人肺组织DNA加合物含量的某些影响因素分析

为探讨人肺组织ＤＮＡ加合物的形成与某些影响因素之间的关系，分析了３７例肺癌患者（男１９例、女１８例）及３７例非肺癌肺部疾病患者（男１９例、女１８例）肺组织ＤＮＡ加合物的含量与年龄、性别、吸烟等影响因素之间的关系。结果表明：引起肺组织ＤＮＡ加合物含量增高的主要因素是吸烟；年龄、性别与肺组织ＤＮＡ加合物含量无相关性。     

城市与农村不吸烟女性肺组织中DNA加合物含量

为更客观地评价空气污染与肺癌的关系，用＾３２Ｐ后标记法检测城市与农村不吸烟女性肺癌患者与非肺癌患者正常肺组织中ＤＮＡ加合物的含量。城乡妇女，城乡肺癌患者，城乡非肺癌妇女，城市肺癌妇女与农村非肺癌妇女，农村肺癌患者与非肺癌妇女之间均未见统计学差异，但发现城市患者比农村患者，肺癌患者比非肺癌患者的肺组织ＤＮＡ加合物含量高的趋势。     

吸烟与非吸烟肺癌病人正常肺组织中DNA加合物定量研究

应用核酸酶Ｐ１介导的￣（３２）Ｐ后标记分析方法，分析了３２例胸科手术后切除的肺癌病人的正常肺组织中ＤＮＡ加合物。在３２例肺癌手术者中，２２例为吸烟者，１０例为非吸烟者。本实验吸烟组与非吸烟组肺组织ＤＮＡ加合物水平差异有显著性（Ｐ＜０．００１）；在吸烟者的放射自显影图片上出现一条斜的放射带。相关性分析表明，随着吸烟量的增加，肺组织中ＤＮＡ加合物也增加，有显著相关（ｒ＝０．７３，Ｙ＝０．４１１Ｘ＋３．５２，Ｐ＜０．０１）。     

肺癌组织和体外人气管上皮细胞癌变模型中10环氧化物-DNA加合物的检测

目的探明10G环氧化物(BPDE)-DNA加合物在人群肺癌发生中的作用及其分子机制.方法使用针对BPDE-DNA加合物的单克隆抗体,通过免疫学方法检测150例的肺癌组织、120例的癌旁肺组织、40例的肺良性病变组织和40例的正常肺组织中BPDE-DNA加合物的含量,同时检测相应肺组织中p53、C-MYC、K-RAS、BCL-2、hTERT等癌变相关基因的表达,分析BPDE-DNA加合物与上述基因的关系.并在BPDE诱导的体外人气管上皮细胞癌变模型上检测癌变过程中BPDE-DNA加合物的变化.结果82.0%的肺癌组织中可检出BPDE-DNA加合物,加合物阳性细胞的比率为11.52%±14.44%(x±s);37.5%的癌旁肺组织可检出BPDE-DNA加合物,加合物阳性细胞的比率为2.25%±5.07%;15.0%的肺良性病变组织可检出BPDE-DNA加合物,加合物阳性细胞的比率为0.75%±2.30%;40例正常肺组织中仅1例可检出BPDE-DNA加合物,该组人群平均加合物阳性细胞比率为0.03%±0.16%;肺癌组织中加合物的含量显著高于癌旁肺组织、肺良性病变组织和正常肺组织,P＜0.001.将肺癌病例按性别、年龄、细胞类型和吸烟史分组,发现男性病例加合物检出率为89.9%,高于女性的检出率(51.6%),P＜0.01.99.1%的吸烟患者其癌组织可检出BPDE-DNA加合物,加合物阳性细胞比率为13.91%±15.53%;27.8%的非吸烟肺癌患者其癌组织也可检出BPDE-DNA加合物,加合物阳性细胞含量为4.68±7.44;吸烟患者BPDE-DNA加合物的含量显著高于非吸烟患者,t=3.44,P＜0.001.肺癌组织BPDE-DNA加合物含量在p53、K-RAS、BCL-2基因阳性表达者中显著高于阴性表达者,而C-MYC、TERT基因表达与BPDE-DNA加合物无关联.在体外用BPDE作用于人气管上皮细胞系,可诱导该细胞系发生转化和癌变,在其癌变过程中BPDE-DNA加合物由阴性变为强阳性.结论BPDE-DNA加合物是反映多环芳烃暴露和产生致癌效应的重要生物标志物,其致癌作用可能与p53、K-RAS、BCL-2等基因有关.     

性别、年龄因素对人肺组织DNA加合物形成量影响的探讨

探讨了ＤＮＡ加合物的量在人肺组织中随年龄、性别的分布。实验结果表明：年龄与肺组织中ＤＮＡ加合物的相关系数很低，不同年龄组ＤＮＡ加合物的平均相对加合物标记（ＲＡＬ）值无显著性差异。男性肺组织中ＤＮＡ加合物的量显著高于女性（Ｐ＜０．０５），除与吸烟因素有关外，男女肺组织中ＤＮＡ加合物量的差异也不能排除内分泌因素的影响。     

反式二羟环氧苯并(a)芘-DNA加合物在肺癌发病中的作用

[目的]反式二羟环氧苯并 (a)芘 (BPDE)为苯并 (a)芘在体内的代谢产物 ,是一种直接的致癌物 ,可攻击DNA形成BPDE_DNA加合物 ,本研究目的为探明该加合物在人群肺癌发生中的作用及其分子机制。[方法]使用针对BPDE_DNA加合物的单克隆抗体 ,通过免疫学方法检测150例肺癌、120例癌旁肺组织、40例肺良性病变和40例正常肺组织中BPDE_DNA加合物的含量 ,同时检测相应肺组织中P53、C_MYC、K_ras、BCL_2、hTERT等癌变相关基因的表达 ,分析BPDE_DNA加合物与上述基因的关系。并在BPDE诱导的体外人气管上皮细胞癌变模型上检测癌变过程中BPDE_DNA加合物的变化。[结果]82.0 % (123/150)的肺癌组织 ,37.5 % (45/120)的癌旁肺组织 ,15.0% (6/40)的肺良性病变和2.5% (1/40)的正常肺组织可检出BPDE_DNA加合物 ,肺癌组织中加合物的含量显著高于其他肺组织 ,P<0.01。分层分析发现男性肺癌病例加合物检出率为89.9% (107/119)高于女性的检出率51.6 % (16/31) ,P<0.05。有吸烟史的肺癌患者加合物检出率为99.1% (113/114)高于非吸烟肺癌患者的27.8% (10/36),P<0.01。肺癌组织P53、K_ras、BCL_2基因的阳性表达与BPDE_DNA加合物有关联 ,而C_MYC、hTERT基因的表达与BPDE_DNA加合物无关联。在体外用BPDE作用于人气管上皮细胞系 ,可诱导     

接触室内煤烟的肺癌患者多环芳烃DNA加合物的研究

本实验是为了探索宣威肺癌病因和肺癌早期危险性评价方法做一点尝试，应用３２Ｐ后标记法检测了宣威３０例（实验组）、昆明１０例（对照组）肺癌病人的纤维支气管镜（纤支镜）刷落细胞的多环芳烃（ＰＡＨ）－ＤＮＡ加合物。结果表明宣威肺癌病人的ＰＡＨ－ＤＮＡ加合物水平远远高于对照组。该结果从分子水平上证明宣威室内煤烟污染与肺癌有直接联系，ＤＮＡ加合物的检测可以作为人群危险性评价的指标。     

利用生物发光法测定人群外周淋巴细胞DNA加合物水平

目的：利用生物发光法测定人群外周淋巴细胞DNA加合物水平,并分析其影响因素,为进一步探讨水污染与人群DNA加合物水平之间的关系奠定基础,方法：采用随机整群抽样方法,抽取234例健康人群,测定其外周淋巴细胞DNA加合物水平,并对年龄,吸烟,饮食习惯等进行分析。结果：健康人群中男性DNA加合物水平略高于女性,但二之间差异无显意义;人群DNA加合物与年龄,吸烟,饮茶,饮食习惯和饮酒等因素均有显相关性,其中年龄,吸烟与DNA加合物的相关性最为明显;随着年龄的增加,DNA加合物水平上升;吸烟越多;DNA加合物水平越高,结论：人群DNA加合物水平影响因素很多,其在人体生物监测,肿瘤形成风险评估中的应用,还有待进一步的研究。     

肺癌患者K-ras、FHIT基因异常与吸烟关系

目的 探讨吸烟与肺癌患者原癌基因K-ras点突变和人类脆性组氨酸三联体(FHIT)基因转录异常的关系,探讨吸烟致肺癌作用靶点.方法 应用PCR-RFLP和RT-PCR分别检测80例肺癌患者及20例正常肺组织中K-ras、FHIT基因的异常情况,分析吸烟与K-ras、FHIT基因异常的关系.结果 肺癌组织K-ras基因突变率为52.58%,FHIT基因转录异常阳性率为71.25%,与正常肺组织比较差异均有统计学意义(P＜0.05).肺癌组吸烟者的K-ras、FHIT基因异常率高于不吸烟者(P＜0.05).K-ras、FHIT基因异常与吸烟指数相关联,列联系数P分别为0.337和0.399;吸烟与肺腺癌K-rss基因点突变、肺鳞癌和小细胞肺癌的FHIT基因异常转录关系密切(P＜0.05).肺癌患者K-ras突变与FHIT转录异常无明显关联性,但两者在肺癌组织中差异有统计学意义(P＜0.01).结论 K-ras、FHIT基因异常与肺癌发生密切相关.吸烟是肺腺癌中K-ras基因点突变和肺鳞癌、小细胞肺癌中FHIF基因异常转录的一个重要因素.     

苯DNA加合物的组织分布及其与细胞遗传毒性的关系

用Ｐ１增强的３２Ｐ－后标记方法测定了经腹腔注射染苯小鼠不同组织ＤＮＡ加合物的分布及其与苯引起的外周血白细胞（ＷＢＣ）减少、淋巴细胞微核形成及骨髓细胞染色体畸变的关系。结果表明：１．苯在小鼠骨髓、肝脏和外周血ＷＢＣ均可形成ＤＮＡ加合物，其加合物含量以骨髓最高，肝脏次之，ＷＢＣ最低。本结果与苯的代谢及毒性作用特点相一致。２．ＤＮＡ加合物形成与细胞毒性有关系，ＤＮＡ加合物量增加，淋巴细胞微核及骨髓细胞染色体畸变亦增加，而外周血白细胞数明显减少，显示细胞遗传毒性和细胞毒性均增大。本研究为ＤＮＡ加合物作为生物学监测指标，筛选高危人群提供了有力的实验依据。     

肺癌组织中的8-OH-dG及其与几种癌变相关基因的关系

为探讨 8 羟基 脱氧鸟苷 (8 OH dG)与人群肺癌发生及癌变相关基因的关系 ,使用针对 8 OH dG加合物的鼠抗人单克隆抗体 ,通过免疫学方法检测 1 50例肺癌、1 2 0例癌旁肺组织、40例肺良性病变和 40例正常肺组织中氧化损伤标志物 8 OH dG的含量 ;同时检测相应肺组织中P53、C MYC、K RAS、BCL 2、hTERT等癌变相关基因的表达 ,分析 8 OH dG与上述癌变相关基因表达的关系。结果显示 ,92 7% (1 39 1 50 )的肺癌组织中可检出氧化损伤标志物 8 OH dG ,其阳性标志细胞的比率为 (2 4 0 0± 2 5 1 1 ) % ;1 7 5 % (2 1 1 2 0 )的癌旁肺组织可检出 8 OH dG ,阳性标志细胞的比率为 (2 42± 5 98) % ;1 0 0 % (4 40 )的肺良性病变组织可检出 8 OH dG ,阳性标志细胞的比率为 (0 80± 1 30 ) % ;5 0 % (2 40 )的正常肺组织可检出 8 OH dG加合物 ,阳性标志细胞的比率为 (0 34± 1 0 1 ) % ,肺癌中 8 OH dG的含量高于其它肺组织 (P <0 0 1 )。将肺癌病例按性别、年龄、细胞类型和吸烟史分层 ,它们皆与 8 OH dG无关联。分析 8 OH dG与癌变相关基因的关系 ,发现肺癌组织K RAS、BCL 2基因阳性表达者 8 OH dG的含量高于上述基因阴性表达者 ,P值分别为 0 0 35和 0 0 34 ;而P53、C MYC和hTERT基因表达与 8 OH dG的含     

天津市肺癌与吸烟关系的病例对照研究

我们于1981年3月至10月在天津市六所大医院里进行了肺癌的病例对照研究,着重了解吸烟与肺癌的联系。调查了肺癌病例135人(男99,女36)、对照病人135人。病例与对照均为住院病人,90%的肺癌病例有病理学诊断依据。病例与对照作年龄、性别、民族、居住地配对。病例组与对照组的吸烟习惯有显著差异。吸烟者患肺癌的相对危险性男性为6,女性为4,两者的99%可信限均大于1。男女性均可见吸烟量与相对危险性之间有显著的剂量反应关系,其回归系数的95%可信限都不包括零。开始吸烟至发现肺癌的时间(潜隐期)的分布为正态分布,其均数为30年。     

Exposure to urban and rural air pollution: DNA and protein adducts and effect of glutathione-S-transferase genotype on adduct levels

Ambient air in urban areas is polluted by agents suspected of causing cancer in humans. A number of epidemiological studies have revealed an increased cancer risk in urban communities, especially in lung cancer. The relative risk have been estimated to be in the order of 1.5. The objective of this study was to evaluate differences in genotoxic exposure through air pollution in urban and rural areas using DNA and protein adducts as biomarkers. Another objective was to investigate whether the GSTM1 genotype has any effect on adduct level. The analyses included ³²P postlabelling of DNA adducts in lymphocytes, enzyme-linked immunosorbent assay for measuring benzo[a]pyrene protein adducts and polymerase chain reaction amplification of the GSTM1 genotype. The study was a cross-sectional study of non-smoking, healthy males from rural and urban Danish areas and from Athens, Greece. All individuals in the study were healthy, non-smoking males. The Danish urban group included 74 university students, the rural group 29 students from agricultural colleges and the Greek group 17 individuals. Adduct levels differed significantly in the three groups with median levels of 0.152 fmol/g DNA (rural), 0.205 fmol/g (urban) and 0.285 fmol/g (Athens). The adduct patterns showed some identical spots, but also specific adducts. Here we report increasing DNA adduct levels comparing residents in rural, small urban and large urban residential areas; we found no influence of GSTM1 genotype on DNA or protein adduct levels in non-smokers exposed to low levels of air pollution.     

Smoking and other risk factors for lung cancer in Xuanwei, China

In Xuanwei County, Yunnan Province, lung cancer mortality rates are among the highest in China in both males and females. Previous studies have shown a strong association of lung cancer mortality with indoor air pollution from 'smoky' coal combustion. In the present case-control study, 110 newly-diagnosed lung cancer patients and 426 controls were matched with respect to age, sex, occupation (all subjects were farmers), and village of residence (which provided matching with respect to fuel use). This design allowed assessment of known and suspected lung cancer risk factors other than those mentioned above. Data from males and females were analysed by conditional logistic regression. In females who do not smoke, the presence of lung cancer was statistically significantly associated with chronic bronchitis (odds ratio [OR] = 7.37, 95% confidence interval [Cl]: 2.40-22.66) and family history of lung cancer (OR 4.18, 95% Cl: 1.61-10.85). Females' results also suggested an association of lung cancer with duration of cooking food (OR 1.00, 9.18 and 14.70), but not with passive smoking (OR 0.77, 95% Cl: 0.30-1.96). In males, lung cancer was significantly associated with chronic bronchitis (OR 7.32, 95% Cl: 2.66-20.18), family history of lung cancer (OR 3.79, 95% Cl: 1.70-8.42), and personal history of cooking food (OR 3.36, 95% Cl: 1.27-8.88). In males a dose-response relationship of lung cancer with smoking index (years of smoking*amount of smoking) was shown by risks of 1.00, 2.61, 2.17 and 4.70.     

Quantitative relationship between cumulative cigarette consumption and lung cancer mortality in Japan

BACKGROUND: Sufficient evidence has been accumulated to demonstrate the causal relationship between cigarette smoking and lung cancer risk. Therefore, the lung cancer risk of a country is supposedly determined by the amount of cigarettes consumed in the country, but this quantitative relationship has yet to be clarified at a national level. OBJECTIVE: To find the quantitative relationship between cigarette smoking and subsequent lung cancer risk at a national level. METHODS: The quantitative relationship between cigarette smoking and lung cancer mortality is formulated as a function of cumulative cigarette consumption. The formulae for ages 25-29 to 70-74 are estimated by examining the increment of the lung cancer death rate in relation to the unit increase in cumulative cigarette consumption in different birth cohorts. The validity of the quantitative relationships is then examined by comparing lung cancer deaths expected from the formulae with observed deaths in past studies. RESULTS: Cumulative cigarette consumption was found to have increased in later birth cohorts for all ages of males and females. The age-specific lung cancer death rates from 35-39 to 70-74 were found to increase in proportion to cumulative cigarette consumption. Comparison of the results with past studies showed good agreement. CONCLUSION: The change over time in the lung cancer death rate of males and females in Japan can be explained fairly well by the increase in cumulative cigarette consumption at the national level.     

Tobacco and cancer: epidemiology and the laboratory.

Tobacco smoke contains many mutagenic and carcinogenic chemicals. Both whole tobacco smoke and extracts induce tumors in experimental animals. Work with carcinogen-macromolecule adducts provided evidence for the action of specific chemicals. Molecular epidemiology studies suggested that point mutations in tumor-suppressor genes (e.g., p53) and oncogenes (e.g., ras) may be specific both for the type of tumor and for the critical environmental exposure. The consistency among investigations on oncogene/tumor-suppressor gene mutations in lung cancer (and other tobacco-related cancers) in smokers is highly suggestive, although we still lack information about the time sequence between exposure, gene mutation, and cancer onset. Current work that deserves emphasis includes investigations revealing that lungs of smokers contain benzo[a]pyrene diol-epoxide-guanine DNA adducts, which are in accordance with the type of mutations found in K-ras or p53 genes (G to T transversions). In addition, DNA in human exfoliated bladder cells showed a derivative of 4-aminobiphenyl as a main adduct; there was also an association between smoking habits (amount and type of tobacco) and the levels of both DNA adducts and hemoglobin adducts formed by aromatic amines. Increasing evidence indicates that genetically based metabolic polymorphisms exert a role in modulating individual susceptibility to the action of tobacco carcinogens. Overall, the weight of evidence strongly supports the causal nature of the association between smoking and cancer and falsifies Fisher's hypothesis that the association was due to confounding by genetic predisposition.