氨磷汀对卵巢癌化疗患者的保护作用25例分析

[目的]探讨化疗保护剂氨磷汀（Amifostine）对卵巢癌化疗患者的应用价值。[方法]25例卵巢癌患者接受单纯化疗组（紫杉醇＋顺铂）与氨磷汀＋静脉化疗组（紫杉醇＋顺铂）．化疗前后检测血常规、血生化、血清CA-125及影像学CT增强扫描，对比观察化疗药物的毒副反应和临床疗效。[结果]与自身对照相比较，氨磷汀＋静脉化疗组消化道反应有所增加（评分分别为35分及46分。P〈0．05）；但总体毒副反应较单纯化疗组明显减少，尤其是血液学毒性（评分分别为43分及28分），肾毒性（分别为12分及3分）及耳毒性（分别为19分及3分），均明显减轻（P〈0．05）。经检验血清CA-125指标，并结合影像学结果，使用氨磷汀前后化疗药物的有效率分别为64％和72％（P〉0．05）。[结论]氨磷汀作为高效、安全的化疗保护剂，值得在大剂量化疗以及既往化疗出现明显毒副反应的卵巢癌患者中应用。     

Fas、FasL在肝癌组织中的表达及其意义

目的 检测Fas、FasL在肝癌病变中的表达，探讨它们与肝癌病变的关系。方法 应用免疫组化方法检测Fas、FasL在61例肝癌病变组织和其癌旁组织以及13例正常肝脏标本中的表达。结果 Fas在肝瘾组织中表达显著降低（P〈0．01）；FasL在肝癌中表达显著升高（P〈0．05）：Fas表达与肝癌临床分期存在相关性（P〈0．05），Fas与FasL的表达呈负相关（r=-0．51，P〈0．01）。结论 Fas表达缺失及FasL，表达升高町能参与肝癌的发生发展过程．检测Fas、FasL的表达对于肝癌预后判别具有临床参考意义。     

人参皂苷Rg3与顺铂对荷卵巢癌裸鼠免疫功能及肿瘤相关蛋白的影响

[目的]观察人参皂苷Rg3联合顺铂对荷高转移人卵巢癌细胞系HO．8910PM转移瘤裸鼠白细胞介素．2（IL-2）、干扰素-γ（INF-γ）及nm23、血管内皮生长因子（VEGF）及增殖细胞核抗原（PCNA）的影响。[方法]移植瘤裸鼠随机分成6组腹腔给药：荷瘤空白对照组fA组）;不同Rg3浓度药物组：2．5mg／kg（B组）、5mg／kg（C组）和lOmg／kg（D组）;Rg3和顺铂联用组（E组）以及顺铂阳性对照组（F组）。分别测定各组裸鼠转移瘤体积变化、IL-2、INF-γ、nm23、VEGF及PCNA的变化情况。[结果]与A组比较,E组（P〈0．05）和F组（P〈0．01）小鼠血清中IL-2、INF-γ含量均能显著降低;B（P〈0．05）、C、D和E（P〈0．01）组小鼠移植瘤组织nm23的表达均增强。Rg3给药后,小鼠移植瘤组织VEGF、PCNA表达均呈下降趋势。[结论]人参皂苷Rg3和顺铂联用具有协同抗肿瘤及减毒的作用。Rg3可能通过增强mm23的表达．使VEGF及PCNA表达呈下降趋势等多途径产生抗肿瘤作用。     

鼻咽癌患者外周血单个核细胞Fas和FasL的表达及其意义

目的：研究凋亡相关基因Fas和FasL在鼻咽癌患者诱导化疗前后外周血单个核细胞中表达水平的变化,探讨其在鼻咽癌发生、发展中的作用及意义。方法：采用流式细胞仪对38例鼻咽癌患者诱导化疗前后及15例正常健康对照组外周血单个核细胞中的Fas和FasL表达进行检测,并结合临床资料进行分析。结果：（1）鼻咽癌患者外周血单个核细胞中Fas、FasL的表达明显高于正常健康对照组（P〈0．05）;Ⅲ＋Ⅳ期患者的表达明显高于Ⅱ期患者（P〈0．05）。（2）T3＋4期患者外周血单个核细胞Fas表达明显高于T1＋2期患者（P〈0．05）,而其FasL的表达稍高于T1＋2期患者（P〉0．05）。（3）N1期患者的Fas表达明显高于N0期患者（P〈0．05）,而其FasL的表达稍高于N0期患者（P〉0．05）;N2＋3期患者的Fas表达明显高于N1期（P〈0．05）,而其FasL表达稍高于N0期和N1期（P〉0．05）。（4）鼻咽癌患者经诱导化疗后,其Fas表达明显增高（P〈0．05）,FasL表达稍有增高（P〉0．05）。结论：外周血单个核细胞Fas、FasL表达水平与鼻咽癌发生、增殖、局部转移有关,对其进行检测可作为鼻咽癌的诊断及病期判断的辅助指标。     

131I-EGF显像对肺癌荷瘤裸鼠化疗疗效的评价

目的探讨131I-EGF动态显像技术对肺癌倚瘤裸鼠化疗疗效的评价。方法将肺癌细胞株A549种植到BALB／cA—nil裸鼠体内,待移植瘤长至直径0．8～1．2cm时,随机分为4组：空白对照组、实验组（紫杉醇组、顺铂组和联合化疗组）。空白对照组腹腔注射0．1ml生理盐水;紫杉醇组腹腔注射紫杉醇5mg／kg;顺铂组腹腔注射ill@34rag／kg;联合化疗组腹腔注射紫杉醇5mg／kg和顺铂4mg／kg。裸鼠化疗后分别丁即刻和第7、14、21及28犬注射131I-EGF0．5h后开始显像,勾画感兴趣区（ROI）,计算肿瘤／健侧对应部位放射性（T／NT）比值,并测量肿瘤体积。第28天完成显像后,处死裸鼠,测量肿瘤／血液及肿瘤／肌肉放射性比值,计算抑瘤率和131I-EGF的生物学分布。结果肿瘤组织吸收131I-EGF较多,肿瘤／肌肉放射性比值对照组为5．65,高于联合化疗组（1．55,t=9．829,P〈0．01）、紫杉醇组（1．14,t=12．636,P〈0．01）和顺铂组（0．99,t=12．313,P〈0．01）。肿瘤／血液放射性比值对照组为3．15,高于联合化疗组（0．76,t=3．384,P〈0．05）、紫杉醇组（1．22,t=2．826,P〈0．05）和顺铂组（1．22,t=2．713,P〈0．05）。131I-EGF可使肿瘤组织清晰显像,联合化疗组肿瘤体积401．9mm3,与对照组（1134．2mm3）差异有统计学意义（t=9．393,P〈0．01）;紫杉醇组肿瘤体积634．73mm3（t=7．140,P〈0．01）,顺铂组肿瘤体积700．7mm3（t=6．820,P〈O．01）,这2组与对照组差异有统计学意义。各化疗组与对照组间T／NT比值差异有统计学意义（F=1011．251,P〈0．01）。结论化疗效果好的肿瘤,131I-EGF显像示肿瘤体积较小,瘤体内放射性分布较少;而化疗效果差的肿瘤体积逐渐增大,瘤体内放射性分布较多。131I-EGF显像可用于指导倚瘤裸鼠的化疗。     

三七总皂苷对顺铂肾损害大鼠肾组织差异表达蛋白质的影响

目的 探讨三七总皂苷（panax notoginsenosides,PNS）对顺铂肾损害大鼠肾组织差异表达蛋白质的影响。方法 实验大鼠随机分为正常对照组、顺铂模型组和PNS治疗组,对大鼠给药处理10 d后,检测大鼠血清尿素氮（BUN）、肌酐（Scr）和尿N-乙酰-β-氨基葡萄糖苷酶（NAG）的水平,并做肾脏病理检查;采用SELDI-TOF-MS技术筛选大鼠肾组织的差异表达蛋白质,并通过MALDI-TOF-MS/MS、Western blot实验予以鉴定。结果 顺铂模型组大鼠血清BUN、Scr和尿NAG的水平均显著高于正常对照组（P均〈0.05）。电镜下可见肾小管上皮细胞的线粒体明显损伤,说明顺铂肾损害大鼠模型制作成功。PNS干预可使大鼠血清BUN、Scr和尿NAG的水平显著低于顺铂模型组（P〈0.05）,肾小管上皮细胞的线粒体损害程度较顺铂模型组明显改善,提示PNS对其有保护作用。筛选出顺铂模型组与正常对照组肾组织差异表达的蛋白质20个,其中7个蛋白质在顺铂模型组中的表达下调2倍以上;顺铂模型组与PNS治疗组肾组织差异表达的蛋白质18个,其中11个蛋白质在PNS治疗组中的表达下调;有6个共同的差异表达蛋白质在顺铂模型组较正常对照组的表达上调或下调,在PNS治疗组可回调到接近正常对照组水平。差异表达蛋白质m/z 10815.42被鉴定为线粒体热休克蛋白,m/z 16021.67被鉴定为血红蛋白β1亚基、血红蛋白β2亚基。结论 顺铂肾损害可伴随多种蛋白质的表达变化,这些差异表达蛋白质可能与顺铂损害肾脏以及PNS的保护作用有关。通过对其分离和鉴定,进一步了解其性质,将有助于全面、系统地探讨顺铂肾损害以及PNS保护作用的机制。     

共聚焦显微镜观察凋亡相关基因 Fas 和 FasL 在肝外胆管癌组织中的表达

目的：研究肝外胆管癌组织中细胞凋亡相关基因Fas和FasL的表达及意义。方法：采用免疫荧光组织化学方法结合激光扫描共聚焦显微镜对30例肝外胆管癌及10例胆总管囊肿组织进行观察。结果：30例肝外胆管癌中,Fas和FasL阳性21例,阳性率70％,对照组10例胆总管囊肿Fas和FasL阳性1例,阳性率10％,Fas和FasL在朋胆管癌中的表达强于对照组（P＜0．05）;同一肿瘤细胞中Fas定量大于FasL(P＜0．05）;Fas和FasL主要位于胞浆和胞核。结论：Fas和FasL参与了大部分肝外胆管癌的凋亡调控,但肝外胆管癌在发生分化过程中可能部分获得了逃逸Fas介导凋亡的功能。     

氨磷汀对奥沙利铂所致周围神经毒性的改善作用的病例对照研究

目的评价氨磷汀对胃肠道肿瘤化疗药物奥沙利铂所致神经毒性的改善作用。方法将行FOLFOX6方案化疗的86例胃肠道肿瘤患者随机分为氨磷汀组（给予奥沙利铂前静脉注射氨磷汀,n=43）和对照组（不予氨磷汀,n=43）。每2个周期评估神经毒性。结果经过8个周期化疗后,氨磷汀组患者3~4级神经毒性发生率（4.9%）较对照组（16.3%）有明显降低,组间差异具有统计学意义（P〈0.001）。氨磷汀组患者化疗后正中神经和腓神经的感觉神经传导速度分别为（53.75±2.96）m/s和（54.94±2.98）m/s,均明显优于对照组的（45.16±3.13）m/s和（5.05±3.02）m/s,组间差异具有统计学意义（P〈0.001）。化疗近期有效率两组间无显著差异（P=0.451）。结论氨磷汀对奥沙利铂化疗所致神经毒性具有明显改善作用,且不影响化疗的近期疗效。     

脑星形细胞瘤 Fas和 FasL的表达及细胞凋亡与肿瘤恶性程度相互关系的初步探讨

目的：对脑星形细胞瘤Fas和FasL的表达水平及细胞凋亡与肿瘤恶性程度之间的关系进行初步探讨。方法：对41例脑星形细胞瘤标本采用免疫组化法（S－P法）检测Fas和FasL的表达率及表达强度,采用TUNEL法检测凋亡指数。结果：本组星形细胞瘤Fas和FasL的表达率分别为65．9％和78．0％;Fas和FasL的表达率与其病理分级有关（X^2分别为17．552和10．749,P均＜0．05）;Fas和FasL的表达强度也与其病理分级呈负相关（r分别为－0．660和－0．506,P均＜0．01）。本组星形细胞瘤的凋亡指数为0．51－1．57,凋亡指数与肿瘤病理分级有关（F＝18．828,P＜0．05）。结论：本组大部分星形细胞瘤均有Fas和FasL的表达,表达率和表达强度均随肿瘤恶性程度增高而明显下降,星形细胞瘤的凋亡指数随肿瘤恶性程度增高而明显增高。     

胃黏膜癌变过程中Survivin与Fas表达及其相关性

目的探讨凋亡基因Survivin、Fas在胃黏膜癌变过程中的表达、临床意义及其两者的相关性。方法采用免疫组化法检测12例正常组织、136例患者（包括浅表性胃炎22例、肠上皮化生25例、异型增生37例及胃癌52例）组织中的Survivin和Fas表达。结果Survivin在肠上皮化生、异型增生和胃癌中的阳性率分别为16％、37．8％和69．2％。胃癌组明显高于肠上皮化生（P〈0．01）和异型增生组（P〈0．05）。胃癌组Fas表达率为30．8％，显著低于对照组和异型增生组（均P〈0．01）。Survivin表达和淋巴结转移、远处转移密切相关（均P〈0．05）；Fas表达和淋巴结转移密切相关（P〈0．05）。相关回归分析显示胃癌组织病理分期中Survivin与Fas表达呈负相关。结论在胃黏膜癌变过程中，Sur-vivin的表达逐渐上调，而Fas的表达逐渐下调。在胃癌组织中Survivin和Fas的表达呈负相关。     

Direct amifostine effect on renal tubule cells in rats.

Clinical trials indicate that amifostine offers protection against cisplatin-induced nephrotoxicity. It is unclear whether a direct pharmacological t on renal tubular cells is involved. We investigated the effect of amifostine pretreatment on the tubular apparatus and evaluated its nephroprotective potential. A total of 32 rats were treated by i.p. administration of 0.9% saline solution (group 1), 5 mg/kg cisplatin (group 2), 25 mg/kg amifostine (group 3), and 25 mg/kg amifostine followed by 5 mg/kg cisplatin (group 4) after 30 min. We recorded elevation of N-acetyl-beta-D-glucosaminidase (NAG) in 24 h pooled urine as a specific marker for tubular lesions, renal leakage of magnesium as an unspecific nephrotoxicity marker, and survival over a 10-day observation period. A significant (P < 0.002) increase in urinary NAG after treatment was documented only in cisplatin-treated group 2 [day 2 (mean+/-SE), 93+/-2.1 units/gram creatinine; day 4, 70.6+/-16 units/gram creatinine; normalization at day 8]. Treatment with amifostine before cisplatin administration resulted in a slight urinary NAG leakage (day 2, 2.8+/-1.8 units/gram creatinine; day 4, 13.8+/-13 units/gram creatinine; normalization at day 6). No increase in urinary enzyme levels was seen in the other groups, and there were no significant differences in urinary magnesium between all groups. Four of eight rats in the cisplatin-treated group and one of eight rats in the amifostine plus cisplatin-treated group died.     

Hydroxyl radical scavenger ameliorates cisplatin-induced nephrotoxicity by preventing oxidative stress, redox state unbalance, impairment of energetic metabolism and apoptosis in rat kidney mitochondria

Nephrotoxicity is the major dose-limiting factor of cisplatin chemotherapy. Reactive oxygen species generated in mitochondria are thought to be the main cause of cellular damage in such injury. The present study examined, in vivo, the protective potential of the hydroxyl radical scavenger dimethylthiourea (DMTU) against cisplatin-induced effects on renal mitochondrial bioenergetics, redox state and oxidative stress. Adult male Wistar rats (200 to 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 second group was given only DMTU (500 mg/kg body weight, i.p, followed by 125 mg/Kg, i.p., twice a day until they were killed). The third group was given a single injection of cisplatin (10 mg/kg body weight, i.p.). The fourth 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 they were killed. Animals were killed 72 h after the treatment. Besides not presenting any direct effect on mitochondria, DMTU substantially inhibited cisplatin-induced mitochondrial injury and cellular death by apoptosis, suppressing the occurrence of acute renal failure. All the following cisplatin-induced effects were prevented by DMTU: (1) increased plasmatic levels of creatinine and blood urea nitrogen (BUN); (2) decreased ATP content, calcium uptake and electrochemical potential; (3) oxidation of lipids, including cardiolipin; and oxidation of proteins, including sulfhydryl, and aconitase enzyme, as well as accumulation of carbonyl proteins; (4) depletion of the antioxidant defense (NADPH and GSH) and (5) increased activity of the apoptosis executioner caspase-3. Our findings show the important role played by mitochondria and hydroxyl radicals in cisplatin-induced nephrotoxicity, as well as the effectiveness of DMTU in preventing the renal mitochondrial damage caused by cisplatin. These results strongly suggest that protection of mitochondria by hydroxyl radical scavengers may be an interesting approach to prevent the kidney tissue damage caused by cisplatin-chemotherapy.     

灯盏花素对顺铂肾损害的防治及抗氧化的实验

目的观察灯盏花素对小鼠顺铂（cisplatin,DDP）肾损害的防治及抗氧化作用,探究其可能的作用机制。方法以 DDP 8 mg/kg单次腹腔注射制备小鼠肾脏损害模型,再以不同剂量的灯盏花素灌胃,1次/天,连续给药7 d后采样,观察肾脏结构变化,检测血清中肌酐（Scr）、尿素氮（BUN）、丙二醛（MDA）含量及超氧化物歧化酶（SOD）活性,肾皮质 SOD 及 MDA 的变化。 结果灯盏花素可明显改善顺铂肾损害的小鼠肾脏结构,降低血清Scr、BUN及肾皮质 MDA含量（P<0.05,P<0.01）,而 SOD 活性明显升高（P<0.05）。 结论灯盏花素可明显减轻顺铂引起的肾毒性,其机制可能与抑制顺铂肾损害所致血液和肾皮质脂质过氧化反应增强有关。     

Effects of the diuretics mannitol or acetazolamide on nephrotoxicity and physiological disposition of cisplatin in rats

Summary The anticancer drug cisplatin has been known to produce severe renal lesions characterized by high levels of blood urea nitrogen (BUN), toxic nephrosis, and platinum (Pt) retention in the kidney. The effect of IV pretreatment with acetazolamide (ACZ) 30 min before or mannitol (MAN) immediately prior to IP administration of 5 mg/kg cisplatin on Pt excretion, tissue distribution, and nephrotoxicity was investigated in male F344 rats.ACZ pretreatment reduced the cisplatin-induced nephrotoxicity, as indicated by only a slight elevation of BUN, a milder histopathologic lesion, and a more rapid recovery of renal function and structure. Although MAN-pretreated animals exhibited similar changes in BUN to ACZ-pretreated animals, the renal damage was similar to that seen in aninals treated with cisplatin alone. A reduction of kidney Pt content was observed with both diuretics, although there was significantly less retention after ACZ pretreatment.The diuretic ACZ was more effective than MAN in reducing the renal lesions induced by cisplatin and it might be clinically useful in preventing cisplatin nephrotoxicity.     

Amifostine as a protector against cisplatin-induced toxicity in nude mice

The mechanisms mediating the protective effects of amifostine on cisplatin-induced toxicity were investigated in tumor-bearing nude mice by quantitative immunohistochemistry for analysis of cisplatin-DNA adduct levels in tumors and kidneys. The mice were treated with cisplatin 5 or 10 mg/kg i.p. with or without amifostine 200 mg/kg 30 min prior to cisplatin. Toxicity was noted in terms of mortality and changes in body weight. Mortality was similar in the four treatment groups, regardless of cisplatin dose or whether amifostine was added or not. At a cisplatin dose of 5 mg/kg, amifostine did not affect the moderate decrease in body weight. Cisplatin 10 mg/kg alone gave a significant loss of body weight, with the nadir on day 7. By adding amifostine to 10 mg/kg cisplatin the weight loss was much less pronounced. Tumor growth was significantly more retarded among animals treated with 10 mg/kg cisplatin alone compared with amifostine+cisplatin 10 mg/kg. There was no difference in tumor growth retardation between cisplatin 5 mg/kg alone or in combination with amifostine. The most likely explanation was that the pronounced tumor growth retardation with 10 mg/kg cisplatin alone was due to the decline in the general condition of the animals rather than increased antitumoral activity per se. Analysis of cisplatin-DNA adducts in tumors showed no difference whether cisplatin 10 mg/kg was combined with amifostine or not. In kidneys there were significantly fewer tubular cells with very high adduct levels in animals pretreated with amifostine.     

Low urine osmolarity as a determinant of cisplatin-induced nephrotoxicity

Cisplatin is widely used in the treatment of human tumors, but it is a nephrotoxic drug. Early pragmatic clinical trials have shown that cisplatin-induced renal toxicity is greatly reduced through the use of high hydration, a large NaCl supply and mannitol infusion, but the precise mechanisms of these nephroprotective measures are not fully understood. We show here an increase in the cisplatin uptake and cytotoxicity on 56/10 A1 human glomerular and HK-2 human tubular cells when the drug incubation was performed in a hypotonic phosphate-buffered saline solution or in human urine ("drag in" transport hypothesis). When 4 mg/kg cisplatin was intraperitoneally injected in rats in 20 ml of a hypotonic 4 g/l NaCl solution, the platinum accumulation increased in both the cortex and papilla but not in the subcutaneously grafted colon tumors when compared to rats injected with cisplatin in normal or hyperosmotic solutions (9 and 14 g/l NaCl, respectively). The urea and creatinine blood levels were significantly increased, and more apoptotic cells were detected by the caspase-3 cleavage and TUNEL assays in the tubular cells of rats treated with cisplatin in a hypotonic solution compared to animals that received normal or hypertonic solutions. Osmolarity was sometimes low in urine from patients receiving an intravenous hydration for a cisplatin treatment or from healthy volunteers who were given an oral hydration with a 50 g/l glucose solution. Our results show that low urine osmolarity could be a major determinant in the increase of cisplatin-induced nephrotoxicity and justify the widely used concurrent infusion of osmotically active substances during intravenous hydration.     

Studies on adequate intervals of cisplatin administration to ameliorate cisplatin-induced nephrotoxicity

Experimental studies were designed in order to ameliorate cisplatin-induced nephrotoxicity. Cisplatin was injected intravenously into DS mice at a dose of 5.0 mg/kg. Plasma platinum levels declined in a biphasic fashion and were undetectable after 5 days post-infusion. Renal platinum levels decreased in the same manner as the plasma levels and revealed detectable plateau levels 5 days after single injection. Cisplatin was administer once a week for 3 consecutive weeks; serial plasma and renal platinum levels and BUN were measured 7 days after each injection. The results showed that there was no significant change in the levels of plasma platinum and BUN but that the renal platinum levels increased progressively (1.6 +/- 0.3, 3.1 +/- 0.4, 4.8 +/- 2.7 micrograms/g wet wt.). After another 6 successive weeks of cisplatin administration, 55% of mice died. The renal platinum levels and BUN of the survivors were highly increased. The renal tissue revealed histologically acute renal failure. However the renal concentration of platinum was decreased to a low level of 1.1 +/- 0.4 micrograms/g wet wt. 4 weeks after the third injection. These results suggested that cisplatin-induced nephrotoxicity could be ameliorated by adequate intervals of cisplatin administration.     

Coadministration of dimethyl sulfoxide reduces cisplatin nephrotoxicity.

The administration of dimethyl sulfoxide with cisplatin at a mole ratio of 200:1 results in a considerable reduction in the nephrotoxicity produced when cisplatin alone is administered to Sprague-Dawley rats at 7.5 mg/kg. Observed measures of nephrotoxicity which were significantly improved by the coadministration of cisplatin and DMSO over the values found for cisplatin alone include BUN, serum creatinine, creatinine clearance and histopathological evidence of renal damage. The weight loss associated with cisplatin administration was also significantly reduced by DMSO coadministration. The use of DMSO did not result in any observable loss in antitumor activity of cisplatin against the Walker 256 carcinosarcoma.     

Selective reduction of cis-diamminedichloroplatinum(II) nephrotoxicity by ebselen

2-Phenyl-1,2-benzisoselenazol-3(2H)-one (ebselen) is classified as a relatively nontoxic selenium compound, probably because of its bound selenium moiety. In thiol-rich tissues, such as the kidneys, ebselen is converted into selenol intermediates. Selenols are nucleophilic agents which might be able to react with platinum compounds. The influence of ebselen on cis-diamminedichloroplatinum(II) (cisplatin)-induced nephrotoxicity in mice was assessed, using single doses of both compounds. Ebselen prevented cisplatin-induced elevations of blood urea nitrogen and serum creatinine levels and morphological kidney damage in BALB/c mice. This protective effect of ebselen was dose dependent: at a cisplatin dose of 14.5 mg/kg, maximal protection was achieved when a single dose of 10 mg of ebselen/kg was administered 1 h before cisplatin. Administration of ebselen, 10 mg/kg, 1 h after cisplatin also protected against severe nephrotoxicity. Treatment with ebselen did not reduce the antitumor activity of cisplatin against MPC 11 plasmacytoma or Prima breast tumor in BALB/c mice. However, this reduction of cisplatin-induced nephrotoxicity would be of little clinical value if it was achieved at toxic doses of ebselen. Ebselen, 10 mg/kg, did not induce blood urea nitrogen, serum creatinine, serum glutamic pyruvate transaminase, or serum glutamic oxalate elevations in the mice. These results are in agreement with the reported low toxicity of ebselen, which is now in Phase I clinical trials as an antiinflammatory drug. The present results indicate that ebselen may provide protection against cisplatin-induced nephrotoxicity, when it is given before or after cisplatin. This might open new perspectives in cancer chemotherapy.     

Protection against cisplatin-induced nephrotoxicity by recombinant human erythropoietin

Cisplatin (CDDP) is a potent nephrotoxin, and nephrotoxicity is its most important dose-limiting toxicity. In this study, we aimed to investigate the role of recombinant human erythropoietin (rhEPO) in the protection of cisplatin-induced nephrotoxicity and compare its efficacy with the cell-protective agent amifostine. All experiments were conducted on female Wistar albino rats. Animals were randomly assigned to four groups, each including six rats. Group A received only CDDP, group B received CDDP plus rhEPO, group C received CDDP plus amifostine, and group D received only rhEPO. At the end of 7 wk, hemoglobin (Hgb), hematocrite (Htc), blood urea nitrogen (BUN), and creatinine (Cr) levels were determined and kidneys of the rats were removed. The weights of the kidneys were measured and sent for histopathological examination. Proximal tubules from four areas of the kidney (outer cortex, inner cortex, the medullary ray, and outer stripe of outer medulla [OSOM]) were evaluated. There were statistically significant differences among the groups in terms of tubular scores, including overall renal tubular score, cortex, inner cortex, OSOM, and medullary ray tubular scores, and Htc levels. Group A rats had the worse tubular scores in all categories when compared to group D rats. When the results of groups B and C were compared, there were no differences in terms of BUN, Cr levels, and tubular scores, but the Htc level was significantly higher in group B. Group B rats had better overall and OSOM tubular scores when compared to group A. Group C also had better overall and OSOM tubular scores compared to group A. The present study showed for the first time that rhEPO plays an important role in the prevention of cisplatin-induced nephrotoxicity and it is as effective as amifostine.