FOLFCIS Treatment and Genomic Correlates of Response in Advanced Anal Squamous Cell Cancer

Background

Treatment of advanced anal squamous cell cancer (SCC) is usually with the combination of cisplatin and 5-fluorouracil, which is associated with heterogeneous responses across patients and significant toxicity. We examined the safety and efficacy of a modified schedule, FOLFCIS (leucovorin, fluorouracil, and cisplatin), and performed an integrated clinical and genomic analysis of anal SCC.

Platinum levels in various tissues of a patient who died 181 days after cisplatin overdosing determined by electrospray ionization mass spectrometry

Platinum (Pt) levels were determined in various tissues and body fluids obtained from a patient who died 181 days after cisplatin overdosing. The symptoms of cisplatin overdose, however, might have almost disappeared by day 40, and the patient’s death was ascribed to the recurrence of malignant lymphoma. Determination of Pt derived from cisplatin was performed by electrospray ionization mass spectrometry (ESI-MS) using silver (Ag) as internal standard. Pt and Ag complexed with diethyldithiocarbamate (DDC) in wetashed blood, and tissue solutions were extracted into isoamyl alcohol, and then acidified with oxalic acid. By injecting an aliquot of the isoamyl alcohol layer into a mass spectrometer in the direct flow injection mode, the quantitation was performed using the signals of Pt(DDC)₃ ⁺ and Ag(DDC)₂ ⁺ at m/z 639 and 403, respectively. The Pt levels ranged from 25ng/ml in blood to 2050ng/g wet weight in the liver of the patient, indicating that Pt remained at high levels in tissues, even after a period as long as 181 days after cisplatin overdosing.     

Determination of metabolites of a novel platinum anticancer drug JM216 in human plasma ultrafiltrates

The present study describes the application of on-line liquid chromatography-electrospray ionisation in conjunction with a high resolution magnetic sector mass spectrometer to identify metabolites of a platinum(IV) anticancer drug JM216 bis(acetato)amminedichloro(cyclohexylamine)platinum(IV)] in human plasma. Four metabolites were identified following incubation of JM216 in human plasma: JM118 [amminedichlorocyclohexylamineplatinum(II)], a platinum(II) complex; JM383 [bis(acetato)amminedihydroxo(cyclohexylamine)platinum(IV)]; JM518 [bis(acetato)amminechloro(cyclohexylamine)hydroxoplatinum(IV)] and its isomer JM559. The platinum complexes mass spectra were dominated by the natriated [M + Na]⁺ ion. Elemental compositions of these natriated ions were confirmed by accurate mass measurement on a magnetic sector mass spectrometer in the course of LC/MS analysis. This study demonstrates the capability of direct LC-ESI/MS with accurate mass measurement for analysis of platinum complexes in biological samples. Our results suggest that LC-ESI/MS is a powerful technique for structure elucidation of novel metabolites, and could make valuable contributions to drug metabolism research.     

Prevalence of respiratory allergy in a platinum refinery

Summary In a cross-sectional study, 65 workers in the chemical industry with exposure to platinum salts were investigated with regard to the prevalence to allergic respiratory tract diseases. A respriatory questionnaire, a skin-prick test with K₂PtCl₆ and environmental allergens, determination of total IgE, platinum-specific IgE and histamine release in basophilic granulocytes and lung function tests were applied before and after a Monday shift and after a Friday shift. Work-related symptoms of respiratory allergy were present in 23% of all workers, but were significantly more frequent in the most exposed group in the platinum refinery (52.4%). Of all workers, 18.7% had a positive skin-prick test with platinum salt. As compared to the other workers, the workers with work-related symptoms of respiratory allergy had significantly more positive skin-prick tests (64.3%) and a higher total IgE and platinum-specific IgE; they did not, however, show higher histamine release. In the course of the week, a significant fall in lung function, namely in FEV₁ and FEF25, was recorded in the group of workers with work-related symptoms.     

Performance of platinum stimulating electrodes,mapped on the limitvoltage plane

The paper introduces the electrode limit-voltage plane (ELVP)—a useful tool for describing in electrical terms what a polarisable electrode is doing under a particular set of conditions. The ELVP is then used to consider the charge-injection capability of a platinum stimulating electrode.     

Combinations of interferon with platinum complexes: synergistic and antagonistic effects on growth inhibition of MCF-7 and MDA-MB231 breast cancer cells

The growth-inhibitory effects of combining interferons (IFN) with platinum(II) complexes were tested with the aim of comparing these in cultures of estrogen-receptor(ER)-negative MDA-MB₂₃₁ and ER-positive MCF-7 breast cancer cell lines. Another aim was to test whether IFN as a biological response modifier could enhance the effect of the Pt complexes in vitro in an attempt to find an explanation for their more potent antitumor effects in in vivo models. Here it is shown that in both cell lines the combinations of different IFN with all three Pt complexes generally resulted in additive growth inhibition, as calculated by the product of the fraction of surviving cells obtained with each compound alone. Moreover, in MCF-7 cells natural IFN (nIFN) combined with aqua[meso-1,2-bis-(2,6-dichloro-4-hydroxyphenyl)ethylenediamine]sulfatoplatinum(II) (meso-6-Pt) resulted in synergistic inhibition. This synergy could be attributed to the estrogenic property of meso-6-Pt, since the ligand and estradiol also enhanced the inhibitory effect of nIFN. In contrast, the combination of recombinant IFN and meso-6-Pt was antagonistic in MDA-MB₂₃₁ cells. These results show that, in spite of the similar responses of the ER-negative and ER-positive cells to each compound alone, these cells show unexpected differences in their sensitivity to combinations of IFN and the new Pt complex meso-6-Pt.Abbreviations ER estrogen receptor - IFN interferon(s) - nIFN natural interferon - rIFN recombinant interferon - meso-4-Pt aqua[meso-1,2-bis(2,6-difluoro-3-hydroxyphenyl)ethylenediamine]sulfatoplatinum(II) - meso-6-Pt aqua[meso-1,2-bis-(2,6-dichloro-4-hydroxyphenyl) ethylenediamine]sulfatoplatinum(II)     

Lipopolysaccharide-induced platinum accumulation in the cerebral cortex after cisplatin administration in mice: Involvement of free radicals

The relationship between the accumulation of platinum in the cerebral cortex following cisplatin administration and injury to the blood-brain barrier after lipopolysaccharide (LPS) treatment was investigated. The appearance of intravenously injected fluorescein in the brain was significantly increased 10–24 h after LPS treatment, the effect being dose-dependent. Platinum was detectable in the cerebral cortex of cisplatin-treated mice 24 h after LPS treatment, but not without LPS treatment. In mice pretreated with -tocopherol, LPS administration did not significantly augment fluorescein penetration into the brain, whereas pretreatment with either allopurinol or ascorbic acid did not modify the LPS-induced increase in fluorescein penetration. In contrast, platinum in the cerebral cortex after cisplatin administration was still detectable in the allopurinol-, ascorbic acid-, and -tocopherol-pretreated groups, and the levels of platinum in these groups were not significantly different from those in the group treated with LPS only. Administration of superoxide dismutase (SOD), but not of catalase, tended to inhibit the penetration of fluorescein. Both SOD and catalase significantly lowered platinum content in the cerebral cortex following cisplatin administration in mice treated with LPS. Thus, free radicals may injure the blood-brain barrier in mice challenged with LPS, and allow cisplatin to penetrate into the cerebral cortex, resulting in platinum accumulation.     

国产紫杉醇及长春瑞宾联合铂类治疗晚期非小细胞肺癌的临床对照研究

目的　探讨国产紫杉醇及长春瑞宾加顺铂及卡铂联合方案对晚期非小细胞肺癌 (NSCLC)的疗效和毒副反应。方法　选取初治晚期NSCLC 181例 ,分别应用NP(长春瑞宾 +顺铂 )、TC(国产紫杉醇 +卡铂 )及TP(国产紫杉醇 +顺铂 )方案治疗。每例均完成两周期化疗后评价疗效及毒副反应。结果　三组患者近期有效率分别为NP组 42 .4%,TC组 40 .3 %,TP组 43 .3 %,三组间有效率比较均无显著性差异 ( χ2 =0 .10 86,P >0 .0 5 )。NP组中位生存期为 8.4个月 ,TC组 9.4个月 ,TP组 8.9个月 (P >0 .0 5 )。NP组 1、2、3年生存率分别为 3 9.0 %、16.9%、5 .1%;TC组分别为 41.9%、2 1.0 %、6.5 %;TP组分别为 40 .0 %、18.3 %、5 .0 %,三组间比较无统计学差异 ( χ2 =0 .14 0 4,P >0 .0 5 )。三组毒副反应均以骨髓抑制、脱发及恶心呕吐为主 ,但均未影响治疗。三组病例均无化疗相关死亡发生。结论　NP、TC及TP联合方案是治疗晚期NSCLC有效且耐受性较好的方案     

切除修复交叉互补基因1与铂类耐药

切除修复交叉互补基因1（excision repair cross-completion1,ERCC1）是DNA修复的重要因子之一,而DNA修复参与了铂类药物耐药的形成,ERCC1表达增高和其多态性均与铂类耐药有关,用药物干预或基因封闭技术抑制ERCC1表达能在一定程度上逆转铂类耐药。     

晚期非小细胞肺癌组织中ERCC1、RRM1表达水平与含铂治疗方案疗效及预后相关性分析

目的：探讨ERCC1及RRM1的表达在预测晚期非小细胞肺癌含铂治疗方案疗效及预后中的作用。方法：用免疫组织化学的方法检测124例ⅢB和Ⅳ期非小细胞肺癌患者的石蜡包埋活检组织标本中ERCC1和RRM1的表达水平,并分析其与临床病理特征以及疗效、预后的相关性。124例均为接受以铂类为基础的三代药物联合化疗的初治患者。结果：ERCC1、RRM1表达阳性者分别为43例（35％）和50例（40％）。ERCC1及RRM1的表达与疗效相关,ERCC1表达阴性者疗效达PR的患者（54％）明显高于阳性者（33％）,差异有统计学意义（P=0．022）。同样,RRM1表达阴性患者疗效为PR的明显高于RRM1阳性者（53％VS34％,P=0．042）。ERCC1和RRM1同时阴性表达者的中位生存时问明显长于同时阳性表达者（11．7个月VS9．2个月,P=0．025）,多因素分析表明,ERCC1为独立的预后预测因素（P=0．0066）。结论：ERCC1的表达与晚期非小细胞肺癌预后及含铂治疗方案疗效相关。