field.%顺铂是临床普遍应用的广谱高效抗肿瘤药物,与多种抗肿瘤药有协同效应、无交叉耐药等特点,为当前联合化疗中最常用的药物之一.然而,顺铂的毒副作用严重困扰着癌症患者,其耳毒性尤为突出.顺铂耳毒性多为双侧、进展性、不可逆性、剂量依赖性听力损伤,往往导致成人、尤其是儿童患者出现语言交流障碍.大量研究证实,顺铂通过诱发活性氧(ROS)升高导致听觉毛细胞发生caspase-3激活的细胞凋亡.哺乳动物听觉毛细胞无自发再生能力,一旦损伤即为永久性.因此,顺铂耳毒性预防的药物研发或治疗策略开发至关重要.目前,越来越多的药物被证实在细胞和动物水平上具有顺铂耳毒性保护作用.然而,绝大部分药物经系统性用药后拮抗顺铂抗肿瘤疗效,无法实现临床上的有效应用.至今仍无有效顺铂耳毒性保护药物被批准上市.耳蜗局部鼓室内用药可部分缓解耳毒性保护候选药物对顺铂抗肿瘤疗效的干扰,但因顺铂需周期性用药,多次鼓室内给予耳毒性保护药物易引起局部创伤和感染.本文总结了具有代表性抗氧化药物预防顺铂耳毒性的基础和临床研究进展,为顺铂耳毒性新药研发提供理论依据.【期刊名称】《中华耳科学杂志》【年(卷),期】2018(016)002【总页数】5页(P145-149)【关键词】顺铂;耳毒性;药物;预防【作者】於得红;汪雪玲;陈聿名;吴皓【作者单位】上海交通大学医学院附属第九人民医院耳鼻咽喉头颈外科,上海交通大学医学院耳科学研究所,上海市耳鼻疾病转化医学重点实验室;上海交通大学医学院附属第九人民医院耳鼻咽喉头颈外科,上海交通大学医学院耳科学研究所,上海市耳鼻疾病转化医学重点实验室;上海交通大学医学院附属第九人民医院耳鼻咽喉头颈外科,上海交通大学医学院耳科学研究所,上海市耳鼻疾病转化医学重点实验室;上海交通大学医学院附属第九人民医院耳鼻咽喉头颈外科,上海交通大学医学院耳科学研究所,上海市耳鼻疾病转化医学重点实验室【正文语种】中文【中图分类】R764顺铂作为一种广谱抗癌药，对泌尿生殖系统肿瘤、恶性淋巴瘤、头颈部鳞癌、软组织肉瘤等均具有一定的治疗效果。

顺铂肾毒性

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。

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