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.     

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     

血清HE4水平对预测卵巢癌铂类化疗效果的临床观察

目的:探讨卵巢上皮癌患者血清中人附睾蛋白4(HE4)的水平与患者铂类化疗效果的关系。方法:回顾分析52例卵巢上皮癌患者的临床资料和随访信息,采用电化学发光法检测患者治疗前和随访时血清HE4及CA125水平,分析血清HE4及CA125水平与铂类化疗效果的关系。结果:52例患者中,31例铂类化疗敏感,21例铂类化疗抵抗。铂类化疗抵抗组患者治疗前血清HE4及CA125水平明显高于铂类化疗敏感组。治疗前血清HE4水平对卵巢癌铂类化疗疗效的预测效能高于CA125。铂类化疗抵抗组患者随访时血清HE4水平明显高于铂类化疗敏感组(276.5pmo/L vs 56.38pmo/L,P0.001)。随访时血清HE4可预测铂类化疗效果,当界值点为127.40pmo/L时,灵敏度达81%,特异度达93.5%,阳性预测值(PPV)为89.5%,阴性预测值(NPV)为87.9%,曲线下面积(AUC)为0.919。随访时血清CA125取界值点为76.4U/L时预测铂类化疗效果的灵敏度为95.2%,特异度为90.3%,PPV为85%,NPV为87.5%,AUC为0.876。随访时血清HE4预测铂类化疗效果的AUC也大于CA125。Logistic多因素回归分析结果显示,随访时血清HE4水平与发生铂类化疗抵抗密切相关(P=0.027)。结论:随访时血清HE4水平可以预测卵巢癌铂类化疗的反应。     

Urinary excretion of platinum (Pt) following skin and respiratory exposure to soluble Pt at South African precious metals refineries

Adverse respiratory and skin health effects have been associated with occupational exposure to soluble platinum (Pt). However, the relationship between skin exposure and urinary Pt excretion has not yet been investigated. In this study we examined the relationship between skin and respiratory exposure to soluble Pt and urinary Pt excretion at two South African precious metals refineries.The skin and respiratory exposure to soluble Pt as well as the urinary Pt excretion of forty precious metals refinery workers was assessed simultaneously using Ghostwipes?, Methods for the Determination of Hazardous Substances method 46/2 and spot urine tests, respectively.The geometric mean for skin exposure to soluble Pt on four anatomical positions (palm, wrist, neck and forehead) was 0.008?μg/cm² [95% confidence interval (CI): 0.005-0.013?μg/cm²], while the geometric mean for respiratory exposure was 0.301?μg/m³ (95%CI: 0.151-0.601?μg/m³) and the geometric mean for urinary Pt excretion was 0.212?μg/g creatinine (95%CI: 0.169-0.265?μg/g creatinine). Partial correlations identified significant positive correlations between skin exposure, respiratory exposure and urinary Pt excretion (r?=?0.580 to 0.754).Skin and respiratory exposures to soluble Pt were both positively correlated with urinary Pt excretion, and both exposure routes should be considered when investigating occupational exposure to soluble Pt.     

A newly synthesized platinum-based compound (PBC-II) increases chemosensitivity of HeLa ovarian cancer cells via inhibition of autophagy

There are many mechanisms of resistance, chemoresistance of HeLa cells to anti-cancer agents seems to be autophagy-mediated. While using very effective anti-cancers such as Doxorubicin and cisplatin, cells overcome the cytotoxicity of these drugs through promotion of what so-called cytoprotective autophagy. Here in this study, we sought to introduce a novel platinum-based compound PBC-II that possesses anti-cancer activity. Our data showed that PBC-II is able to induce apoptosis at relatively low concentrations, with no detectable reactive oxygen species (ROS). However, further experiments demonstrated that exposure of HeLa cells to PBC-II did not promote autophagy; rather, it resulted in accumulation of p62 and decrease in LC3-II levels. Autophagy was then promoted in HeLa cells pharmacologically by Doxorubicin and genetically by siRNA IL-10. In order to confirm promotion of autophagy in our model, we performed acridine orange staining to assess for autophagy under microscope as well as via flow cytometry. We then measured protein level of autophagy markers p62 and LC3 by western blot. Our data indicated that PBC-II interferes with therapy-induced autophagy. We also determined PI3K activity while co-incubation of PBC-II with autophagy inducers. It was clear that PI3K activation decreased when PBC-II was co-administered with autophagy inducers. Collectively, PBC-II exerts unique anti-proliferative effects associated with inhibition of autophagy, which indicates that PBC-II is potentially a promising agent to be used in resistant ovarian tumors.