散发性大肠管状腺瘤癌变过程中JNK1 Raf-1和Livin的表达及其意义

目的 探讨JNK1、Raf-1和Livin在散发性大肠管状腺瘤癌变过程中的可能作用.方法 采用免疫组化方法,检测21例正常大肠黏膜、65例散发性大肠管状腺瘤伴上皮不同程度异型增生及22例管状腺瘤癌变组织中,JNK1 、Raf-1和Livin的蛋白表达水平.结果 正常大肠黏膜组、散发性大肠管状腺瘤伴上皮异型增生组、大肠管状腺瘤癌变组,JNK1蛋白的阳性表达率分别为33.3%、63.1%和90.9%,Raf-1蛋白的阳性表达率分别为23.8%、52.3%和77.3%,Livin蛋白的阳性表达率分别为14.3%、52.3%和77.3%,大肠管状腺瘤伴上皮异型增生组和癌变组JNK1 Raf-1和Livin蛋白的阳性表达率均高于正常大肠黏膜组(均P＜0.05),而癌变组均高于大肠管状腺瘤伴上皮异型增生组(均P＜0.05).在大肠管状腺瘤伴上皮异型增生组中,Raf-1的阳性表达率随异型增生程度的增高而升高(P＜0.05),而上皮不同程度异型增生组间JNK1和Livin蛋白的阳性表达率差异无统计学意义(均P＞0.05).87例散发性大肠管状腺瘤组织中,JNK1、Raf-1和Livin蛋白表达两两正相关(JNK1和Raf-1:r=0.451,P＜0.05;JNK1和Livin:r于0.499,P＜0.05;Raf和Livin;r=0.445,P＜0.05).结论 JNK1、Raf-1和Livin在大肠管状腺瘤癌变过程中可能起一定作用.     

Stat3通路相关基因在散发性大肠管状腺瘤癌变中的表达及意义

目的 探讨Stat3及CyclinD1、Bcl-xL在散发性大肠管状腺瘤癌变过程中的可能作用。方法 采用免疫组化方法检测107例散发性大肠管状腺瘤异型增生及癌变组织中Stat3和CyclinD1、Bcl-xL在蛋白水平的表达情况。结果 腺瘤伴异型增生组和癌变组中的Stat3蛋白的表达明显高于正常大肠黏膜组(P=0.000),且癌变组中Stat3蛋白的表达高于腺瘤伴异型增生组(P=0.003);腺瘤伴异型增生组和癌变组中CyclinD1蛋白的表达均明显高于正常大肠黏膜组(P=0.000),且癌变组中CyclinD1蛋白的表达高于腺瘤伴异型增生组(P=0.000);大肠管状腺瘤伴异型增生组和癌变组中Bcl-xL在蛋白水平的阳性表达率均明显高于正常大肠黏膜组（P=0.000),而且癌变组中Bcl-xL的表达明显高于腺瘤伴异型增生组(P=0.000);Stat3、CyclinD1和Bcl-xL均随腺瘤异型增生程度的增高呈递增趋势。Stat3与CyclinD1、Bcl-xL 的表达存在正相关关系。结论 Stat3、CyclinD1和Bcl-xL可能在散发性大肠管状腺瘤癌变过程中起一定的作用。     

散发性大肠管状腺瘤癌变过程中STAT3和p38的表达及意义

目的探讨STAT3和p38在散发性大肠管状腺瘤癌变过程巾的可能作用。方法采用免疫组化方法检测107例散发性大肠管状腺瘤伴不同程度异型增生及癌变组织中STAT3和p38的蛋白表达水平,采用原位杂交方法检测STAT3 mRNA的表达。同时选取25例正常大肠黏膜作为对照。结果STAT3蛋白在正常大肠黏膜、大肠管状腺瘤伴上皮异型增生和癌变组中的阳性表达率分别为12.0%、59.0%和91.7%,STAT3 mRNA的阳性表达率分别为8.0%、51.8%和100.0%,p38蛋白的阳性表达率分别为8.0%、47.0%和91.7%。大肠管状腺瘤伴上皮异型增生组和癌变组STAT3蛋白、STAT3 mRNA和p38蛋白的阳性表达率均明显高于正常大肠黏膜组(P均<0.05),而癌变组均高于大肠管状腺瘤伴上皮异型增生组(P均<0.05)。大肠管状腺瘤伴上皮异型增生患者中,STAT3蛋白、STAT3 mRNA和p38蛋白的阳性表达率均随异型增生程度增高而增高(P<0.05)。STAT3与p38的表达呈正相关(r=0.515)。结论STAT3和p38均可能在散发性大肠管状腺瘤癌变过程中起一定作用。     

散发性大肠管状腺瘤癌变过程中NGX6ILK和c-Jun的表达及意义

目的:探讨NGX6、ILK和c-Jun在散发性大肠管状腺瘤癌变过程中的可能作用.方法:采用免疫组化法检测22例异型增生性畸变隐窝灶(ACF)、68例大肠管状腺瘤伴上皮不同程度异型增生、21例大肠管状腺瘤癌变和21例正常对照中NGX6、ILK和c-Jun的表达情况.结果:NGX6蛋白在正常对照、异型增生性ACF、大肠管状腺瘤伴上皮异型增生及大肠管状腺瘤癌变组中阳性表达率逐步降低,而ILK蛋白和c-Jun蛋白的阳性表达率则明显升高(P<0.05).异型增生性ACF、大肠管状腺瘤伴上皮轻、中、重度异型增生组中NGX6蛋白的阳性表达率分别为77.27%、70.83%、37.50%、35.00%,其中,大肠管状腺瘤伴上皮中、重度异型增生组中NGX6蛋白的阳性表达率明显低于异型增生性ACF及腺瘤伴上皮轻度异型增生组(P<0.05).异型增生性ACF、大肠管状腺瘤伴上皮轻、中度异型增生组中ILK蛋白的阳性表达率明显低于腺瘤伴上皮重度异型组(P<0.05);c-Jun蛋白阳性表达率在大肠管状腺瘤伴上皮轻、中、重度异型增生和大肠管状腺瘤癌变组明显高于异型增生性ACF(P<0.05).在大肠管状腺瘤癌变过程中NGX6和ILK间呈负相关(r=-0.455,P<0.05);NGX6和c-Jun间呈负相关(r=-0.417,P<0.05);ILK和c-Jun之间呈正相关(r=0.390,P<0.05).结论:NGX6低表达可能与ILK及c-Jun高表达有关,这可能在散发性大肠管状腺瘤形成及癌变过程中发挥一定作用.     

MTA1和TSLC1表达与结肠腺瘤癌变相关性研究

目的 结肠腺瘤是结肠癌的癌前病变,积极诊断和治疗结肠腺瘤是控制、减少结肠癌发病的重要途径.本研究探讨肿瘤转移相关基因1(metastsis associated gene 1,MTA1)和肺癌肿瘤抑制因子1(tumor suppressor in lung cancer 1,TSLC1)在结肠腺瘤和结肠癌组织中的表达,以及MTA1和TSLC1在结肠腺瘤癌变过程中的作用.方法 选择2010-04-01-2015-12-31河北医科大学附属邢台市人民医院手术切除的结肠癌标本104例、肠镜活检结肠腺瘤标本114例及癌旁正常结肠组织(距离癌组织>3 cm)30例为研究对象,应用免疫组织化学法检测3组标本中MTA1和TSLC1蛋白的表达.结果 正常结肠组织中MTA1阳性表达率为6.67%,管状腺瘤为42.86%,绒毛状腺瘤为63.64%,结肠癌为84.62%,呈逐渐上升趋势,χ2=68.668,P<0.001;中重度异型增生结肠腺瘤中MTA1的阳性表达率(81.25%)高于轻度异型增生结肠腺瘤(39.02%),χ2=16.421,P<0.001;正常结肠组织中TSLC1阳性表达率为96.67%,管状腺瘤为88.57%,绒毛状腺瘤为63.64%,结肠癌组为42.31%,呈逐渐下降趋势,χ2=52.679,P<0.001;中重度异型增生结肠腺瘤中TSLC1阳性表达率(37.50%)明显低于轻度异型增生结肠腺瘤(95.12%),差异有统计学意义,χ2=45.982,P<0.001.结论 结肠癌组织中MTA1呈高表达,TSLC1表达缺失.MTA1和TSLC1参与正常组织、癌前病变和癌组织的发生发展,在结肠腺瘤的癌变过程中起着重要的作用.     

食管鳞癌中CD151、ERK1/2及血管生成拟态的表达及临床意义

摘 要：［目的］ 研究组织分化抗原151（CD151）及细胞外调节蛋白激酶1/2（ERK1/2）在食管鳞状细胞癌（ESCC）中的表达情况,分析两者表达与血管生成拟态（VM）的相关性。［方法］ 选取100例存档石蜡包埋ESCC组织标本作为观察组和50例癌旁（≥5cm）正常食管组织作为对照组,采用免疫组织化学ElivisionTM plus法检测ESCC中CD151及ERK1/2的表达,运用CD34/PAS双染检测食管癌中VM存在情况;并用Kaplan-Meier法分析VM与预后的关系。［结果］ 观察组CD151（82%）、ERK1/2（75%）蛋白阳性表达率及VM存在率（29%）均明显高于对照组（10%、36%、8%）（P均＜0.05）。CD151蛋白表达与ESCC的浸润深度、淋巴结转移、临床分期、分化程度有关（P均＜0.05）;ERK1/2蛋白表达与ESCC 的淋巴结转移、临床分期、分化程度有关（P均＜0.05）;ERK1/2在CD151阳性组的表达明显高于CD151阴性组,且两者表达呈正相关（r=0.451,P<0.001）;CD151和ERK1/2表达均与VM存在呈正相关（r=0.299,P=0.002;r=0.318,P=0.001）。Kaplan-Meier生存分析显示有VM组与无VM组5年生存率分别为10.3%和50.7%（P＜0.05）。Cox多因素回归分析显示：浸润深度、临床分期、VM存在是食管鳞癌患者术后5年生存率的独立影响因素（P均＜0.05）。［结论］ CD151、ERK1/2在食管鳞癌的发生及发展中具有重要作用,可能通过VM的形成,影响食管鳞癌的发生发展、转移及预后。     

错配修复基因hMLH1和hMSH2在散发性大肠癌中的表达及其意义

目的 探讨错配修复基因hMLH1和hMSH2在散发性大肠癌(SCC)组织中的表达及其临床意义.方法 采用免疫组化Max Vision二步法对63例SCC标本中的癌组织、距癌灶3 cm以外的癌旁组织、距癌灶10 cm以外的正常组织中hMLH1和hMSH2蛋白的表达进行检测.结果 hMLH1蛋白在63例正常大肠组织、癌旁组织和SCC组织中的阳性表达率分别为95.2%、85.7%和81.0%,hMLH1蛋白在SCC组织中的阳性表达率明显低于正常大肠组织(P＜0.05).hMSH2蛋白在63例正常大肠组织、癌旁组织和SCC组织中的阳性表达率分别为76.2%、66.7%和52.4%,hMSH2蛋白在SCC组织中的阳性表达率明显低于正常大肠组织(P＜0.01).hMLH1蛋白在＜60岁的SCC患者组织中的阳性表达率(100%)明显高于≥60岁的SCC患者组织(75.0%,P＜0.05),在有淋巴结转移的SCC组织中的阳性表达率(50.0%)明显低于无淋巴结转移的SCC组织(93.3%,P＜0.05).hMSH2蛋白在＜60岁的SCC患者组织中的阳性表达率(80.0%)明显高于≥60岁的SCC患者组织(43.8%,P＜0.05),在癌组织浸润至肠壁浆膜层SCC组织中的阳性表达率(61.5%)明显高于浸润至黏膜下层和肌层的SCC组织(37.5%,P＜0.05).SCC组织中hMLH1和hMSH2蛋白的表达呈正相关关系(r=0.254,P＜0.01).结论 hMLH1和hMSH2蛋白在SCC组织中的表达均有一定的缺失,并且与患者的年龄、淋巴结转移和癌组织浸润的范围有关.hMLH1和hMSH2基因可以作为临床预测和判断SCC发生和发展有用的实验室指标.     

乳腺导管内增生性病变中Skp2和p27kip1的表达及意义

目的从蛋白水平研究导管内增生性病变中Skp2和p27kip1表达异常与乳腺癌发生之间的相关性。方法采用免疫组织化学法分别检测120例导管内增生性病变,包括普通型导管上皮增生(usualductal hyperplasia,UDH),平坦型上皮不典型性病变(flat epithelial atypia,FEA),不典型导管上皮增生(atypical ductal hyperplasia,ADH),导管原位癌(ductal carcinoma in situ,DCIS)各30例石蜡包埋组织,以及健康对照组中Skp2和p27kip1蛋白表达水平,分析比较四组病变中Skp2和p27kip1蛋白阳性表达率以及这两种蛋白表达的相关性。结果四个亚型Skp2蛋白阳性表达率均高于健康对照组(P<0.05),DCIS组、ADH组和FEA组Skp2蛋白阳性表达率均高于UDH组(P<0.05),DCIS组Skp2蛋白阳性表达率高于ADH组和FEA组(P<0.05);p27kip1蛋白在UDH组、FEA组、ADH组、DCIS组的阳性表达率均低于健康对照(P<0.05),p27kip1蛋白在DCIS组阳性表达率低于UDH组、ADH组和FEA组(P<0.05)。Skp2与p27kip1阳性细胞率在四组导管内增生性病变中的蛋白表达阳性率总体上呈负相关(r=-0.411,P=0.000)。在UDH组与DCIS组内Skp2与p27kip1表达均呈负相关(r=-0.406,P=0.026;r=-0.544,P=0.002)。结论 Skp2蛋白表达水平升高p27kip1蛋白水平下降与乳腺导管上皮不典型增生和乳腺癌发生相关。     

食管鳞癌组织中Cerb-B-2、P27的表达及意义

目的 探讨Cerb-B-2、P27基因的表达与食管癌发生、发展及浸润、转移的关系.方法 采用免疫组织化学S-P法检测60例食管鳞癌组织、32例癌旁不典型增生组织及60例正常食管黏膜组织中Cerb-B-2及P27蛋白表达.结果 食管鳞癌组织中Cerb-B-2蛋白表达与癌的组织学分级、浸润深度及淋巴结转移密切相关(P＜0.05);P27蛋白表达与淋巴结转移密切相关(P＜0.05);在食管鳞癌癌变过程中Cerb-B-2蛋白表达在正常黏膜组织、癌旁不典型增生组织及癌组织中的表达率依次增高,分别为25.0%(15/60)、71.9%(23/32)、86.7%(52/60),组间比较有明显差异(P＜0.05);而P27蛋白在正常黏膜组织、癌旁不典型增生组织及癌组织中的表达率依次降低,分别为88.3%(53/60)、62.5%(20/32)、31.7%(19/60),组间比较有明显差异(P＜0.05),Cerb-B-2与P27在食管鳞癌中的表达呈负相关.结论 Cerb-B-2、P27基因在食管黏膜上皮癌变过程中起重要作用;联合检测Cerb-B-2、P27基因蛋白可成为食管鳞癌早期诊断和判断预后的分子指标.     

食管癌变过程中Stat3和C-erbB-2基因表达的动态观察

目的 动态观察Stat3和C-erbB-2基因在食管癌变过程中的表达,探讨其在食管癌变过程中的作用.方法 本实验采用的标本为1998年和2000年内镜普查的食管活检组织标本.对1998年普查中诊断为异型增生的57例进行2年随访,40例仍为异型增生,定为未癌变组.17例进展为早期癌,为癌变组.对未癌变组和癌变组2次活检组织标本分别采用免疫组织化学S-P法进行Stat3和C-erbB-2蛋白的动态检测.结果 Stat3和C-erbB-2在1998年未癌变组和癌变组中的表达差异无统计学意义(P＞0.05);两者的表达在2000年癌变组中高于未癌变组(P＜0.05).对未癌变组和癌变组Stat3和C-erbB-2在2年前后的表达进行观察比较,未癌变组2000年Stat3和C-erbB-2的表达均有升高,但与1998年相比,差异无统计学意义(P＞0.05);癌变病例Stat3和C-erbB-2的表达均有升高,与癌变前相比,差异具有统计学意义(P＜0.05).Stat3和C-erbB-2在癌变组2年中由阴性变为阳性的比率分别高于其在未癌变组中的比率(P＜0.05).对进展为食管早期癌的17例标本中Stat3和C-erbB-2的表达进行相关分析,存在正相关(P＜0.05).结论 Stat3和C-erbB-2基因在食管癌变演进的过程中可能起一定的作用.     

Effects of occupation, lifestyle and genetic polymorphisms of CYP1A1, CYP2E1, GSTM1 and GSTT1 on urinary 1-hydroxypyrene and 2-naphthol concentrations

This study was undertaken to determine the effects of occupation, lifestyle and the genetic polymorphisms of cytochrome P450 1A1 (CYP1A1), cytochrome P450 2E1 (CYP2E1) and glutathione S-transferases micro1 (GSTM1) and 1 (GSTT1) on the concentrations of urinary 1-hydroxypyrene (1-OHP) and 2-naphthol among Korean coke oven workers and university students. The study subjects included 90 coke oven workers and 128 university students. A questionnaire was used to obtain detailed data about the work area, smoking habits and food intake of subjects. Associations between urinary polycyclic aromatic hydrocarbon (PAH) concentrations and occupation, smoking status, total airborne PAH level and genetic polymorphisms were tested. Urinary 1-OHP and 2-naphthol concentrations were higher in coke oven workers than in students and correlated significantly with work area. Urinary 2-naphthol concentrations increased with an increase in the level of cigarette smoking in students. Total airborne PAH level correlated with urinary 1-OHP concentration in coke oven workers. Urinary 1-OHP and 2-naphthol concentrations were higher in coke oven workers with the c1/c2 or c2/c2 genotype of CYP2E1 than in those with the c1/c1 genotype. Urinary 2-naphthol concentrations were higher in GSTM1-null workers than in GSTM1-positive workers. In multiple regression analysis CYP2E1 was a significant factor determining urinary 1-OHP concentrations in coke oven workers. CYP2E1 and GSTM1 were significant determinants for urinary 2-naphthol concentrations in coke oven workers and GSTM1 and smoking were prognosticators among university students. Urinary 1-OHP is a better indicator of occupational exposure to PAH in coke oven workers than 2-naphthol, whereas urinary 2-naphthol may be more sensitive for non-occupational inhalation exposure to PAH. In occupationally exposed populations CYP2E1 and GSTM1 appear to play an important role in the metabolism of pyrene and naphthalene. In individuals not occupationally exposed to PAHs GSTM1 and smoking seem to influence the urinary concentration of 2-naphthol.     

Effect of cigarette smoke on CYP1A1, CYP1A2 and CYP2B1/2 of nasal mucosae in F344 rats

Enzymes of the nasal tissue, one of the first tissues to contact inhaled toxicants, are relatively resistant to induction by traditional inducers. Because tobacco smoke has been shown to induce cytochrome P450 1A1 (CYP1A1) in rat and human lung tissue, we hypothesized that it would also alter levels of xenobiotic-metabolizing enzymes in nasal mucosae. In the present study, the effect of mainstream cigarette smoke (MCS) on nasal CYP1A1, CYP1A2 and CYP2B1/2 was explored. Four groups of 30 F344 rats were exposed to MCS (100 mg total particulate matter/m3) or filtered air for 2 or 8 weeks. Western analysis of microsomes from nasal tissue of MCS-exposed rats showed an induction of CYP1A1 in respiratory and olfactory mucosae, as well as liver, kidney and lung. Relative to controls, CYP1A2 levels increased slightly in the liver and olfactory mucosa. CYP2B1/2, which increased in the liver, appeared to decrease in upper and lower respiratory tissues. Little to no immunoreactivity with CYP1A1 antibody was observed in fixed nasal sections of control rats, yet intense immunoreactivity was seen in epithelia throughout the nasal cavity of MCS-exposed rats. Ethoxyresorufin O-deethylase activity (associated with CYP1A1/2) decreased approximately 2-fold in olfactory mucosa, but increased in non-nasal tissues of rats exposed to MCS. Methoxy- and pentoxyresorufin O-dealkylase activities (associated with CYP1A2 and CYP2B1/2, respectively) decreased in olfactory and respiratory mucosae, as well as lung (CYP2B1/2), yet increased in liver. These data suggest that xenobiotic-metabolizing enzymines of the nasal mucosae may be regulated differently than other tissues.      

Mouse models of neurofibromatosis 1 and 2

The neurofibromatoses represent two of the most common inherited tumor predisposition syndromes affecting the nervous system. Individuals with neurofibromatosis 1 (NF1) are prone to the development of astrocytomas and peripheral nerve sheath tumors whereas those affected with neurofibromatosis 2 (NF2) develop schwannomas and meningiomas. The development of traditional homozygous knockout mice has provided insights into the roles of the NF1 and NF2 genes during development and in differentiation, but has been less instructive regarding the contribution of NF1 and NF2 dysfunction to the pathogenesis of specific benign and malignant tumors. Recent progress employing novel mouse targeting strategies has begun to illuminate the roles of the NF1 and NF2 gene products in the molecular pathogenesis of NF-associated tumors.     

Association of CYP1A1, CYP1A2, GSTM1 and NAT2 gene polymorphisms with colorectal cancer and smoking.

We investigated CYP1A1*2A, CYP1A1*2C, CYP1A2*1C, CYP1A2*1F, GSTM1 and NAT2 gene polymorphisms, involving enzymes which metabolize many carcinogens, with reference to colorectal cancer risk. The distribution of these genotypes was not associated with risk overall. However, the CYP1A1*2A T/C genotype showed a significant association with colorectal cancer risk in never-smokers (odds ratio [OR], 3.06; 95% confidence interval [95% CI], 1.11-8.40; p = 0.030). The risk of the NAT2 rapid genotype in never-smokers was also statistically significantly increased (OR, 5.38; 95%CI, 1.80-16.1; p = 0.003). Furthermore, the joint effects of NAT2 rapid plus other genotypes were associated with colorectal cancer overall (OR, 3.12; 95%CI, 1.15-8.51; p = 0.026, for NAT2 rapid plus combined CYP1A1*2C Ile/Val and Val/Val, OR, 3.25; 95%CI, 1.09-9.74; p = 0.035, for NAT2 rapid plus CYP1A2*1C G/G, and OR, 4.20; 95%CI, 1.09-16.1; p = 0.037, for NAT2 rapid plus GSTM1 null, respectively). In never-smokers, the joint effects of NAT2 rapid plus other genotypes were remarkable (OR, 15.9; 95%CI, 1.87-135.8; p = 0.011, for NAT2 rapid plus combined CYP1A1*2A T/C and C/C, OR, 5.71; 95%CI, 1.49-21.9; p = 0.011, for NAT2 rapid plus combined CYP1A1*2C Ile/Val and Val/Val, and OR, 9.14; 95%CI, 2.05-40.7; p = 0.004, for NAT2 rapid plus CYP1A2*1F A/A, respectively). The joint effect of CYP1A2*1F A/A plus CYP1A2*1C G/G genotypes was also increased in never-smokers (OR, 6.16; 95%CI, 1.26-30.1; p = 0.025). Our findings suggest that the CYP1A1*2A T/C and NAT2 rapid genotypes is associated with colorectal cancer susceptibility without smoking exposure. These results also indicate that the NAT2 in combination with CYP1A1*2C, CYP1A2*1C, or GSTM1 genotypes may strongly confer susceptibility to colorectal cancer. In particular, the combination of NAT2 plus CYP1A1*2A, CYP1A1*2C, or CYP1A2*1F genotypes, and that of CYP1A2*1F plus CYP1A2*1C genotype may define a group of persons who are genetically susceptible to colorectal cancer in never smokers.     

Human glutathione S-transferase P1-1 interacts with TRAF2 and regulates TRAF2-ASK1 signals

Human glutathione S-transferase P1-1 (GSTP1-1) is an ubiquitously expressed protein that plays an important role in the detoxification and xenobiotics metabolism. It has been shown that GSTP1-1 interacts with c-Jun NH(2)-terminal kinase (JNK) and suppresses its activity. Here, we report a novel function of GSTP1-1 in regulating tumor necrosis factor-alpha (TNF-alpha)-triggered signaling. The present experiments showed that GSTP1-1 physically associated with tumor necrosis factor receptor-associated factor 2 (TRAF2) in vivo and in vitro. Overexpression of GSTP1-1 inhibited TRAF2-induced activation of both JNK and p38 but not of nuclear factor-kappaB (NF-kappaB). Glutathione S-transferase P1-1 also attenuated TRAF2-enhanced apoptosis signal-regulating kinase 1 (ASK1) autophosphorylation and inhibited TRAF2-ASK1-induced cell apoptosis by suppressing the interaction of TRAF2 and ASK1. Conversely, silencing of GSTP1-1 expression through RNA interference (RNAi) resulted in increase of TNF-alpha-dependent TRAF2-ASK1 association followed by hyper-activation of ASK1 and JNK. A mutant GSTP1-1 lacking TRAF domain-binding motif exhibited a significant decline of capacity to bind TRAF2 and block TRAF2-ASK1 signaling compared with the wild type of GSTP1-1. Moreover, the glutathione-conjugating activity of GSTP1-1 was not involved in the regulation of TRAF2 signaling. These findings indicate that GSTP1-1 plays an important regulatory role in TNF-alpha-induced signaling by forming ligand-binding interactions with TRAF2, which provides a new insight for analysing the protective effects of GSTP1-1 in tumor cells.     

Alkylating derivatives of 2-amino-2-deoxysugars and 1-methylamino-1-deoxypolyols (synthesis and experimental study)

A number of derivatives of 2-amino-2-deoxysaccharides and 1-methylamino-1-deoxypolyols acylated by cytotoxic phenylalkanic and amino acids were synthesized and experimentally tested for antitumor activity. Some compounds showed a high antitumor activity against plasmacytoma MOPC-406: a 2-fold increase in experimental animals survival and a 80--100% cure rate were observed. Physicochemical properties, particularly, stability in aqueous solution and antitumor activity of one of the most potent compounds--1-methylamino-1-deoxy-1-N[p-di(2-chloroethyl) aminophenylacetyl]-D-glucitol (Agluphen)--are described in detail.     

CYP2E1*5B,CYP2E1*6, CYP2E1*7B,CYP2E1*2, and CYP2E1*3 Allele Frequencies in Iranian Populations

Background: CYP2E1 encodes an enzyme which is mainly involved in bioactivation of potential carcinogenssuch as N-nitrosamines. Polymorphisms in the gene have been reported to be associated with cancer. The aim ofthis study was to evaluate genotype distributions and allele frequencies of five CYP2E1 polymorphisms in IranMaterials and Methods: Two hundred healthy individuals of an Iranian population from the southwest wereincluded in this study. PCR-restriction fragment length polymorphism and Tetra-ARMS PCR methods wereapplied for CYP2E1 genotyping. Results: The allele frequencies for *5B, *6, *7B, *2, and *3 were calculated tobe 1.5%, 16%, 28.5%, 0%, and 2.75% respectively. Results of this study showed that no significant differencesin genotype and allele frequencies of five single nucleotide polymorphisms with respect to the gender andtribes. The chi-square test showed that the genotype frequencies of CYP2E1*5B were similar to Caucasians,but the distribution of CYP2E1*6 genotypes was similar to Asians. The frequencies of CYP2E1*2 (0%) andCYP2E1*3 (2.75%) alleles were within the range for Caucasians and Orientals. In the case of CYP2E1*7B, thedata werelimited. Accordingly, the results were only compared with Europeans and the comparison showedsignificant differences. Conclusions: In conclusion, ethnic and geographic differences may explain discrepanciesin the prevalence of CYP2E1 polymorphisms.     

Effect of chlorinated hydrocarbons on expression of cytochrome P450 1A1, 1A2 and 1B1 and 2- and 4-hydroxylation of 17beta-estradiol in female Sprague-Dawley rats

Chlorinated hydrocarbons (CHCs) are environmental contaminants that bioaccumulate and hence are detected in human tissues. Epidemiological evidence suggests that the increased incidence of a variety of human cancers, such as lymphoma, leukemia and liver and breast cancers, might be attributed to exposure to these agents. The ability of CHCs to disrupt estrogen homeostasis is hypothesized to be responsible for their biological effects. The present study examined the effect of CHCs on the expression of cytochrome P450 (CYP)1A1, CYP1A2 and CYP1B1 mRNAs and the consequent 2- and 4-hydroxylation of 17beta-estradiol (E(2)) in female Sprague-Dawley rats. Animals were administered a single dose of the LD(50) of 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD) (25 microg/kg), 2, 4-dichlorophenoxyacetic acid (2,4-D) (375 mg/kg) and dieldrin (DED) (38 mg/kg) by gavage. Seventy-two hours after treatment, increased expression of CYP1A1, CYP1A2 and CYP1B1 was observed in the liver, kidney and mammary tissue. Since CYP1A and CYP1B1 are the major enzymes catalyzing 2- and 4-hydroxylation of E(2), respectively, the effect of these CHCs on the metabolism of E(2) was investigated in rat tissues. Formation of 2- and 4-catechol estrogens was increased in a tissue-specific manner in response to treatment. TCDD was the most potent inducer for CYP1 enzyme mRNA and for the 2- and 4-hydroxylation of E(2). 2,4-D and DED induced similar responses, but less than that of TCDD. These results suggest that induction of CYP1 family enzymes and consequent increases in estrogen metabolism by CHCs in target tissues may be factors contributing to the biological effects associated with exposure to these agents.