Transport of cisplatin in rat brain following microinfusion: an analysis

The post-microinfusion transport of cis-diamminedichloroplatinum(II) (cisplatin) in rat brain has been modeled as a linear diffusion-reaction-permeation process. The model has been used to analyze the experimental data of Kroin and Penn to obtain the macromolecular binding constant of cisplatin in the brain, k = 0.0050 +/- 0.0023 min-1, and the capillary permeability, p = (9.0 +/- 4.4) X 10(-7) cm/s. Inclusion of saturation effects led to the same p value and a higher k value of 0.007 min-1. The corresponding diffusion length is 0.8 mm. The reaction constant is similar to those reported for plasma (0.008 min-1) and muscle (0.004 min-1), and the permeability value is within the range predicted by correlation with the permeability-octanol/water partition coefficient. Fits to data were accomplished with mathematical expressions giving the average total platinum concentration in saggital cerebellar sections which were not subdivided. Both time-dependent and steady-state solutions were obtained for the transport model, the former predicting a half-time to steady state of 3 h. Boundary effects were also investigated. Concentration profiles, calculated for a point source and for a 23-gauge cannula, were shown to differ by 7%. Similar comparisons between two profiles, one computed for an infinite diffusion range and another computed for drug diffusion into a flowing cerebrospinal fluid (CSF) at a finite range of 3 mm, showed differences of less than 3%. Free and bound drug forms, protein turnover, and CSF uptake have been accounted for as well as the percent infusate recoveries at 100 and 160 h reported by Kroin and Penn.(ABSTRACT TRUNCATED AT 250 WORDS)     

Different cell cycle modulation following treatment of human ovarian carcinoma cells with a new platinum(IV) complex vs cisplatin

Summary Platinum (IV) derivative with adamantylamine—LA-12—represents a new generation of highly efficient anti-cancer drug derived from cisplatin and is currently in the final stage of phase I clinical trials. Understanding the specific mechanisms of its effects on cell cycle is necessary for defining the mode of action of LA-12. In this study, we characterized the ability of LA-12 to induce cell cycle perturbations in ovarian cancer cell line A2780 as compared to equitoxic cisplatin treatment. LA-12 induced a permanent accumulation of A2780 cells in S phase while cisplatin caused G₂/M arrest at 24-h time point, where we also detected an increased expression of Gadd45α protein. Although both derivatives induced a rapid increase of p53 expression, this was not associated with a down-regulation of Mdm2 protein. Increased expression of p21^Cip1/WAF1 protein and its association with cyclins A and B1 suggested that this cyclin-dependent kinase inhibitor might contribute significantly to the observed perturbations of cell cycle. The results of this study provide insight into the mechanism of action of platinum-based derivative with adamantylamine on cell cycle in ovarian cancer cells. The differences between effects of LA-12 and cisplatin suggest that more attention should be paid to elucidation of modes of action of novel platinum(IV) complexes at cellular level.     

顺铂软膏治疗银屑病临床疗效观察

顺铂 (ｃｉｓｐｌａｔｉｎ)是细胞周期非特异性抗肿瘤药物 ,常以注射给药。我们研制的顺铂软膏 ,动物实验可促进皮肤颗粒层细胞生长[1] 。我们于 1999年 6月至 2 0 0 0年 12月 ,应用 0 .1%顺铂软膏治疗银屑病患者 10 0例 ,疗效观察的结果如下。1　对象与方法1.1　病例选择　全部病例均为我院门诊就诊的寻常型银屑病患者。所有病例近 1月来均未接受全身皮质类固醇、免疫抑制剂或其他方法治疗 ,2周内未行外用药物治疗。将患者随机分成 2组。治疗组10 0例 ,其中男 5 4例 ,女 4 6例 ;年龄 15～ 5 2岁 ,平均(34.0± 12 .7)岁 ;病程 2年至 2 0年 ,…     

卵巢癌对顺铂类药物耐药性的相关分析

摘要： 目的 筛选影响卵巢癌顺铂耐药性的靶点基因。方法 从 GEO 数据库中下载对顺铂敏感和产生抗药性 的人类卵巢癌细胞基因表达谱和甲基化谱数据（GSE15709）, 利用 R 的相关工具包筛选 A2780 和 A2780/DDP（顺铂 耐药卵巢癌细胞系）两类卵巢癌细胞之间的差异表达和差异甲基化的基因; 使用 DAVID 数据库对差异表达基因进 行功能富集分析; 对同时发生了差异甲基化、 差异表达且甲基化水平、 表达水平的变化趋势相反的基因, 进一步利用 qRT-PCR 技术检测这些基因在两种卵巢癌细胞中的表达值。结果 研究发现在两种卵巢癌细胞之间发生了 416 个 差异表达和 281 个差异甲基化的基因, 这些差异表达基因主要富集于细胞周期、 核分裂和蛋白修饰负调控等生物过 程。此外, 细胞周期、 DNA 复制和 p53 等通路在这些基因中同样富集。共发现 4 个发生了差异甲基化、 差异表达且 甲基化变化水平、 表达水平变化趋势相反的基因, qRT-PCR 实验验证了这些基因在两种卵巢癌细胞中的表达水平。 结论 利用生物信息学和分子生物学相结合的方法, 可以筛选出部分影响卵巢癌对顺铂抗药性的基因, 为进一步揭 示其中的分子机制提供实验参考。     

Murine macrophage activation after cisplatin or carboplatin treatment.

Murine peritoneal macrophages when treated in vitro with cisplatin (9 micrograms/ml) or carboplatin (50 micrograms/ml) for 2 h are stimulated to form cytoplasmic extensions seeking out tumor cells and establishing cytoplasmic connections; however, no contact is observed with normal cells (fibroblasts and hepatocytes). In addition, cisplatin and carboplatin treatment leads to an increase in the number of lysosomes and their transfer to the tumor cells resulting in lysis (as studied by confocal microscopy). Although calcium seems to be involved in the signalling of macrophage activation, cytosolic calcium does not seem to influence this activation.     

Enhanced cell mediated immunity in mice after cisplatin treatment

Tumor regression in mice after cisplatin treatment and the role of cell mediated immunity were studied through Winn assay (in vivo) and capillary cell migration inhibition assay (in vitro). The immunization of mice with the platinum complex results in specific enhancement of host cellular immune system by stimulating splenocytes and peritoneal exudate cells against the specific tumor antigens.     

顺铂与环磷酰胺联合应用剂量优化的实验研究

目的 :观察低剂量顺铂 (DDP)和环磷酰胺(DTX)联合用药治疗恶性肿瘤疗效及其对免疫器官的毒性。方法 :采用小鼠肉瘤S180 进行体内实验 ,观察两药单独及联合使用对小鼠S180 及胸腺和脾脏的影响。结果 :DDP组和不同剂量的DTX配伍应用与DDP组相比抑瘤率分别提高 13.6 %～ 2 9.6 % ,与相应剂量DTX组相比抑瘤率分别提高 33.5 %～34.3% ,其中DDP DTX 0 .75 7.5mg·kg-1组与DDP及相应剂量DTX组相比较有显著意义 (P <0 .0 1～ 0 .0 0 1) ;DDP组及两药联合应用各剂量组使小鼠胸腺指数和脾指数明显低于对照组。结论 :低剂量DDP与DTX联合使用加强了对肿瘤生长的抑制作用 ,与DDP组相比 ,联合应用引起的免疫器官的萎缩与DDP组无差别     

Pharmacokinetics of cisplatin during hyperthermic intraperitoneal treatment of peritoneal carcinomatosis

Purpose

Cisplatin during hyperthermic intraperitoneal chemotherapy (HIPEC) has not previously been measured with a selective technique. The primary aims were to examine the pharmacokinetics of active cisplatin and its monohydrated complex (MHC) during HIPEC using a specific measuring technique, to compare cisplatin’s systemic absorption with oxaliplatin, and to compare active cisplatin levels to that of total platinum.

Methods

Ten patients treated with cytoreductive surgery and HIPEC (cisplatin 50 mg/m²,doxorubicin 15 mg/m²) were recruited. Blood and perfusate samples were drawn during and after HIPEC. Cisplatin analysis was conducted using liquid chromatography (LC) with post-column derivatization with diethyldithiocarbamate and compared with inductively coupled plasma-mass spectrometry (ICP-MS).

Results

The mean half-life (t1/2) of perfusate cisplatin was 18.4 min, with area under the time-concentration curve (AUC) 0–90 min of 2.87 mM·min and estimated 0–60 min of 2.45 mM·min. The absorption t1/2 was 9.0 min for cisplatin and 18.2 min for oxaliplatin. The ratio of total platinum to active cisplatin increased in a linear manner by time of perfusion.

Conclusions

Cisplatin is absorbed quicker than oxaliplatin. Lowering the perfusion time to 60 min does not significantly change the pharmacokinetics of cisplatin, and is therefore to be considered. As the HIPEC perfusion progresses, the ICP-MS technique does not adequately reflect active cisplatin levels in the perfusate.     

多西他赛联合顺铂治疗非小细胞肺癌的临床疗效分析

目的以多西他赛（TXT）联合顺铂（DDP）治疗非小细胞肺癌的临床疗效来进行分析。方法我院肿瘤科2007年12月至2008年12月住院治疗的NSCLC患者,共选取30例。30例患者完成3个周期的TXT加DDP化疗。结果完全缓解（CR）0例,部分缓解（PR）8例（26.67%）,稳定（SD）7例（23.33%）,进展（PD）15例（50%）,疾病控制率（CR＋PR＋SD）15例（50%）。差异有统计学意义。结论采用多西他赛（TXT）联合顺铂（DDP）治疗非小细胞肺癌疗效确切。     

复方苦参注射液联合顺铂与顺铂单药治疗恶性腹水的临床观察比较

目的:采用复方苦参注射液(岩舒)静脉滴注联合顺铂(DDP)腹腔内给药或单药顺铂腹腔内给药两种方法治疗恶性肿瘤并恶性腹水患者,以评价其临床疗效和不良反应。方法:将46例患者随机分为两组,A组予顺铂腹腔内注射联合复方苦参注射液静脉滴注;B组予单药顺铂腹腔内注射;两组均每周治疗1次,共4次,以评价临床疗效和不良反应。结果:顺铂联合复方苦参注射液组(A组)较单药顺铂组(B组)有效率有所提高(60.9%vs 30.4%),差异有统计学意义(P<0.05);不良反应方面,顺铂联合复方苦参注射液组(A组)出现的Ⅲ～Ⅳ度胃肠道反应及肝功能损害较单药顺铂组(B组)少,两组的差异有统计学意义(P<0.05)。结论:复方苦参注射液联合顺铂治疗恶性腹水在提高临床疗效的同时,可减轻顺铂腹腔内化疗出现的不良反应。     

来曲唑与紫杉醇联合顺铂治疗转移性乳腺癌的疗效观察

目的 观察来曲唑与紫杉醇联合顺铂治疗转移性乳腺癌的疗效及不良反应.方法 我院62例转移性乳腺癌患者随机分成2组.观察组31例,采用来曲唑与紫杉醇联合顺铂治疗;对照组31例,以紫杉醇化疗为主,加来曲唑进行内分泌治疗.观察两组患者预后及不良反应发生情况.结果 采用来曲唑与紫杉醇联合顺铂治疗组患者缓解率及生存率明显高于对照组,且不良反应较少,与对照组比较差异有统计学意义（P〈0.05）.结论 来曲唑与紫杉醇联合顺铂治疗转移性乳腺癌效果显著,不良反应较少.     

Hyperglucagonemia induced in mice by tryptamine: involvement of the peripheral 5-HT2 receptors.

The effects of an indoleamine, tryptamine, on plasma glucagon levels were investigated in mice. Tryptamine induced dose-related increases in plasma glucagon levels. The hyperglucagonemia effects of tryptamine were completely antagonized by methysergide and ketanserin which have a high affinity to 5-HT2 receptors. In addition, the peripheral 5-HT2 receptor antagonist, xylamidine, also strongly inhibited tryptamine-induced hyperglucagonemia. Our results indicate that the peripheral 5-HT2 receptors mediate the increase in plasma glucagon levels induced by tryptamine and that these receptors may have a role in the control of glucagon secretion.     

利奈唑胺致全血细胞减少

1例75岁男性患者因房室传导阻滞行永久起搏器植入术,术后出现感染性心内膜炎。首先单独给予头孢哌酮钠-舒巴坦钠3.0 g1、次/12 h静脉滴注4 d,然后改为万古霉素1.0 g1、次/12 h静脉滴注3 d,最后单独应用利奈唑胺600 mg1,次/12 h静脉滴注44 d。应用利奈唑胺前实验室检查示患者外周血白细胞12.00×109/L,红细胞3.92×1012/L,血小板158×109/L,血红蛋白115 g/L。用药第19天血常规示白细胞2.81×109/L,红细胞3.39×1012/L,血小板74×109/L,血红蛋白102 g/L。其后血常规检查显示各项指标均低于正常范围,最低值如下:白细胞2.69×109/L,红细胞2.51×1012/L,血小板48×109/L,血红蛋白69 g/L。由于病情需要未停用利奈唑胺,给予重组人粒细胞集落刺激因子、琥珀酸亚铁及红细胞悬液等对症治疗。患者应用利奈唑胺共44 d。停药后18 d血常规恢复正常:白细胞5.07×109/L,红细胞3.02×1012/L,血小板156×109/L,血红蛋白102 g/L。     

长春瑞滨联合顺铂治疗晚期非小细胞肺癌

目的观察长春瑞滨联合顺铂治疗晚期非小细胞肺癌(NSCLC)的疗效及毒副反应。方法长春瑞滨25mg/m2,第一、五天,顺铂25mg/m2,第一～三天,第二十一天为1周期,两周期以上评价疗效。结果可评价疗效57例,其中完全缓解(CR)1例,部分缓解(PR)23例,无变化(NC)20例,疾病进展(PD)13例,总有效率CR PR42.1%。全组中位PFS为4个月,中位生存期9个月。主要毒副反应为骨髓抑制、恶心、呕吐。结论长春瑞滨联合DDP治疗晚期非小细胞肺癌疗效高,毒副反应可耐受,可以作为治疗晚期非小细胞肺癌的一线治疗方案。     

Cost effectiveness of paclitaxel/cisplatin compared with cyclophosphamide/cisplatin in the treatment of advanced ovarian cancer in Belgium

OBJECTIVE: To assess the economic impact of two polychemotherapy regimens for patients with advanced ovarian cancer from the perspective of the Belgian health insurance and financing system. DESIGN: An economic evaluation was integrated in an intergroup randomised controlled trial (EORTC 55931) in which patients were randomised to receive the new treatment of paclitaxel and cisplatin or the standard therapy of cyclophosphamide and cisplatin. Data on the use of medical resources were collected prospectively for the 231 European Organization for Research and Treatment of Cancer (EORTC) patients in the trial and costs were valued by using unit prices. The outcome for the economic evaluation was mean survival time as determined by the so-called restricted means method, with the time point of restriction fixed by statistical criteria. A correction of censoring of the cost data collected in the trial was also performed. MAIN OUTCOME MEASURES AND RESULTS: The paclitaxel and cisplatin group experienced a statistically significant improvement in mean survival time of 4 months, which was associated with an increase in the average total cost per patient of 6795 euros (EUR; 1998 values), when costs were assessed over the same period as the gain in mean survival time. This corresponds to a point estimate of the incremental cost-effectiveness ratio of EUR20 385 per life-year gained. The impact of uncertainty was assessed by using a bias-corrected and accelerated bootstrap method with 5000 resamples, and the final results of the analysis are expressed in terms of a cost-effectiveness acceptability curve. CONCLUSIONS: The present economic evaluation has shown that the substitution of paclitaxel for cyclophosphamide in the chemotherapy regimen for women with advanced ovarian cancer leads to a significant improvement in patient survival, which is associated with an increase in costs for the Belgian health insurance system.