Thermal enhancement of melphalan and oxaliplatin cytotoxicity in vitro

It has been established that hyperthermia can enhance cytotoxicity of some chemotherapeutic agents. This has led to various clinical trials of thermochemotherapy, although many questions remain unanswered. The effects of various agents have been studied on animal tumours with different histopathology at elevated temperatures. These studies indicated that alkylating agents were most effective to all tumours at a moderately elevated temperature. Cisplatin was also effective to all tumours, but its effectiveness at 41.5°C was less than that of alkylating agents. To quantitatively study these findings, the magnitude of thermal enhancement of melphalan, an alkylating agent, and that of oxaliplatin, a new platinum compound, were studied at 37-44.5°C by the colony formation assay. The dose of each agent was kept constant, and cell survival was determined as a function of treatment time. The cell survival curve was exponentially related with treatment time at all test temperatures, and the T 0 (the time to reduce survival from 1 to 0.37) decreased with an increasing temperature. These results suggested that the cytotoxic effect of these agents occurred with a constant rate at 37°C, and the rate was facilitated with an increasing temperature. This suggests that heat can accelerate the cytotoxic chemical reaction, leading to substantial thermal enhancement. The thermal enhancement ratio (TER, the ratio of the T 0 at 37°C to the T 0 at an elevated temperature) increased with an increase in the temperature. The activation energy for melphalan at moderately elevated temperatures was largest among the agents tested in the laboratory and that for oxaliplatin was approximately half of the melphalan activation energy. This suggests that the thermal enhancement for the cytotoxicity of melphalan or alkylating agents might be the greatest. Potential mechanisms of thermal enhancement of cytotoxicity were discussed.     

XRCC1基因多态性与晚期非小细胞肺癌铂类化疗敏感性的研究

目的：研究XRCC1基因多态性与非小细胞肺癌（NSCLC）患者对铂类为基础的联合化疗的敏感性。方法：收集我院NSCLC患者54例,提取外周白细胞DNA,采用多重PCR对XRCC1194,399两个多态性住点同时扩增,对扩增产物进行纯化后直接测序,判定基因分型。结果：携带XRCC1399Arg／Arg的化疗有效率是Gln／Gln的2．5倍（P=0．035。95％CI=0．892-7．094）。携带一个Gln等位基因的化疗失败风险是携带Arg／Arg的1．7倍（P=0．044,95％CI=1．012～2．720）。未发现XRCC1194不同基因型对铂类化疗敏感性有差异。结论：XRCC1399Gln／Arg基因多态性与晚期NSCLC接受铂类为基础的化疗敏感性相关。     

铂催化-非散射红外吸收法测定过氧化氢中的总有机碳

目的：建立测定过氧化氢产品中总有机碳的方法。方法：采用铂催化法对过氧化氢进行自催化处理，非散射红外吸收法测定过氧化氢中的总有机碳含量。结果：样品前处理简单，测定结果准确度高，精密度好，检测限为：0．1mg／kg。结论：该方法适用于过氧化氢产品中总有机碳的检测。     

Intracellular glutathione and cytotoxicity of platinum complexes

Although there have been a number of reports correlating cellular GSH levels with cytotoxicity of platinum agents, none has examined the relationship between GSH concentrations and cytotoxicity. In this study, using a highly specific HPLC method for measuring GSH and expressing GSH as concentration and also per cell number, we evaluated the correlation between GSH levels and the cytotoxicity to five agents in ten human tumor cell lines. The five platinum agents included the platinum(II) complexes cisplatin, carboplatin and oxaliplatin and platinum(IV) complexes iproplatin and tetraplatin. The correlation between intracellular GSH concentration and cytotoxicity was highly significant only for iproplatin (P=0.002) followed by tetraplatin, which demonstrated a trend toward statistical significance (P=0.06). Cytotoxicity of the other platinum complexes showed no relation to GSH concentration, cisplatin itself showing aP-value of 0.09. In contrast, the GSH levels normalized to cell number showed a statistically significant correlation with the cytotoxicity of four of the five platinum agents, the exception being carboplatin; the strongest correlation observed was that for iproplatin and tetraplatin. Glutathione-S-transferase (GST) activity in these cell lines showed no correlation with cytotoxicity of any of the platinum complexes. Our results, from the analyses of both GSH concentration as well as GSH per cell number, suggest a significantly higher interaction between GSH and iproplatin compared with the other platinum agents. Moreover, our data suggest that relationships between cytotoxicity and GSH levels on a per-cell basis may not persist when differences in cell volume are taken into account.     

切除修复交叉互补基因1与铂类药物耐药

铂类药物耐药是多种复杂机制共同作用的结果.其中,肿瘤细胞切除修复交叉互补基因1(ERCC1)表达及其多态性是肿瘤细胞产生铂类药物耐药的重要机制之一.抑制ERCC1的表达可逆转铂类药物耐药性.     

Retrospective evaluation of thromboembolic events in patients with non-small cell lung cancer treated with platinum-based chemotherapy

Objectives

Thromboembolic events (TE) are common in patients with cancer and are potentially life-threatening. In lung cancer, little is known about thrombosis during chemotherapy treatment. The aim of this study was to describe the incidence of TE in patients with non-small cell lung cancer (NSCLC), occurring during treatment with platinum-based chemotherapy.

Methods

We retrospectively selected patients with NSCLC treated with platinum-based chemotherapy at the VU University Medical Center Amsterdam between 2000 and 2012. Patients who underwent recent surgery were excluded. All TE were included that occurred from start of chemotherapy treatment until 30 days after last administration.

Results

Among 784 included patients, 63 (8.0%) patients had 69 TE during treatment. Forty-five venous TE (VTE) and 24 arterial TE (ATE). Six patients had multiple events within treatment period, 3 of which had simultaneous ATE and VTE. In total, 613 patients were treated with cisplatin, 119 patients received carboplatin and 52 patients received both in first- or second-line treatment. In 8% (55/665) of the patients exposed to cisplatin a TE had occurred vs. 5% (8/171) in patients exposed to carboplatin (p = 0.42). The majority of TE occurred in the first 2 cycles (70%). History of TE was related to occurrence of TE during chemotherapy (p < 0.01). Median PFS was similar in patients with and without TE (6.2 vs. 7.2 months, respectively; p = 0.10). Median OS was significantly shorter in patients with TE (9.5 vs. 12.9 months, respectively; p = 0.03).

Conclusion

In our series, both ATE and VTE were a common finding during chemotherapy. TE was a poor prognostic factor. No difference in TE incidence was found between patients treated with cisplatin or carboplatin.     

MTHFR C677T基因多态性与晚期非小细胞肺癌化疗不良反应的关系

背景与目的：亚甲基四氢叶酸还原酶(methylene tetrahydrofolate reductase,MTHFR)是叶酸代谢的关键酶,在DNA甲基化中起重要作用。本研究旨在探讨MTHFR C677T多态性与晚期非小细胞肺癌(nonsmall cell lung cancer,NSCLC)化疗不良反应的关系。方法：收集2007年6月-2009年5月在浙江省肿瘤医院经病理学确诊的晚期NSCLC患者100例。所有患者均接受铂类药物联合吉西他滨的方案化疗。用等位基因特异-PCR技术检测患者MTHFR基因型。结果：100例晚期NSCLC患者中,MTHFR C677T T/T、T/C和C/C基因型频率分别为20%、44%和36%。在血液学不良反应中,C/C基因型血小板减少发生率较T/T、T/C基因型低,差异有统计学意义(P=0.039)。本研究未发现MTHFR各基因型与化疗后恶心、呕吐不良反应相关。结论：MTHFRC677T基因多态性对预测晚期NSCLC含铂类药物方案化疗后不良反应有临床意义。     

铂类抗肿瘤药联合甘露聚糖肽治疗恶性胸腔积液的系统评价

目的:系统评价甘露聚糖肽注射液治疗恶性胸腔积液的有效性及安全性。方法:电子检索Cochrane图书馆、Medline、Embase、CNKI、VIP、CBM,手工检索相关杂志、会议论文、学位论文,收集甘露聚糖肽治疗恶性胸腔积液的随机及半随机对照试验。由2名研究者独立选择试验、评价质量、提取数据,并交叉核对。使用RevMan5.0软件进行Meta分析。结果:纳入17个研究,分为3个亚组,结果显示:(1)近期疗效:亚组A、B中治疗组优于对照组[RR=1.38,95%C(I1.27,1.50),P<0.01],[RR=1.34,95%CI(1.17,1.54),P<0.01],亚组C中2组差异无统计学意义;(2)KPS评分:治疗组优于对照组[RR=1.82,95%CI(1.51,2.20),P<0.01];(3)生存期:治疗组优于对照组(P<0.05);(4)不良反应:使用甘露聚糖肽可能减少由铂类抗肿瘤药引起的骨髓抑制、胃肠道反应及胸痛反应,但其可引起轻微发热。结论:联用甘露聚糖肽可提高铂类抗肿瘤药化疗的近期疗效,减轻不良反应,改善生活质量,但其可引起轻微发热。但由于纳入研究的方法质量较低和可能存在发表偏倚,上述结论有待进一步开展大样本、高质量、多中心的随机双盲对照试验来证实。     

新型铂（Ⅱ）类配合物对结肠癌SW620 细胞系的体外抗癌活性研究*

目的：本实验研究了两种新型铂（Ⅱ）类配合物（2,3- 吡啶二羧酸二水合铂、2,3- 吡嗪二羧酸二水合铂）对结肠癌SW620 细胞系的体外抗癌活性及其对细胞凋亡的影响。同时与奥沙利铂作一对照,以明确该两种新型铂（Ⅱ）类配合物是否具有更好的体外抑瘤效果。方法：采用人结肠癌细胞系SW620 作为研究对象,三种药物分别以不同浓度作用于对数生长期的SW620细胞24h、48h 后,应用软琼脂糖集落形成试验检测集落形成抑制率,以AnnexinV/PI双染法测定细胞凋亡率,以扫描电镜观测三种
药物作用后细胞形态和超微结构的改变。结果：软琼脂糖细胞集落形成抑制率实验显示出奥沙利铂、吡嗪、吡啶三种药物做用24h 后对 SW620 细胞系的半数抑制浓度（IC 50）分别为 266.51,176.18,159.25μ mol/L,48h 的IC 50分别为 158.84,161.27,125.67μ mol/L,其药物作用强度为吡啶>吡嗪>Oxa,有显著性差异（P<0.01）。AnnexinV/PI双染法显示出三种药物均可诱导SW620 细胞产生凋亡,其作用呈浓度和时间依赖性,并且随药物作用浓度及时间延长死亡细胞增多,作用强度为吡啶> 吡嗪>Oxa,有显著性差异（P<0.01）。电镜下可见细胞典型早晚期细胞凋亡特征。结论：这两种新型铂（Ⅱ）配合物对结肠癌SW620 细胞系显示出良好的体外抑瘤效果,该作用呈浓度和时间依赖性,并且强于奥沙利铂。药物作用靶点之一在于诱导细胞产生凋亡。     

晚期非小细胞肺癌中SOD2基因多态性与含铂方案化疗敏感性的研究

目的 探讨超氧化物歧化酶2（SOD2）基因多态性与晚期非小细胞肺癌（NSCLC）患者含铂方案化疗疗效的关系。方法 采用直接测序法检测162例以含铂方案化疗的晚期NSCLC患者外周血DNA中SOD2 rs7855、rs5746151、rs5746136、rs2758331和rs4880的基因多态性;162例患者中,43例接受多西他赛联合顺铂方案,63例接受吉西他滨联合顺铂方案,56例接受培美曲塞联合顺铂方案化疗,2个周期后采用RECIST 1.0版标准评价疗效并将患者分为化疗敏感组（CR+PR）和不敏感组（SD+PD）,分析疗效与临床病理特征及以上多态性位点的关系。结果 162例晚期NSCLC患者SOD2 rs7855、rs5746151、rs5746136、rs2758331和rs4880位点基因型频率均符合Hardy-Weinberg平衡（P>0.05）。162例患者经2个周期化疗后,获PR 43例、SD 68例、PD 51例,分为化疗敏感组43例和不敏感组119例,化疗敏感率为265%。年龄、性别、病理类型、分期、ECOG评分和化疗方案与化疗敏感性均无关。SOD2 rs7855、rs5746151、rs5746136和rs2758331位点中,各基因型及等位基因化疗敏感率的差异无统计学意义,且突变型等位基因相对于野生型等位基因及携带突变等位基因的基因型相对于野生型纯合子化疗不敏感的风险未升高（P>0.05）;SOD2 rs4880 TT、TC、CC基因型的敏感率依次为42.1%、19.6%和16.7%,差异有统计学意义（P<0.05）;T、C等位基因的敏感率分别为35.2%和17.6%,差异有统计学意义（P<0.05）;以野生型TT型为参照,TC、CC基因型化疗不敏感的风险升高,且C等位基因相对于T等位基因化疗不敏感的风险亦升高,差异均有统计学意义（P<0.05）。 结论 SOD2 rs4880多态性与晚期NSCLC患者含铂方案的疗效有关,且携带突变等位基因者化疗不敏感的风险较高,SOD2 rs4880多态性可用于预测晚期NSCLC患者对含铂方案的疗效。