国产大剂量顺铂肾毒性的临床研究

顺铂(Cisplatin,DDP)的肾毒性一直是临床应用受限制的主要因素。近年来由于应用水化利尿、分次静滴和高渗盐水等保护肾功能的方法,DDP的肾毒性已明显减轻,但在国外因DDP肾损伤致死的报道仍时有所见。为了解国产DDP对我国患者的肾毒性,本研究采用多种指标综合观察了国产大剂量 DDP对肾损伤情况,现报道如下。     

中药预防和减轻顺铂肾毒性的临床和实验研究

化学治疗是恶性肿瘤的主要治疗方法之一。顺铂(PDD)是一种常用的新型抗癌药,临床使用广泛。顺铂对肾脏有一定的毒性,大剂量顺铂对肾脏的毒性更大,它是临床应用受到限制的主要原因。化疗引起的肾功能衰竭,临床上并不少见。我们采用中药复方进行预防和减轻化疗药肾毒性的临床和实验研究,现将研究结果报告如下。     

顺铂的肾毒性作用及其防治

顺铂(cisplatin)是一种广谱抗癌药物,但其对肾脏的毒性作用,在一定程度上限制了它的应用。单用顺铂时,肾毒性发生率高达28～36％。近年来许多学者致力于探讨顺铂的肾毒性机理及其防治方法,并取得了一定进展。本文对此作一简要综述。 一、肾毒性及其机理 顺铂的肾毒性作用主要是由金属铂离子产生。血浆中高浓度的铂离子在用药后6小时就可对肾小管产     

顺铂肾毒性预防的研究进展

顺铂是临床应用最广泛的抗癌药物，如何减轻其肾毒性是当前的研究热点，并且已取得可喜进展，如调整给药时间，控制水铂，血浆铂峰浓度，改变谷胱甘肽含量，应用高氯液体，止吐剂，微量元素，氨基酸，抗生素，糖皮质激素，含苯甲酸基团药物，硫代氨基甲酸酯类药物，中药等均可不同程度地降低顺铂的肾毒性，对其临床应用具有重要意义。     

顺铂肾毒性作用的初步实验研究

顺铂(DDP)的肾毒性作用是影响临床应用的关键因素,其机理目前尚不清楚。本文进行了初步动物试验观察,以提供初步参考材料。     

减轻顺铂毒性的研究进展

顺铂的主要不良反应是肾毒性,胃肠道反应,耳毒性以及外周神经病变,肾毒性成为限制该药用量的主要因素。近年研究发现,顺铂的上述毒性可能与其在体内产生自由基有关。采用抗氧化剂等可能减轻顺铂的毒性反应,增加顺铂用量,从而增强其抗肿瘤作用。     

顺铂肾毒性早期发病机理的初步研究

实验选用毒性Ｓｐｒａｇｕｅ－Ｄａｗｌｅｙ大鼠研究顺铂后肾毒性发生的机理。实验动物静脉注射１０ｍｇ／ｋｇ顺铂后３小时，肾脏光镜与透镜电镜检查及肾小球滤过率无明显变化。但顺铂注射后３０分钟尿钠，钾浓度分别增加５６％及２．６倍，３小时后肾小管细胞粒体功能明显异常。     

大蒜素对顺铂肾毒性的保护作用

目的：研究大蒜素对顺铂（DDP）导致的人胚肾HEK293细胞氧化损伤的保护作用并探讨其作用机制。方法：体外培养HEK293细胞,MTT法分别测定不同浓度大蒜素和DDP对HEK293细胞生长的影响,以及大蒜素预处理对DDP诱发细胞毒性的影响。进一步将HEK293细胞分为对照组（未加入DDP和大蒜素）、DDP组（20 mg/L）、大蒜素组（2 mg/L）、大蒜素（4 mg/L）+DDP（20 mg/L）组,黄嘌呤氧化酶法检测各组细胞内超氧化物歧化酶（SOD）活力,硫代巴比妥酸法测定细胞内丙二醛（MDA）含量,二硫代二硝基苯甲酸法测定还原型谷胱甘肽（GSH）的含量。结果：与对照组相比,DDP导致细胞存活率显著降低,且呈剂量效应关系（P < 0.01）。大蒜素预处理后,对DDP（20 mg/L）所致细胞存活率的抑制作用有显著改善（P < 0.01）。与DDP组相比,大蒜素能显著抑制DDP所致细胞内MDA含量的升高以及SOD活力和GSH含量的下降（P < 0.01）。结论：大蒜素可拮抗DDP所致HEK293细胞氧化损伤,对顺铂肾毒性具有明显的保护作用。     

氨磷汀对顺铂肾毒性损害的保护作用

顺铂(DDP)是临床常用的化疗药物之一,其抗瘤谱广,广泛用于治疗肺癌、食管癌、大肠癌、睾丸和头颈部恶性肿瘤等,但明显的肾毒性在一定程度上限制了其临床应用。氨磷汀是美国FDA按一类新药优先批准上市的第1个泛细胞保护剂,即广谱的选择性细胞     

氨磷汀对顺铂致肾功能异常患者再化疗的肾脏保护作用

目的观察氨磷汀对顺铂（DDP）致肾功能异常患者再化疗的肾脏保护作用。方法对19例因DDP化疗致肾功能异常患者,再次应用含DDP方案化疗,静脉用DDP前30min加用氨磷汀250mg/m^2,治疗前及治疗后不同时间分别测定血尿素氮、血肌酐值,观察肾功能的变化情况。结果19例患者,有效4例,稳定12例,进展3例,总有效率达84.2%。结论DDP化疗后肾功能轻度异常患者,再次采用含DDP方案化疗时,加用氨磷汀可以防止肾功能的进一步损害。     

Cisplatin-Induced Nephrotoxicity; Protective Supplements and Gender Differences

Cisplatin (CDDP) has been widely used as a chemotherapeutic agent for solid tumors. The most common side effect of CDDP is nephrotoxicity, and many efforts have been made in the laboratory and the clinic to employ candidate adjuvants to CDDP to minimize this adverse influence. Many synthetic and herbal antioxidants as well as trace elements have been investigated for this purpose in recent years and a variety of positive and negative results have been yielded. However, no definitive supplement has so far been proposed to prevent CDDP-induced nephrotoxicity; however, this condition is gender related and the sex hormone estrogen may protect the kidney against CDDP damage. In this review, the results of research related to the effect of different synthetic and herbal antioxidants supplements are presented and discussed with suggestions included for future work.     

Incidence of Cisplatin-Induced Nephrotoxicity and Associated Factors among Cancer Patients in Indonesia

Background: Cisplatin is still used as a first-line medication for solid tumors. Nephrotoxicity is a serious sideeffect that can decrease renal function and restrict applicable doses. This research aimed to obtain the profile ofcisplatin-induced nephrotoxicity and its associated factors in adult cancer patients at Dharmais National CancerHospital (DNCH). Materials and Methods: The design was cross-sectional with data obtained from patientmedical records. We retrospectively reviewed adult cancer patients treated with cisplatin ≥60mg/m2 for at leastfour consecutive chemotherapy cycles from August 2011 to November 2013. The nephrotoxicity criterion wasrenal function decline characterized by creatinine clearance <60 ml/min using the Cockroft-Gault (CG) equation.Results: Eighty-eight subjects received at least four chemotherapy cycles of cisplatin. The prevalence of cisplatinnephrotoxicity was 34.1%. Symptoms could be observed after the first cycle of chemotherapy, and the degree ofrenal impairment was higher with increased numbers of cycles (r=-0.946, r2=89.5%). Factors that affected thedecline of renal function were patient age (p=0.008, OR=3.433, 95%CI= 1.363-8.645) and hypertension (p=0.026,OR=2.931, 95%CI=1.120-7.670). Conclusions: Cisplatin nephrotoxicity occurred in more than one-third ofpatients after the fourth cycle of chemotherapy and worsened after each cycle despite preventive strategies suchas hydration. The decline of renal function induced by cisplatin ≥60 mg/m2 was affected by age and hypertension.     

Cisplatin-incorporated Polymeric Micelles Eliminate Nephrotoxicity, While Maintaining Antitumor Activity

cis -Diamminedichloroplatinum (II) (cisplatin, CDDP), a potent anticancer agent, was bound to the aspartic acid residues of poly(ethylene glycol)-poly(aspartic acid) (PEG-P(ASP)) block copolymer by ligand substitution reaction at the platinum atom of CDDP. The polymeric drug thus obtained was observed to form a micelle structure in aqueous medium, showing excellent water solubility. In the present study, in vitro and in vivo antitumor activity against several human tumor cell lines, toxicity and pharmacokinetic characteristics in rodents of CDDP-incorporated polymeric micelles (CDDP/m) were evaluated in comparison with those of CDDP. In vitro , CDDP/m exhibited 10-17% of the cytotoxicity of CDDP against human tumor cell lines. CDDP/m given by intravenous (i.v.) injection yielded higher and more sustained serum levels than CDDP. In vivo CDDP/m treatment resulted in higher and more sustained levels in tumor tissue than CDDP, and showed similar antitumor activity to CDDP against MKN 45 human gastric cancer xenograft. CDDP/m treatment caused much less renal damage than CDDP. These results indicate that CDDP/m treatment can reduce CDDP-induced nephrotoxicity without compromising the anticancer cytotoxicity of CDDP.     

氨磷汀对顺铂肾毒性损伤的保护作用及其机制的研究

目的 观察顺铂的肾毒性损伤部位、形式与肾功能检查结果的相关性,以了解细胞凋亡的发生机制和氨磷汀的保护机制是否与肾组织Fas和FasL表达改变有关。方法 随机将大鼠分成3组,即对照组（生理盐水）、顺铂组（6mg／kg）和氨磷汀组（顺铂6mg／kg＋氨磷汀200mg／kg）,取其血清标本和肾组织,分别做血清BUN、Cr检测和肾组织病理学检查,并用原位缺口末端标记法（TUNEL）做肾组织凋亡细胞检测、Fas和FasL免疫组化染色,再用图像分析软件对其做阳性细胞计数和染色总灰度值测定。结果 顺铂组动物血清BUN、Cr值均明显高于对照组和氨磷汀保护组,3d时,差异已有统计学意义（P〈0．05）;5d时,两者差异分别为P〈0．01和P〈0．05;10d时,恢复正常。顺铂组肾小管上皮细胞坏死和凋亡均很严重,其凋亡细胞计数明显高于对照组和氨磷汀组（P值均〈0．01）,肾组织Fas和FasL表达的总灰度值,明显高于对照组和氨磷汀组（P值均〈0．01）。结论 氨磷汀对顺铂的肾毒性损伤有保护作用,其机制可能与抑制肾组织Fas和FasL的表达有关。     

Effects of Lycopene Alone or Combined with Melatonin on Methotrexate-Induced Nephrotoxicity in Rats

Methotrexate (Mtx), used for its anticancer and immunsuppresive properties, is known to be a nephrotoxicagent. We aimed to investigate the effects of lycopene (Lyc) alone or combined with melatonin (Mel) on Mtxinducednephrotoxicity since both of these agents have antioxidant and anti-inflammatory effects. Nephrotoxicitywas induced by intraperitoneal administration of methotrexate at a dose of 20 mg/kg. Treatment both with Lycalone and Lyc combined with Mel provided significant reduction in tumor necrosis factor-alpha, interleukin1-beta and ceruloplasmin levels in Mtx administered rats. Hovewer, Lyc combined with Mel provided a significantreduction also in NO levels. Hstopathological examination showed that there was an obvious improvement inthe degenerative changes compared to Mtx administrated group with the Lyc combined Mel group giving bestprotection. In conclusion Lyc alone and combined with Mel provided significant improvement against renaldamage caused by Mtx, preseumably via antioxidant and anti-inflammatory activities.     

改良肠道水化对顺铂治疗肺癌的肾毒性的影响

目的：观察改良肠道水化对顺铂（PDD）治疗肺癌的肾毒性的影响.方法：212例肺癌予以PDD为主的联合化疗,PDD 75～80mg/m^2静滴,第1天,化疗当天通常静脉补液1 000～2 000ml,摄水量1 500～2 000ml,PDD后半小时静脉推注速尿,并予积极止吐处理,连续3天记录24小时出入量,化疗前后测定肾功能.结果：212例肺癌均顺利完成化疗,仅11例（5.1%）有一过性轻度肾功能异常,与常规水化方案相比未增加肾毒性,所有病例无胸闷、气急.结论：改良的肠道水化方案也能较好地预防顺铂的肾毒性,且补液量少,患者易接受,临床上是可行的.     

Differential Neutralizing Effect of Tiopronin on the Toxicity of Neocarzinostatin and SMANCS: A New Rescue Cancer Chemotherapy

The toxic effect and antitumor activity of neocarzinostatin (NCS) and SMANCS [copoly(styrenemaleic acid)-conjugated NCS] were greatly affected by N-(2-mercaptopropionyl)-glycine [tiopronm] both in vitro and in vivo , in cultured HeLa cells and RL♂1 tumor-bearing mice. The cytotoxicity of NCS and SMANCS against HeLa cells was remarkably reduced by the addition of tiopronin during drug treatment. Interestingly, the neutralizing effect of tiopronin on the toxicity of SMANCS was greater than that in the case of NCS. In the continuous presence of 10 mM tiopronin during a 1 h drug treatment, the 50% cell-killing doses of NCS and SMANCS were increased 72 and 208 times as compared to those without tiopronin, respectively, whereas tiopronin itself has no cytotoxicity to HeLa cells up to 100 mM. Furthermore, more effective reduction of the lethal toxicity of SMANCS was observed by the intraperitoneal (ip) administration of tiopronin after ip injection of a lethal dose of SMANCS as compared to the same protocol in the case of NCS in mice. Therapeutic studies on RL♂1 tumor-bearing mice revealed that delayed (time lag) ip administration of tiopronin after high-dose SMANCS administration ip was much superior to the combination of NCS with tiopronin, or SMANCS alone. In this time-lag combination chemotherapy of SMANCS with tiopronin, 60% of treated mice survived more than 60 days after tumor inoculation, while all the untreated control mice died within 20 days.