顺铂和噪声联合作用对听觉器官的影响

研究了顺铂与噪声联合作用对耳蜗的毒性,发现联合作用后听阈偏移大于单独顺铂作用后阈移和单独噪声作用后阈移的总和。此外,联合作用后听觉脑干诱发电位振幅下降非常明显。结果表明,顺铂与噪声联合作用对内耳的毒性有协同作用。     

抗癌药顺铂耳毒性机制及防治方法的研究进展

顺铂是目前临床上常用的广谱抗癌药之一,但它具有较强的肾及耳毒性,限制了它的大剂量应用及更好地发挥疗效。对于顺铂的肾毒性,目前已有了较好的防护措施。因此,顺铂耳毒性的产生机制及防护办法就成为当前人们关心的热点。从目前国内外的研究资料来看,在顺铂耳毒性的防护措施方面,虽也找到了一些能显著改善其毒性的药物,但其毒性很可能是多途径作用的结果,因此,应选用不同拮抗机制的多种药物联合应用,以达到最佳的防治效果。     

谷胱甘肽对顺铂致小鼠染色体畸变的保护作用

为了研究谷胱甘Lk．（GSH）对顺铂（cDDP）所致染色体畸变的影响,将昆明小鼠随机分为空白对照组、GSH组、CDDP组、GSH＋CDDP组进行实验,GSH组按照1200mg／（kg·d1连续3天尾静脉注射GSH,对照组注射等量生理盐水;CDDP组于第2天一次注射顺铂20mg/ｋg。对小鼠尾静脉取血检测血常规,处死小鼠,取骨髓进行有核细胞计数、微核实验和染色体G显带,双盲阅片并进行统计学分析。结果表叽对照组细胞染色体数目与形态完好,微核出现的机率极低。GSH组与空白对照组相比无显著差异（Ｐ〉0．05）。CDDP组、GSH＋CDDP组出现了明显的骨髓抑制现象,染色体畸变率及微核率显著增高,与空白对照组比较均有显著性差异（Ｐ〈0．01）。GSH＋CDDP组与CDDP组相比染色体畸变率明显下降（Ｐ〈0．05）。表明谷胱甘肽对顺铂所致的染色体损伤具有一定的保护作用。     

卡维地洛对顺铂所致大鼠肾毒性预防作用的形态学研究

目的研究顺铂诱导大鼠肾损伤的组织病理学和超微结构变化以及卡维地洛对大鼠肾损伤的预防作用。方法雄性Wistar大鼠随机分为4组,给药后3～6d处死,取肾组织,常规石蜡切片,HE染色、PAS反应,超薄切片电镜观察。结果卡维地洛组较顺铂肾脏损伤模型组的组织病理学及超微结构变化明显减轻。结论卡维地洛预防性灌胃给与能明显减轻大鼠顺铂所致的肾损伤,其机制可能与其抗氧化和清除自由基活性有关。     

加味黄连阿胶汤对顺铂致肾损伤大鼠TGF-β_1表达的影响

目的：观察加味黄连阿胶汤对顺铂致肾损伤大鼠TGF-β1表达的影响。方法：采用尾静脉注射顺铂的方法,制备顺铂肾毒性大鼠模型,然后给以相应的药物治疗,连续8周。剖取肾脏行HE、免疫组织化学染色,观察肾组织TGF-β1的表达情况,测定其平均吸光度。结果：模型组大鼠24h尿蛋白定量、NAG含量及TGF-β1的平均吸光度均明显高于正常对照组（P〈0.01）,而各治疗组均明显低于模型组（P〈0.05或P〈0.01）。结论：加味黄连阿胶汤可明显下调肾小管上皮细胞内TGF-β1的表达,减轻顺铂引起的肾小管和肾小管间质损伤。     

铜绿假单胞菌注射液联合顺铂治疗消化道恶性腹腔积液的临床研究

目的：比较铜绿假单胞菌注射液联合顺铂与单纯使用顺铂治疗消化道恶性腹腔积液的疗效。方法：将250例消化道恶性中等量以上腹腔积液患者分为对照组和实验组各125例。所有患者行穿刺置管引流术,地塞米松预防发热,予盐酸利多卡因预防腹痛。铜绿假单胞菌注射液每周两次,顺铂每周一次,疗程一周,最多两个疗程。结果：实验组患者有效率为85．6％,其中,完全缓解40例,部分缓解67例。对照组例患者有效率为52％,其中,完全缓解24例,部分缓解4l例。两组比较差异有统计学意义（x2=32．87,P〈0．05）。实验组患者WHO体力状态评分（1分和2分）为104例,有效率为83．2％;对照组患者WHO体力状态评分（1分和2分）为72例,有效率为57．6％。两组比较差异有统计学意义（x2=19．67,P〈0．05）。结论：铜绿假单胞茵注射液联合顺铂腹腔内给药治疗消化道恶性腹腔积液。临床疗效显著。     

TRAIL与顺铂联用对人骨肉瘤细胞杀伤作用的实验研究

目的探讨TRAIL与顺铂联合应用对人骨肉瘤细胞的杀伤作用.方法将TRAIL与顺铂单独及联合应用于体外培养的骨肉瘤OS-732细胞,采用MTT法测定细胞抑制率,于倒置相差显微镜、荧光显微镜、扫描及透射电镜下观察细胞的形态学改变及超微结构变化.结果 50ng/ml的TRAIL与5μg/ml顺铂合用于OS-732细胞24小时后,细胞抑制率为84.37%,明显高于单用TRAIL(50μg/ml)时的9.68%及单用顺铂(5μg/ml)时的24.39%(P<0.01).细胞的形态与超微结构观察均显示,合用比单用促凋亡效应更显著.结论 TRAIL与顺铂合用,可高效杀伤人骨肉瘤细胞,此协同作用主要是通过诱导肿瘤细胞凋亡来实现的.     

抗癌药物顺铂对DNA结构的影响

本文采用脉冲激光荧光技术及常规的荧光分光光度计详细地研究了顺铂对DNA变性温度的影响,DNA氢键受损的碱基对数随温度变化,DNA的G—C碱基含量对顺铂作用效果以及顺铂浓度的影响,初步探讨了抗癌药物顺铂对DNA的结构影响.     

顺铂对大鼠小肠电活动的影响

顺铂是近年来临床上广泛应用的一种抗癌药,有明显的消化道副作用。为探讨顺铂消化道副作用的发生机理,我们以移行性综合肌电(MMC)~[1]为指标,观察顺铂对大鼠小肠电活动的影响以及这种影响与植物神经系统的关系。 1 材料和方法 采用体重250～300g雄性Wistar大鼠,异戊巴比妥钠(30mg/kg)麻醉后,沿小肠浆膜面埋植两对铂丝双极电极。十二指肠1对,位于幽门下2cm处。空肠1对,位于Treitz韧带下10cm处。电极导线自腹     

顺铂作用卵巢癌细胞株的蛋白质组学研究

应用蛋白质组学技术观察顺铂作用于人卵巢癌SKOV3细胞株后蛋白质分子的表达差 异, 探讨蛋白质组学方法在化疗药物抗肿瘤作用机制研究方面的应用. 用顺铂(6 mg/mL)作用人卵巢癌SKOV3细胞6 h, 分别收集实验组与对照组细胞, 裂解并提取细胞内总蛋白; 以固相IPG胶条(17 cm, pH4~7)为载体, 进行第一向等电聚焦和第二向SDS-PAGE电泳, 得到实验组与对照组双向电泳凝胶图; 经考马斯亮蓝染色后, 在PDQuest软件的辅助下进行实验组与对照组蛋白质表达的比较, 选择并切取明显差异点共11个, 经肽质量指纹谱(PMF)和串级质谱(MS/MS)分析, 检测出差异点中包含的主要蛋白. 通过质谱分析显示, 顺铂处理后表达明显上调的有原肌球蛋白家族、肌动蛋白家族、热休克蛋白60(HSP60)、磷酸丙糖异构酶(TIM)家族等; 表达下调的有烯醇酶家族等. 这几类蛋白质多参与细胞内能量代谢、细胞形态维持、细胞转化凋亡等生理过程, 提示顺铂的抗肿瘤机制可能与此有关.     

丹参注射液对庆大霉素耳中毒豚鼠耳蜗NOS异构体表达的影响

目的：研究丹参注射液（SM）对庆大霉素（GM）耳中毒豚鼠耳蜗一氧化氮合酶（NOS）异构体表达的影响,探讨SM对GM耳毒性的防护机制。方法：40只豚鼠随机分成对照组、GM组、SM组和GM＋SM组,应用SABC免疫组织化学方法及显微图像分析技术,观察NOS三型异构体在豚鼠耳蜗的表达;同时结合听脑干反应（ABR）测试,观察用药前后豚鼠听阈的变化。结果：GM＋SM组豚鼠耳蜗诱导型NOS（iNOS/NOSⅡ）表达和ABR阈值均明显低于GM组（P〈0.01）;且iNOS表达变化与ABR阈值改变高度相关（｜r｜〉0.7,P〈0.01）;而各组豚鼠耳蜗神经元型NOS（nNOS/NOSⅠ）和内皮型NOS（eNOS/NOSⅢ）表达均无显著性差异。结论：SM对GM耳中毒后豚鼠耳蜗nNOS和eNOS表达无影响,但可通过抑制GM所致iNOS高表达,以减少NO的过量生成,从而对GM的耳毒性损伤发挥防护作用。     

大鼠肢体缺血/再灌注后多器官水肿及丹参的预防作用

目的:探讨大鼠肢体缺血/再灌注(LI/R)导致的多器官水肿及丹参的防治作用。方法:Wistar大鼠24只随机分为3组(n=8):对照组(C组)、缺血/再灌注组(I/R组)和丹参预处理组(SM组)。以止血带法制作大鼠肢体缺血/再灌注模型,SM组在再灌注前30 min经尾静脉推注丹参注射液5 ml/kg。准确留取每只动物的心、肝、肾、肺、脑、肠及骨骼肌组织各1 g,恒温烘干后称其干重并计算各组织的湿干重比值(W/D)。采用ELISA法测定血清白细胞介素1(IL-1)、白细胞介素6(IL-6)、肿瘤坏死因子α(TNFα-)含量;采用生物化学方法测定超氧化物歧化酶(SOD)活性及丙二醛(MDA)含量。光镜下观察骨骼肌组织的形态学变化。结果:LI/R后各组织W/D均增加(P<0.05,P<0.01),血浆SOD活性降低而MDA含量增加(P<0.05,P<0.01),血清IL-1、IL-6、TNFα-水平均升高(P<0.05,P<0.01),骨骼肌组织镜下可见炎细胞浸润、肌纤维间隙增宽等病理改变。而SM组与单纯再灌注组比较,血清炎症因子水平下降,氧化损伤程度减轻,镜下组织形态学变化有所改善。结论:大鼠肢体缺血/再灌注可导致多器官水肿,丹参可通过抑制炎症反应、抗氧化等途径在一定程度上预防肢体缺血/再灌注后多器官的水肿。     

Protection of salvia miltiorrhiza against aflatoxin-B1-induced hepatocarcinogenesis in Fischer 344 rats dual mechanisms involved.

Extract of Salvia Miltiorrhiza (SM) has been widely used in traditional Chinese medicine for treating liver diseases. Recent experimental evidence indicates that it has anti-tumor potential. In this study, the effect of SM on alfatoxin B1 (AFB1)-induced hepatocarcinogenesis was investigated in male Fischer 344 rats. AFB1 (40 microg/100 g body wt, by gavage) was administered once a week for 24 weeks. In SM treatment group, rats were given SM (0.25g/100g body wt, 5 days/week by gavage) for a total of 28 weeks, including 4 weeks before and 24 weeks during AFB1 exposure. Results showed that the elevation of serum alanine aminotransferase and aspartate aminotransferase activities due to AFB1 dosing was almost completely abolished by the treatment of SM, indicating that SM could prevent AFB1-induced liver cell injury. It was further observed that SM substantially reduced glutathione S-transferase placenta form (GST-P) positive foci formation and GST-P mRNA expression caused by AFB1, which clearly suggests that SM is effective in preventing AFB1-induced hepatocarcinogenesis. Furthermore, the inhibition on AFB1 hepatocarcinigenesis was associated with a corresponding decrease in AFB1-DNA adducts formation as well as AFB1-induced oxidative DNA damage (8-hydroxydeoxyguanosine) in rat liver. Our results also indicate that the protective effect of SM might be mediated through dual mechanisms: (i) the enhancement of AFB1 detoxification pathway, especially the induction of GST-Yc2 mRNA expression, and (ii) the antioxidant property of SM.     

Protective effect of aminoguanidine against nephrotoxicity induced by cisplatin in normal rats

The effect of aminoguanidine (AG) on nephrotoxicity induced by cisplatin (CDDP) was investigated. A single dose of CDDP (7.5 mg/kg i.p.) induced nephrotoxicity, manifested biochemically by a significant elevation in serum urea, creatinine and a severe decrease in serum albumin. Moreover, marked increases in kidney weight, urine volume and urinary excretion of albumin were observed. Nephrotoxicity was further confirmed by a significant decrease in glutathione-S-transferase (GST, E.C. 2.5.1.18), glutathione peroxidase (GSH-Px, E.C. 1.11.1.9) and catalase (E.C. 1.11.1.6) and a significant increase in lipid peroxides measured as malondialdhyde (MDA) in kidney homogenates. Administration of AG (100 mg/kg per day p.o.) in drinking water 5 days before and 5 days after CDDP injection produced a significant protection against nephrotoxicity induced by CDDP. The amelioration of nephrotoxicity was evidenced by significant reductions in serum urea and creatinine concentrations. In addition, AG tended to normalize decreased levels of serum albumin. Urine volume, urinary excretions of albumin and GST and kidney weight were significantly decreased. Moreover, AG prevented the rise of MDA and the reduction of GST and GSH-Px activities in the kidney. These results suggest that AG has a protective effect on nephrotoxicity induced by CDDP and it may therefore improve the therapeutic index of CDDP.     

Carvedilol protects against the renal mitochondrial toxicity induced by cisplatin in rats

The clinical use of cisplatin is highly limited by its nephrotoxicity, which has been associated with mitochondrial dysfunction. We investigated the protective effect of carvedilol, an antihypertensive with strong antioxidant properties, against the nephrotoxicity induced by cisplatin in rats. Carvedilol was able to counteract the renal damage by preventing the mitochondrial dysfunction induced by cisplatin. The mitochondrial eletrochemical potential, calcium uptake, respiration and the phosphorylative capacity were preserved by the co-administration of carvedilol. The mechanism of protection probably does not involve alterations in the cellular and sub-cellular distribution of cisplatin. The study suggests that carvedilol is a potential drug for the adjuvant nephroprotective therapy during cisplatin chemotherapy.     

Dimethylthiourea protects against mitochondrial oxidative damage induced by cisplatin in liver of rats

Cisplatin is one of the most effective chemotherapeutic agents. However, at higher doses liver injury may occur. The purpose of this study was to explore whether the hydroxyl radical scavenger dimethylthiourea (DMTU) protects against cisplatin-induced oxidative damage in vivo and to define the mitochondrial pathways involved in cytoprotection. Adult male Wistar rats (200–220 g) were divided into four groups of eight animals each. The control group was treated only with an intraperitoneal (i.p.) injection of saline solution (1 ml/100 g body weight). The DMTU group was given only DMTU (500 mg/kg body weight, i.p), followed by 125 mg/kg body weight, i.p. (twice a day) until sacrifice. The cisplatin group was given a single injection of cisplatin (10 mg/kg body weight, i.p.). The DMTU + cisplatin group was given DMTU (500 mg/kg body weight, i.p.), just before the cisplatin injection (10 mg/kg body weight, i.p.), followed by injections of DMTU (125 mg/kg body weight, i.p.) twice a day until sacrifice (72 h after the treatment). DMTU did not present any direct effect on mitochondria and substantially inhibited cisplatin-induced mitochondrial damage in liver, therefore preventing elevation of AST and ALT serum levels. DMTU protected against (a) decreased hepatic ATP levels; (b) lipid peroxidation; (c) cardiolipin oxidation; (d) sulfhydryl protein oxidation; (e) mitochondrial membrane rigidification; (f) GSH oxidation; (g) NADPH oxidation; (h) apoptosis. Results suggest that antioxidants, particularly hydroxyl radical scavengers, protect liver mitochondria against cisplatin-induced oxidative damage. Several mitochondrial changes were delineated and proposed as interesting targets for cytoprotective strategy.     

Proteasome inhibition prevents cell death induced by the chemotherapeutic agent cisplatin downstream of DNA damage

Cisplatin is a highly effective chemotherapeutic drug acting as a DNA-damaging agent that induces apoptosis of rapidly proliferating cells. Unfortunately, cellular resistance still occurs. Mutations in p53 in a large fraction of tumor cells contribute to defects in apoptotic pathways and drug resistance. To uncover new strategies to eliminate tumors through a p53-independent pathway, we established a simplified model devoid of p53 to study cisplatin-induced regulated cell death, using the yeast Saccharomyces cerevisiae. We previously showed that cisplatin induces an active form of cell death accompanied by DNA condensation and fragmentation/degradation, but no significant mitochondrial dysfunction. We further demonstrated that proteasome inhibition, either with MG132 or genetically, increased resistance to cisplatin. In this study, we sought to determine how proteasome inhibition is important for cisplatin resistance by analyzing how it affects several phenotypes associated with the DNA damage response. We found MG132 does not seem to affect the activation of the DNA damage response or increase damage tolerance. Moreover, central modulators of the DNA damage response are not required for cisplatin resistance imparted by MG132. These results suggest the proteasome is involved in modulation of cisplatin toxicity downstream of DNA damage. Proteasome inhibitors can sensitize tumor cells to cisplatin, but protect others from cisplatin-induced cell death. Elucidation of this mechanism will therefore aid in the development of new strategies to increase the efficacy of chemotherapy.