卡铂和顺铂肾毒性的比较

类抗癌药是当代最主要的抗癌药物之一,它在肿瘤治疗中起着越来越重要的作用,但由于顺铂的主要剂量限制性毒性为肾毒性,影响了该药物剂量的提高。卡拍是第二代铂类低毒高效的抗癌药,文献报道卡铂肾毒性远远低于顺铂,我们用血清ＢＵＮ、Ｃｒ和尿β2—ｍＧ的测定对卡铂和顺铂化疗的肾毒性作用结果进行比较分析,以了解卡铂和顺铂使用不同的剂量和不同的治疗方法对肾脏的毒副作用的影响。材料与方法　本组病例病理诊断均为恶性肿瘤,在化疗前的肾功能均为正常,每例在化疗前和化疗后2周分别测定血清ＢＵＮ、Ｃｒ和尿β2—ｍＧ。顺铂治疗组分为Ａ、…     

大鼠静注双环铂、卡铂与顺铂后铂的肾排泄与肾分布比较研究

目的比较顺铂、卡铂和双环铂3种铂制剂的肾排泄速度和肾组织中浓度,探讨铂类抗癌药的肾毒性机制,为临床用药提供参考。方法大鼠按铂元素10mg·kg-1剂量静脉注射3种铂制剂后,采用原子吸收法测定大鼠尿液中3种铂的排泄量,计算4h尿药累积排泄百分率。结果顺铂组4h的累积排泄量平均为(33.7±5.7)%;卡铂组为(89.1±8.5)%;双环铂组为(70.1±9.8)%,由此结果可见顺铂排泄最少,双环铂和卡铂则较多;静注顺铂、卡铂和双环铂后4h测定肾组织中铂的浓度分别为(70.6±31.6),(217.7±97.6)和(278.8±112.0)μg·g-1。结论与顺铂相比,双环铂与卡铂肾排泄较快,肾组织中的铂浓度相对较高,肾组织中铂浓度与肾毒性间可能无直接关系。     

顺铂和卡铂对胃癌细胞系的毒性作用比较

目的：体外比较顺铂和卡铂对胃癌细胞系的毒性作用,为临床化疗提供参考。方法：采用二甲基噻唑基四氮唑试验（MTT）在不同的培养时间,用不同浓度的药物,通过其细胞抑制率和半数抑制率（IC50）比较两种药物的细胞毒性。结果：不同培养时间的肿瘤细胞抑制率顺铂明显高于卡铂（P＜0．05）,顺铂的IC50也远小于卡铂。结论：顺铂对胃癌细胞系的体外细胞毒性作用大于卡铂。     

磷霉素减轻顺铂肾毒性实验研究

目的 考查磷霉素对顺铂肾毒性的影响。方法 测定中性磷霉素钠与顺铂合并单次静注后小白鼠生存天数，LD50；通过病理以及血液学检查，测定对大鼠肾毒性的影响。结果 磷霉素对顺铂在未产生蓄积中毒时所致的肾功能改变有保护作用。     

顺铂肾毒性的防治措施

顺铂肾毒性的防治措施１０００３９军事医学科学院附属医院药理室梁月琴综述郭军华张秀国审校顺铭是１９６５年Ｒｏｓｅｎｂｅｒｇ等’“发明的抗肿瘤药物，它对卵巢癌、肺癌、膀优癌、乳腺癌、头颈部肿瘤和星丸肿瘤有极好的治疗作用，但顺铂易引起严重的肾毒性，且肾毒性...     

大鼠静脉注射3种铂制剂后铂的肾排泄与肾分布比较研究

目的:探讨铂类抗癌药的肾毒性机制。方法:12只大鼠均分为3组,分别按铂元素10mg·kg-1剂量静脉注射顺铂、卡铂和双环铂,采用原子吸收法测定并计算4h尿药累积排泄率及肾组织中浓度。结果:4h累积排泄率顺铂、卡铂、双环铂分别平均为(33.7±5.7)%、(89.1±8.5)%、(70.1±9.8)%,肾组织中铂的浓度分别为(70.6±31.6)、(217.7±97.6)、(278.8±112.0)μg.g-1。结论:与顺铂相比,双环铂与卡铂肾排泄较快,肾组织中的铂浓度相对较高;肾组织中铂浓度高低与肾毒性大小之间可能无直接关系。     

铂类抗癌新药双环铂的体内外抗肿瘤活性

目的观察铂类抗癌新药双环铂的体内外抗肿瘤活性及其对细胞周期的影响。方法MTT法观察双环铂对人肿瘤细胞增殖的抑制作用;小鼠动物肿瘤模型观察双环铂对肿瘤的体内抑制作用;碘化丙锭PI染色流式细胞术分析药物所致人卵巢癌细胞A2780细胞的周期变化。结果双环铂于体外抑制多种人肿瘤细胞增殖,体内抑制小鼠肉瘤S180、肝癌Heps及黑色素瘤B16的生长,并导致A2780细胞S期细胞明显增加及G₂/M期细胞少许增加。结论双环铂具有明显的体内外抗肿瘤活性,并影响肿瘤细胞的细胞周期分布。     

铂类抗癌新药双环铂的体内外抗肿瘤活性

目的观察铂类抗癌新药双环铂的体内外抗肿瘤活性及其对细胞周期的影响。方法MTT法观察双环铂对人肿瘤细胞增殖的抑制作用;小鼠动物肿瘤模型观察双环铂对肿瘤的体内抑制作用;碘化丙锭PI染色流式细胞术分析药物所致人卵巢癌细胞A2780细胞的周期变化。结果双环铂于体外抑制多种人肿瘤细胞增殖,体内抑制小鼠肉瘤S180、肝癌Heps及黑色素瘤B16的生长,并导致A2780细胞S期细胞明显增加及G2/M期细胞少许增加。结论双环铂具有明显的体内外抗肿瘤活性,并影响肿瘤细胞的细胞周期分布。     

硝酸铋与丙磺舒合用对顺铂肾毒性的保护作用

毒性剂量的顺铂（ＣＰ３０μｍｏｌ．ｋｇ＾－１ｉｐ）可引起血尿毒氮（ＢＵＮ）升高。硝酸铋（ＢＮ）５μｍｏｌ．ｋｇ＾－１于ＣＰ前４８和２４ｈｓｃ，丙磺舒（Ｐｒｏ）７００μｍｏｌ．ｋｇ＾－１于ＣＰ前１５，１ｈ及ＣＰ后５ｈｉｇ，或ＢＮ与Ｐｒｏ二半量合用，按上述给药，均能抑制ＣＰ引起的ＢＵＮ升高，尤以ＢＮ＋Ｐｒｏ组抑制作用显。肾脏光镜和电镜标本显示，ＣＰ使肾上管受损严重；ＢＮ组，Ｐｒｏ组和ＢＮ＋Ｐｒｏ组     

国产氨磷汀预防顺铂肾毒性的临床研究

目的 :观察氨磷汀预防顺铂肾毒性的疗效和安全性。方法 :46例恶性肿瘤患者随机分为化疗加氨磷汀组 (试验组 )和单纯化疗组 (对照组 ) ,两组各23例。于化疗前和化疗后不同时期分别测定其血象、血钙、肝功能、血尿素氮、肌酐、尿微量蛋白(包括α1-微球蛋白(α1-MG)、白蛋白 (A1b)和转铁蛋白 (TRF) )。结果 :试验组与对照组各有20例完成2个周期化疗。两组化疗后尿α1-MG、A1b和TRF的最高值比较 ,试验组均低于对照组 ,差异有显著性 (P<0 05或P<0 01)。试验组部分病例有轻度的血压和血钙降低。结论 :氨磷汀能安全有效地预防顺铂引起的肾毒性     

顺铂、樟脑胺氯乙酸铂及碳铂对染色体损伤的比较

以CHL细胞为材料,比较了顺铂(DDP)、碳铂(JM 8)和樟脑胺氯乙酸铂(CCP)的细胞毒作用和对CHL细胞的染色体损伤。实验表明,这三种铂络合物都有较强的细胞毒作用,其中顺铂最强而CCP最弱。DDP,JM-8和CCP的IC~(90)(±SD)分别为0.68±0.21,4.4±0.6,10.8±1.5μmol/L。在微核及染色体畸变实验中,观察到在药物浓度小于或等于IC_(90)时,这三种化合物诱发的微核及染色体损伤相当,但药物浓度增加时,CCP所诱发的微核及染色体畸变均大于DDP而JM-8最轻。     

Discrepancy between cytotoxicity and DNA interstrand crosslinking of carboplatin and cisplatin in vivo

We used the method of alkaline elution to compare quantitatively the DNA lesions produced by cisplatin and carboplatin in the AKR leukemia in vivo. These data were compared with cytotoxicity of each drug in the same animal model and in a solid tumor murine model (colon 26).DNA-protein and DNA-DNA interstrand crosslinks were formed in similar proportions by both drugs when peak values of crosslinking were compared. No clear difference in the rate of formation of both types of crosslinks could be observed between these drugs.On a molar basis a 3- to 4-fold more carboplatin had to be given to obtain equivalent frequencies of both types of crosslinks. In contrast, to obtain equitoxicity in the same animal tumor model, 13 fold higher doses of carboplatin had to be given. This difference in cytotoxicity between both drugs is comparable to the difference measured in colon 26 in vivo (16 fold). Both values are in the range of literature data (10–25 fold) dealing with the relative potency of cisplatin and carboplatin in murine tumor models.Abbreviations DIC DNA-DNA Interstrand Crosslinks - DPC Protein-DNA Crosslinks - EDTA Ethylene-Diammine-Tetra-Acetic Acid - PK Proteinase K - PSA Puck's Saline A - SSB Single Strand Breaks - ILS Increase in Life Span - Carboplatin-Cis-(diammino)(1,1-cyclobutane-dicarboxylato)-Platinum (II), Cisplatin Cis-Diamminedichloroplatinum (II) Supported by an award from the Belgian Work against Cancer.American Cancer Society Cancer Development Award Recipient.     

国产卡铂和顺铂在兔体内的药物动力学

本文以石墨炉原子吸收分光光度法为测定方法,对国产卡铂和顺铂在家兔体内的药物动力学进行了初步的研究和比较。本法中卡铂和顺铂在0～20μg/ml范围内药物血浆浓度同吸收峰高呈线性关系,相关系数r>0.99(P相似文献   

培美曲塞联合卡铂或顺铂对复发性卵巢上皮癌患者的疗效及安全性分析

目的 探讨培美曲塞联合卡铂与顺铂对复发性卵巢上皮癌患者的疗效及安全性。方法 回顾性选择濮阳市油田总医院2012年1月-2015年12月收治的53例复发性卵巢上皮癌患者,根据化疗方法的不同分为A组及B组,A组26例,采用培美曲塞联合顺铂治疗,B组27例,采用培美曲塞联合卡铂治疗,对比两组的临床疗效、无进展生存期及不良反应。结果 A组治疗有效率为34.6%,B组为40.7%,两组有效率对比无统计学意义。A组平均无进展生存期为（9.1±1.9）个月,B组为（9.7±1.8）个月,组间对比无统计学意义。A、B两组的Ⅲ~Ⅳ血液学毒性、乏力、Ⅲ~Ⅳ消化道反应对比无统计学意义;而B组的Ⅲ~Ⅳ周围神经病变、Ⅲ~Ⅳ脱发、发热发生率明显低于A组,差异有统计学意义（P<0.05）。结论 培美曲塞联合卡铂与培美曲塞联合顺铂对复发性卵巢上皮癌的效果相当,但培美曲塞联合卡铂的安全性较高。     

Randomized cross-over clinical trial to study potential pharmacokinetic interactions between cisplatin or carboplatin and etoposide

AIMS: Cisplatin and carboplatin are often used in combination with etoposide. In a randomized cross-over study, the potential interaction between the two platinum drugs and the metabolism of etoposide was explored. In vitro investigations using human liver microsomes were also performed. METHODS: Etoposide was administered to 15 patients over 3 days, with the platinum drug administered on day 2. The alternate platinum drug was administered on the second course. The pharmacokinetics of etoposide were determined on all 3 days of each cycle. The effect of platinum drugs on etoposide metabolism by human liver enzymes was explored in vitro. RESULTS: Neither cisplatin nor carboplatin coadministration affected the pharmacokinetics of etoposide during cycle 1. When carboplatin was administered on course 2, etoposide AUC was 8% higher on day 2 compared with day 1 or day 3 (for day 2 vs day 3, 95% CI: -0.72, -0.08 mg ml(-1) min). In contrast, cisplatin on course 2 increased the AUC of etoposide (28%) on day 3 (day 3 vs day 1, 95% CI: 0.67, 2.09 mg ml(-1) min), with no effect on day 2. In vitro carboplatin and cisplatin (10-100 microm) inhibited the metabolism of etoposide, if rat liver microsomes were preincubated (30 min) with NADPH and the platinum complexes. With human liver microsomes a small effect on etoposide metabolism, but not on catechol formation, was observed. CONCLUSIONS: The interaction between etoposide and platinum drugs is small and, given the pharmacokinetic variability seen with etoposide, the clinical impact is unlikely to be significant.     

Interaction of platinum agents,cisplatin, carboplatin and oxaliplatin against albumin in vivo rats and in vitro study using inductively coupled plasma‐mass spectrometory

The protein binding rates (PBR) of platinum‐containing agents cisplatin (CDDP), carboplatin (CBDCA) and oxaliplatin (L‐OHP) have been reported as 98%, 25–50% and 98%, respectively. To investigate the protein‐binding properties of albumin with cisplatin, carboplatin and oxaliplatin, inductively coupled plasma mass spectrometry (ICP‐MS) was used to measure their plasma concentration in rats over time. The study also examined the effects of cisplatin, carboplatin and oxaliplatin‐binding on albumin in vitro, using CD spectrometry and native‐polyacrylamide gel electrophoresis (native PAGE). The ratios of PBR to irreversible PBR, of cisplatin and oxaliplatin were 98%:98% and 90%:87%, respectively, indicating a higher affinity for irreversible binding with albumin. That of carboplatin was 25%:10%, indicating 60–70% reversible binding with albumin. The plasma protein binding rate concentrations of cisplatin, carboplatin and oxaliplatin after in vivo administration were 96%, 15% and 80%, respectively. The CD spectrometry of albumin was unaffected by cisplatin, carboplatin and oxaliplatin binding. Though similar protein binding rates were observed with oxaliplatin and cisplatin, oxaliplatin had a higher mobility rate during PAGE. It was confirmed that the binding of cisplatin and oxaliplatin with albumin affected its electric charge but not the structure. In conclusion, cisplatin and oxaliplatin bind irreversibly with albumin in plasma and may irreversibly interact with tissue protein and/or DNA. The difficulties involved with predicting the tissue concentrations of cisplatin and oxaliplatin from their plasma concentration inhibits their therapeutic drug monitoring. On the contrary, carboplatin, like some generic drugs, reversibly binds to plasma proteins. It is, therefore, possible to conduct therapeutic drug monitoring for carboplatin.     

Chemotherapy of the squamous cell lung cancer LC-12 with 5-fluorouracil,cisplatin, carboplatin or iproplatin combinations

Summary The combination of Cis-dichlorodiammineplatinum (II) (CisDDPt) + 5-Fluorouracil (5-FU) was compared with two CisDDPt analogues + 5-FU [Iproplatin (CHIP) + 5-FU and Carboplatin (CBDCA) + 5-FU] for relative efficacy against advanced stage squamous cell lung tumors (LC-12) in Balb/c mice. At equitoxic dosages, the numbers of regressions and cures were similar for the three combinations (5-FU/CISDDPt 2/10 PR's, 2/10 CR's, 2/10 cures; 5-FU/CBDCA 1/10 PR's, 5/10 CR's, 3/10 cures; 5-FU/CHIP 1/10 PR's, 3/10 CR's, 3/10 cures). The tumor growth delay among the mice not cured was slightly superior in the 5-FU/ CisDDPt regimen. All the agents were active singly against this tumor model. Based on these results, the substitution of CBDCA or CHIP for CisDDPt in a FU regimen did not offer a cytotoxic advantage. Because of different dose limiting toxicities for the platinum compounds the possibility exists that these analogues could be used in drug combinations in substitution for CisDDPt.     

硝酸铋预处理对顺铂肾毒性的防护作用

大鼠预先sc硝酸铋(30μmol·kg~(-1)·d~(-1))连续3d,可显著降低肾毒性剂量顺铂(5mg·kg~(-1))引起的尿蛋白含量,尿NAG活性和BUN水平的升高;并可有效地防护顺铂造成的肾脏髓层外带近端小管坏死,铋对肾脏MT合成有诱导作用,这可能与其防护顺铂的急性肾毒性有关。     

吉西他滨联合卡铂诱导NK/T细胞淋巴瘤细胞株凋亡的研究

目的:研究吉西他滨联合卡铂对NK/T细胞淋巴瘤细胞株(SNK 6)细胞增殖及凋亡的影响。方法:采用细胞增殖-毒性检测法(CCK-8)检测吉西他滨、卡铂、顺铂对SNK 6细胞增殖的影响,算出各自半数抑制浓度(IC 50)值;再用吉西他滨与卡铂或顺铂做联合实验,用金氏公式计算Q值,评价联合用药效应。应用流式细胞仪检测不同药物组对细胞凋亡的影响。蛋白免疫印迹法(Western Blotting)检测各药物组Cleaved-caspase-3、B淋巴细胞瘤-2蛋白(Bcl-2)、Bcl-2相关X蛋白(Bax)等凋亡蛋白的表达水平。结果:吉西他滨、卡铂、顺铂对SNK 6细胞均有较好的抑制作用;联合用药中,吉西他滨+卡铂组与吉西他滨+顺铂组对SNK 6细胞抑制作用相当,两药联合为相加作用。吉西他滨+卡铂组凋亡率稍低于吉西他滨+顺铂组,但差异无统计学意义(P>0.05)。吉西他滨可上调Cleaved-caspase-3蛋白、Bax蛋白的表达水平,下调Bcl-2蛋白的表达水平(P<0.05),吉西他滨与卡铂或顺铂联合时效果更加显著。结论:在体外环境下,吉西他滨联合卡铂可抑制SNK 6细胞增殖并诱导其凋亡,且一定浓度的吉西他滨联合卡铂对SNK 6细胞株的凋亡率与吉西他滨联合顺铂相似。     

Effect of methotrexate on the pharmacokinetics and renal excretion of cisplatin

Summary The kinetics of platinum in plasma and erythrocytes, and its renal excretion, have been examined in five patients with non-small cell carcinoma of the lung, after treatment with cisplatin 50 mg/m² (Platidiame) and, three weeks later, a combination of 50 mg/m² cisplatin and 40 mg/m² methotrexate. The patients were given 0.9% saline 11 l h prior to drug application.Plasma platinum elimination was biphasic with a short initial phase (t_1/2a 10–31 min) and a long-phase (t_1/2 65–91 h). With the exception of increased AUC values in all five patients 0–8 h after the injection, no significant change in the kinetics of platinum in plasma was found after coadministration of methotrexate.In four of the five patients renal platinum excretion was reduced in the first 6 h after administration of methotrexate. The renal clearance of platinum was 50% lower in those four patients 0–3 h after the injection.With the exception of one patient, no signs of nephrotoxicity were observed after combined drug administration. Other toxic effects were mild and showed no increase after the initial administration of methotrexate.