BSO增强MRP过表达肺癌细胞对顺铂敏感性的作用机制研究

目的：评价使用丁胱亚磺酰亚胺(BSO)克服肿瘤细胞由于高表达MRP而引起对顺铂耐药的可行性，并初步探讨其增敏的作用机制。方法：用基因转染的方法成功建立了一株mrp基因高表达的肺癌细胞株(SPC-A-1／MRP)的基础上，检测BSO作用前后转染细胞对顺铂敏感性的差异，从酶活性测定和转录水平观察了上述过程中谷胱甘肽解毒系统的变化。结果：实验表明同对照(转染不含目的基因的空载质粒)的SPC-A-1／MRP(一)细胞相比，SPC-A-1／MRP细胞对顺铂出现了明显的耐受，BSO可以有效增强MRP高表达的细胞对顺铂的敏感性。BSO通过显著抑制由顺铂引起的肿瘤细胞内GSH解毒系统的活化和MRP蛋白含量升高，有效的克服了肿瘤细胞接触顺铂后过表达MRP而引起的化疗耐受。结论：高表达MRP可以引起肿瘤细胞对顺铂的耐受，BSO针对MRP介导的顺铂耐药有很好的增敏效果。     

Modification of butylated hydroxytoluene-induced pulmonary toxicity in mice by diethyl maleate, buthionine sulfoximine, and cysteine

Treatment of mice with diethyl maleate (DEM) or buthionine sulfoximine (BSO) significantly enhanced the lung injury caused by butylated hydroxytoluene (BHT). Conversely, cysteine protected mice from the lung toxicity of BHT. BHT administration to mice produced a time-dependent reduction of glutathione (GSH) content in the lung, but not in the liver. These results support the concept that conjugation of 2,6-di-tert-butyl-4-methylene-2,5-cyclohexadienone (BHT-quinone methide), a proposed reactive metabolite of BHT, with GSH is involved in the detoxification of BHT in mice.     

Uterine sarcoma in Israel: A study of 104 cases

Data gathered during the first epidemiologic study of sarcoma of the uterus in Israel are presented. In the 7-year period of this survey, 104 new cases of sarcoma of the uterus were diagnosed, representing an incidence of 1.55/100,000 females over the age of 20. Half of the patients were in their fifth and sixth decades of life at the diagnosis of the tumor. Uterine sarcomas were more prevalent in women of European-American origin than in those of Asian-African descent. In 54.9% of the patients the diagnosis was made while the disease was in stage I. A definite correlation between sarcoma of the uterus, diabetes, hypertension, and obesity was not found. The 5-year survival rate in the present survey was 38%. Factors affecting prognosis were the clinical stage of the disease at diagnosis, histologic type, and the method of treatment.     

丁胱亚磺酰亚胺对Acc—2移植瘤放射增敏的实验研究

目的在体内研究放射增敏剂丁胱亚磺酰亚胺（ｂｕｔｈｉｏｎｉｎｅｓｕｌｆｏｘｉｍｉｎｅ,ＢＳＯ）对Ａｃｃ－２移植瘤的放射增敏作用。方法以Ａｃｃ－２移植瘤为模型,实验设对照组、ＢＳＯ组、单放组和ＢＳＯ＋放射组。ＢＳＯ药物剂量为５ｍｍｏｌ／ｋｇ,放射剂量为１０Ｇｙ。结果各组与对照组比较,ＢＳＯ组抑瘤率为８．５％、单放组为１２．６％,ＢＳＯ＋放射组为４５．３７％。结论ＢＳＯ对Ａｃｃ－２移植瘤有放射增敏作用。     

Post‐irradiation approaches to treatment of radiation injuries in the context of radiological terrorism and radiation accidents: a review

Purpose: Events of the recent past have focused attention on the possibility of radiological (nuclear) terrorism and on the implications of such terrorist threats for radiation accident preparedness. This review discusses recent advances in the knowledge about how radiation injuries from such events might be treated pharmacologically, and the practical barriers to clinical utilization of these approaches.

Conclusions: A wide range of pharmacological approaches are being developed in the laboratory that could greatly expand the ability to treat acute and chronic radiation injuries. However, there are currently a variety of practical and legal barriers that would prevent the actual clinical use of most of the approaches. There are also the potential weaknesses in most of the current programmes for dealing with the consequences of radiation accidents or nuclear terrorism, including the absence of widespread radiation biodosimetry capabilities and the resulting inability to triage. If a major radiation accident or terrorist event occurs, the lack of biodosimetry and treatment capabilities will be compounded by widespread public fear of ‘radiation’.     

Photodynamic therapy with photofrin in combination with Buthionine Sulfoximine (BSO) of human glioma in the nude rat

High concentrations of cellular glutathione (GSH) within tumour cells may reduce the ability of photodynamic therapy (PDT) to selectively destroy tumour, consequently, a means of improving the therapeutic ratio of PDT in brain tumour is necessary. Therefore, we hypothesize that PDT in combination with Buthionine Sulfoximine (BSO), an agent which lowers cellular glutathione, can significantly enhance destruction of U87 and U251n tumour cells. PDT was performed using Photofrin as a photosensitiser in combination with BSO administration on male Fisher rats with intracerebral U87 and on non-tumour rats (administered at different optical doses in combination with Photofrin). In vitro experimentation utilising colony forming, cell cytotoxicity, and matrigel artificial basement membrane invasion assays showed significant enhancement of tumour kill and significant reduction of migration in tumour cells treated with BSO in combination with Photofrin PDT in comparison with individual therapies for both U87 and U251n cell lines. In vivo combination PDT-BSO treatment of U87 tumour rats exhibited significantly more tumour necrosis than individual treatments. In conclusion, our data suggests BSO enhances Photofrin PDT treatment of human glioma.     

Vasoactive intestinal peptide (VIP) prevents neurotoxicity in neuronal cultures: relevance to neuroprotection in Parkinson's disease

Vasoactive intestinal peptide (VIP) provides neuroprotection against beta-amyloid toxicity in models of Alzheimer's disease. A superactive analogue, stearyl-Nle17-VIP (SNV) is a 100-fold more potent than VIP. In primary neuronal cultures, VIP protective activity may be mediated by femtomolar-acting glial proteins such as activity-dependent neurotrophic factor (ADNF), activity-dependent neuroprotective protein (ADNP), peptide derivatives ADNF-9 (9aa) and NAP (8aa), respectively. It has been hypothesized that beta-amyloid induces oxidative stress leading to neuronal cell death. Similarly, dopamine and its oxidation products were suggested to trigger dopaminergic nigral cell death in Parkinson's disease. We now examined the possible protective effects of VIP against toxicity of dopamine, 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenylpyridinium ion (MPP+) in neuronal cultures [rat pheochromocytoma (PC12), human neuroblastoma (SH-SY5Y) and rat cerebellar granular cells]. Remarkably low concentrations of VIP (10(-16)-10(-8) M), ADNF-9 and NAP (10(-18)-10(-10) M) protected against dopamine and 6-OHDA toxicity in PC12 and neuroblastoma cells. VIP (10(-11)-10(-9) M) and SNV (10(-13)-10(-11) M), protected cerebellar granule neurons against 6-OHDA. In contrast, VIP did not rescue neurons from death associated with MPP+. Since dopamine toxicity is linked to the red/ ox state of the cellular glutathione, we investigated neuroprotection in cells depleted of reduced glutathione (GSH). Buthionine sulfoximine (BSO), a selective inhibitor of glutathione synthesis, caused a marked reduction in GSH in neuroblastoma cells and their viability decreased by 70-90%. VIP, SNV or NAP (over a wide concentration range) provided significant neuroprotection against BSO toxicity. These results show that the mechanism of neuroprotection by VIP/SNV/NAP may be mediated through raising cellular resistance against oxidative stress. Our data suggest these compounds as potential lead compounds for protective therapies against Parkinson's disease.     

Adaptive cellular protection against UVA-1-induced lipid peroxidation in human dermal fibroblasts shows donor-to-donor variability and is glutathione dependent

Photo-oxidative stress and subsequent lipid peroxidation (LPO) is one of the major mechanisms of UVA-related skin pathology. The skin's protection system against photo-oxidative stress involves low molecular scavengers as well as highly specialised antioxidant enzymes like glutathione peroxidase (GPX). Against repetitive UVA-1 exposures in vitro it is partly adaptive, as recent studies have shown exemplarily for antioxidant enzymes. We now investigated in vitro by repetitively irradiating human dermal fibroblasts with UVA-1 whether this adaptive response might reflect itself in reduced cellular membrane damage, that is, LPO. Our experiments show that the degree of cellular protection against LPO and the adaptive potential of the cells against a repetitive UVA-1 exposure varies from donor-to-donor and depends highly on glutathione.     

Exercise prevents sleep deprivation-associated anxiety-like behavior in rats: potential role of oxidative stress mechanisms

Our previous work suggests that pharmacological induction of oxidative stress causes anxiety-like behavior in rats. Interestingly, sleep deprivation is reported to cause oxidative damage in the brain and is also reported to be anxiogenic. Minimal mechanistic insights are available. In this study, using a behavioral and biochemical approach, we investigated involvement of oxidative stress mechanisms in sleep deprivation-induced anxiety-like behavior of rats and the protective role of treadmill exercise in this process. We report that acute sleep deprivation (SD) increases oxidative stress in the cortex, hippocampus and amygdala while prior treadmill exercise prevents this increase. Serum corticosterones also increase with SD but its levels are normalized in exercised sleep-deprived rats. Also, anxiety-like behavior of rats significantly increases with SD while prior treadmill exercise prevents this increase. Protein expression of two enzymes involved in antioxidant defense, glyoxalase (GLO)-1 and glutathione reductase (GSR)-1 increased after 24 h SD in the hippocampus, cortex and amygdala while their levels were normalized in exercised sleep-deprived rats. It is plausible that oxidative stress via regulation of GLO1 and GSR1 is involved in sleep deprivation-induced anxiety-like behavior of rats.