焦炉工血清 ras P21 水平和外周血淋巴细胞 SCE 率检测
作者：吴逸明 王新朝 徐玉宝 马玉英 李志远 史香林 陈琛
单位：史香林(美国职业安全卫生研究所病理生理学研究室 摩根墩 WV 26505 USA)；陈琛吴逸明 王新朝 徐玉宝 马玉英 李志远(河南医科大学劳动卫生学与卫生毒理学教研室 郑州 450052)
关键词：暴露；焦炉逸散物；P21；SCE；吸烟
河南医科大学学报000303 摘要 目的：为了解接触焦炉逸散物职业性人群遗传效应的改变，从分子水平揭示焦炉逸散物的遗传毒作用。方法：对25名焦炉工和12名正常对照分别检测了血清P21和外周血淋巴细胞姐妹染色单体互换(SCE)率。结果：发现焦炉工P21水平(3 774.2)、SCE率(11.43)明显高于对照组P21水平(1 270.7)和SCE率(6.37)；焦炉工中，炉顶工血清P21均值(4 377.5)高于其它工种(3 300.1)，炉顶工SCE(13.51)明显高于其它工种(10.07)；对焦炉工按是否吸烟进行比较，未发现组间P21和SCE有差异显著性。结论：提示焦炉逸散物具有较强的遗传毒理学效应，可提高机体癌蛋白P21水平和SCE频率。
, 百拇医药
分类号 R135
Detection of serum ras P21 level and sister chromatid exchange frequency in peripheral blood lymphocyte in workers exposed to coke oven volatiles
WU Yiming, WANG Xinchao, XU Yubao, MA Yuying, LI Zhiyuan, CHEN Chen
(Department of Occupational Health and Health Toxicology, Henan Medical University, Zhengzhou 450052, P.R. China)
SHI Xianglin
, http://www.100md.com
(Pathology and Physiology Research, NIOSH, Morgantown, WV 26505, USA)
Abstract Aim: To investigate genotoxic effects in workers occupationally exposed to polycyclic aromatic hydrocarbons (PAHs) such as benzo-(a)-pyrene (BaP) in coke oven volatiles (COV). Methods: 25 workers exposed to COV (exposed group) and 12 health donors (normal group) were studied.Serum P21 levels were detected by Western Blotting. Sister chromatid exchange (SCE) frequencies were measured by culturing with peripheral blood lymphocyte. Results: Serum P21 levels and SCE/cell frequencies in exposed group were significantly higher than those of normal group (P21 (3 774.2±1 494.2)vs(1 270.7±623.7 and SCE(11.43±2.11) vs (6.37±0.59), respectively). P21 levels and SCE frequencies in workers working at coke oven top were remarkably higher than those of workers in other working environments (P21(4 377.5±1 632.7) vs (3 300.1±1 233.3) and SCE(13.51±1.76) vs (10.07±0.44), respectively). There was no significant difference in either P21 levels or SCE between smokers and nonsmokers (P >0. 05) in exposed group. Conclusion: Occupational exposure to COV resulted in an increased level of SCE/cell, P21. The frequency of SCE and the P21 levels were found to be related to exposure to carcinogenic PAHs. The results imply that COV have a potent genotoxic effect.
, http://www.100md.com
Key words occupational exposure; coke oven volatiles; P21; SCE; smoking
Epidemiological studies[1] have shown that there is an enhanced mortality of occupational pulmonary carcinoma in workers exposed to coke oven volatiles (COV). COV contain polycyclic aromatic hydrocarbons (PAHs), such as benzo-(a)-pyrene, which are established carcinogens. Because of a long duration of COV-carcinogenesis, earlier detection for a high-risk population of occupational lung carcinoma is necessary. Sister chromatid exchange (SCE) is an index reflecting genotoxic effect and often used to detect carcinogensis in a shorter period[2]. ras P21 oncoprotein is generally considered as one of a series of biological reactions to carcinogens[3]. In the present study, ras P21 level and SCE were detected in workers exposed to COV in a factory which used coke oven to produce steel and iron in order to find the relationship between the exposure and hazard effect.
, 百拇医药
1 Subjects and methods
1.1 Subjects 25 male workers in a coke oven factory were chosen. Age ranged from 25 to 50 years old (mean 40 years). Work-age exposed to COV was from 9 to 32 years (mean 22. 2 years). 12 donors who never exposed to any known occupational chemical toxin were assigned to normal control group. Smoking habit was carefully monitored throughout the study.
1.2 Methods and reagents Samples for SCE were prepared by culturing peripheral blood lymphocyte. The slides were stained with Giemsa and examined under microscope[4]. Serum P21 was detected by Western Blotting[5]. Monocolonal antibody ( MAb ) for mutant P21 oncoprotein was purchased from Oncogene Science Company. Streptoavidin, BCIP, NBT and biotin-alkaline-phosphase were purchased from Promega Company.
, 百拇医药
1.3 P21 calculation of P21 levels Mutant P21 electrophresis reactive bands on nitrocellular membrane were scanned by means of bi-wave length sheet chromotography (wave length 580 nm). Relative areas of P21 bands were determined as P21 levels. If the P21 area of an exposed worker was 5-fold higher than that of normal group, that worker was considered as a P21 positive[6].
1.4 Statistical analysis Normal distribution test on P21 and SCE/cell was firstly carried out with SPSS software in 586-IBM computer. P21 ,SCE/cell differences were defined by student's t-test. A difference of P≤0.05 was considered significant.
, http://www.100md.com
2 Results
2.1 Comparison of P21, SCE/cell between exposed group and control group Both P21 level and SCE/cell frequency were significantly higher in exposed group than those in control group and the differences were significant (P<0.001). The results were provided in Tab 1.
Tab 1 P21, SCE/cell differences
between exposed group and control group (
±s) Group
, 百拇医药
n
P21
SCE/cell
Exposure group
25
3 774.2±1494.2*
11.43±2.11**
Control group
12
1 270.7±632.7
6.37±0.59
, 百拇医药
* P<0.001， indicates that P21 and SCE/cell of exposure group were significantly elevated compared with the control group as determined by student′s t-test2.2 Comparison of P21, SCE/cell among different working environments Among workers exposed to COV, both mean P21 level and mean SCE/cell in workers in an occupation of coke oven top site were remarkably higher than those in other type of working environments. The differences were significant (Tab 2).
Tab 2 P21,SCE/cell differences
, 百拇医药
in different working environment (±s) Work-type
n
P21
SCE/cell
Furnace top
11
4 377.5±1 632.7*
13.51±1.76**
Other site
, 百拇医药 14
3 300.1±1 233.3
10.07±0.44
* P<0.05 , ** P<0.001, indicates that both P21 and SCE/cell were significantly higher in furnace top workers than those in other working environments as determined by student′s t-test2.3 The differences of P21 level and SCE/cell frequency between smokers and nonsmokers in workers exposed to COV Stratum analysis was performed to compare the smokers and nonsmokers in workers exposed to COV (Tab 3). No significant difference in either P21 level or SCE/cell was found between smokers and nonsmokers (P>0.05, respectively).
, 百拇医药
Tab 3 P21,SCE/cell differences between
smokers and nonsmokers in workers exposed to COV (±s) Group
n
P21
SCE/cell
Smokers
14
3 945.4±1 883.8
13.10±2.34
, 百拇医药
Nonsmokers
11
3 556.3± 807.4
10.89±4.56
3 Discussion
SCE is DNA exchange product formed in DNA synthesis cycle[4] and may be associated with DNA strand breakages. SCE frequency reflects DNA repair after injury in DNA synthesis cycle. SCE is a sensitive index[7] for detection of DNA injury in occupational workers. The SCE may be used as a useful method to screen high-risk population who may have a high risk to carcinoma. The results of the present study have showed that the SCE in exposed workers was significantly higher than that in normal control, indicating that COV has a strong genotoxic effect. SCE can be used as a useful index in workers' physical examination each year and as a biomarker for earlier cancer detection in exposed workers.
, http://www.100md.com
It is generally believed that carcinogenesis is associated with DNA damage and mutation, oncogene activation and antioncogene deficiency[8] . The ras oncogene and its related product P21, were extensively studied as possible biomarkers for earlier cancer detection. It has been demonstrated that the ras has a close relationship with occupational cancers, especially cancers of the lung[8]. The product of ras gene is a protein with a molecular of 21 000 daltons. The ras P21 is similar to G protein[10,11] in its structure and function. P21 is considered be a signal transconduction protein. This protein is the internal part of the cytoplasmic membrane[12,13]. While the exact mechanism for the malignant transformation of the normal cell is not yet known, it has been suggested that the qualitative or quantitative changes in the expression of ras oncogene may play an important role in the cancer development. The P21 levels showed overexpression when ras oncogene occured. Since P21 oncoprotein can be secreted to extracellular domain[14], the P21 can be detected in the serum of occupational workers associated high-risk population. Due to the fact that the elevation of serum P21 levels occur prior to the clinical development of lung cancer[15], it could potentially be an important biomarker for screening lung cancer in high-risk population.
, http://www.100md.com
The results obtained in the present studyed show that P21 levels were significantly higher among 25 cases of COV in exposed group than those in normal group(P<0.001). An important feature in workers occupationally exposed to COV is that these workers are located at different locations within a factory. There are different lung cancer mortalities among them. It has been shown that the mortality of lung cancer is associated with the site according to the sequence of oven top, oven side and non-coke oven[16]. The results obtained on COV workers indicated that both P21 levels and SCE frequency in workers around the oven top were higher than those in other sites. The levels of P21 change in response to carcinogens such as coke oven volatiles and can provide an important clue concerning the mechanism of COV-induced carcinogenesis.
, http://www.100md.com
Smoking as a high-risk factor of lung cancer attracts a world-wide attention. In this study, we did not observe any significant difference in P21 and SCE between smokers and non-smokers of workers exposed to COV. It is possible that the effects resulted from exposed to COV was much stronger than those of smoking. Thus, the smoking effect may not be apparent[17].
SCE is the product of DNA repair after DNA injury. It can reflect the events of genetic end point to mutagens or genotoxic agents as well as carcinogens. The method to detect SCE is simple and easily available. This method may become useful for screening occupational lung cancer of high-risk population. P21 oncogene is a protein of ras gene and can be used as a biomarker for earlier cancer development.
, 百拇医药
All of the cytogenetic and bio-molecular markers were significantly increased in the exposed vs control group. It is concluded that occupational exposure of workers to COV resulted in an increased levels of both SCE/cell and P21. The frequency of both SCE and the P21 levels were found to be related to exposure to carcinogenic PAHs.
基金项目：河南省自然科学基金资助项目 97330001,984020300
作者简介：吴逸明：男，55岁，教授，博士生导师，研究方向：肺癌的病因、预防和早期诊断，References
, 百拇医药
[1]Wu YM, Chen C, Yang TZ, et al. Historical cohort study on malignant tumor in workers exposed to coal tar pitch in a carbon black factory. J Henan Med Univ, 1990, 25(1):50
[2]Poncy JL, Fritsch P, Masse R. Evolution of sister chromatid exchange (SCE) in rat bone marrow cells as a function of time after 2 Gy of whole-body neutron irradiation. Mutat Res, 1988,202(1):45
[3]Soderkvisf P, Axelson O. On the use of molecular biology date in occupational and environmental epidemiology. JOEM, 1995, 37(1):84
, 百拇医药
[4]Huang XS, Cheng XC. Experimental methods on environmental chemical substances. Hangzhou: Zhejiang Scientific and Technical Publishing House, 1985.185
[5]Ausubel FM, Brent R, Kingaton RE, et al. Short protocols in molecular biology. the 2nd edition. New York: John Wiley & Sons , 1990.69
[6]曾晓菲，蒋学之，王簃兰.接触氯甲醚工人血清中ras癌基因产物P21蛋白的检测.中华劳动卫生与职业病杂志，1993，11(5)：273
[7]Kalina I,Brezi P, Gsjdoov D,et al.Cytogenetic monitoring in coke oven workers. Mutant Res, 1998,417(1):9
, http://www.100md.com
[8]Frzier ME,Lindbery KA, Mueller DM, et al. Oncogene involvement in plutonium induced carcinogenesis. Int J Rad Biol, 1986,49:542
[9]Bos JL. ras oncogenes as tools to study tumor development. Contrib Oncol, 1990,39:44
[10]Cross M, Dexser TM. Growth factors in development transformation and tumorigenesis. Cell, 1991,64:27
[11]Cantley LC,Auger KR, Capenter C, et al. Oncogenes and signals transconduction. Cell, 1991,64:281
, http://www.100md.com
[12]Barbaid M. Ras gene. Am Rev Biochem, 1987,56:779
[13]Buse JE, Sefton EM. Direct identification of palmitic acid as the lipid attached to ras P21. Mol Cell Biol,1986,6(11):116
[14]Brandt-Rauf PW. The molecular epidemiology of oncoproteins. Scand J Work Environ Health, 1992,18:546
[15]Brandt-Rauf PW, Smith S, Hemminki S, et al. Serum oncoproteins and growth factors in asbestosis and silicosis patients. Int J Cancer, 1992,50:881
[16]Jia DW,Wu YM,Chen C. Detecting human serum P21 oncoprotein with Western Blotting. J Henan Med Univ, 1995, 30(1):177
[17]王簃兰，刚葆琪主编. 现代劳动卫生学. 北京：人民卫生出版社，1994.515
2000-01-05收稿, http://www.100md.com
单位：史香林(美国职业安全卫生研究所病理生理学研究室 摩根墩 WV 26505 USA)；陈琛吴逸明 王新朝 徐玉宝 马玉英 李志远(河南医科大学劳动卫生学与卫生毒理学教研室 郑州 450052)
关键词：暴露；焦炉逸散物；P21；SCE；吸烟
河南医科大学学报000303 摘要 目的：为了解接触焦炉逸散物职业性人群遗传效应的改变，从分子水平揭示焦炉逸散物的遗传毒作用。方法：对25名焦炉工和12名正常对照分别检测了血清P21和外周血淋巴细胞姐妹染色单体互换(SCE)率。结果：发现焦炉工P21水平(3 774.2)、SCE率(11.43)明显高于对照组P21水平(1 270.7)和SCE率(6.37)；焦炉工中，炉顶工血清P21均值(4 377.5)高于其它工种(3 300.1)，炉顶工SCE(13.51)明显高于其它工种(10.07)；对焦炉工按是否吸烟进行比较，未发现组间P21和SCE有差异显著性。结论：提示焦炉逸散物具有较强的遗传毒理学效应，可提高机体癌蛋白P21水平和SCE频率。
, 百拇医药
分类号 R135
Detection of serum ras P21 level and sister chromatid exchange frequency in peripheral blood lymphocyte in workers exposed to coke oven volatiles
WU Yiming, WANG Xinchao, XU Yubao, MA Yuying, LI Zhiyuan, CHEN Chen
(Department of Occupational Health and Health Toxicology, Henan Medical University, Zhengzhou 450052, P.R. China)
SHI Xianglin
, http://www.100md.com
(Pathology and Physiology Research, NIOSH, Morgantown, WV 26505, USA)
Abstract Aim: To investigate genotoxic effects in workers occupationally exposed to polycyclic aromatic hydrocarbons (PAHs) such as benzo-(a)-pyrene (BaP) in coke oven volatiles (COV). Methods: 25 workers exposed to COV (exposed group) and 12 health donors (normal group) were studied.Serum P21 levels were detected by Western Blotting. Sister chromatid exchange (SCE) frequencies were measured by culturing with peripheral blood lymphocyte. Results: Serum P21 levels and SCE/cell frequencies in exposed group were significantly higher than those of normal group (P21 (3 774.2±1 494.2)vs(1 270.7±623.7 and SCE(11.43±2.11) vs (6.37±0.59), respectively). P21 levels and SCE frequencies in workers working at coke oven top were remarkably higher than those of workers in other working environments (P21(4 377.5±1 632.7) vs (3 300.1±1 233.3) and SCE(13.51±1.76) vs (10.07±0.44), respectively). There was no significant difference in either P21 levels or SCE between smokers and nonsmokers (P >0. 05) in exposed group. Conclusion: Occupational exposure to COV resulted in an increased level of SCE/cell, P21. The frequency of SCE and the P21 levels were found to be related to exposure to carcinogenic PAHs. The results imply that COV have a potent genotoxic effect.
, http://www.100md.com
Key words occupational exposure; coke oven volatiles; P21; SCE; smoking
Epidemiological studies[1] have shown that there is an enhanced mortality of occupational pulmonary carcinoma in workers exposed to coke oven volatiles (COV). COV contain polycyclic aromatic hydrocarbons (PAHs), such as benzo-(a)-pyrene, which are established carcinogens. Because of a long duration of COV-carcinogenesis, earlier detection for a high-risk population of occupational lung carcinoma is necessary. Sister chromatid exchange (SCE) is an index reflecting genotoxic effect and often used to detect carcinogensis in a shorter period[2]. ras P21 oncoprotein is generally considered as one of a series of biological reactions to carcinogens[3]. In the present study, ras P21 level and SCE were detected in workers exposed to COV in a factory which used coke oven to produce steel and iron in order to find the relationship between the exposure and hazard effect.
, 百拇医药
1 Subjects and methods
1.1 Subjects 25 male workers in a coke oven factory were chosen. Age ranged from 25 to 50 years old (mean 40 years). Work-age exposed to COV was from 9 to 32 years (mean 22. 2 years). 12 donors who never exposed to any known occupational chemical toxin were assigned to normal control group. Smoking habit was carefully monitored throughout the study.
1.2 Methods and reagents Samples for SCE were prepared by culturing peripheral blood lymphocyte. The slides were stained with Giemsa and examined under microscope[4]. Serum P21 was detected by Western Blotting[5]. Monocolonal antibody ( MAb ) for mutant P21 oncoprotein was purchased from Oncogene Science Company. Streptoavidin, BCIP, NBT and biotin-alkaline-phosphase were purchased from Promega Company.
, 百拇医药
1.3 P21 calculation of P21 levels Mutant P21 electrophresis reactive bands on nitrocellular membrane were scanned by means of bi-wave length sheet chromotography (wave length 580 nm). Relative areas of P21 bands were determined as P21 levels. If the P21 area of an exposed worker was 5-fold higher than that of normal group, that worker was considered as a P21 positive[6].
1.4 Statistical analysis Normal distribution test on P21 and SCE/cell was firstly carried out with SPSS software in 586-IBM computer. P21 ,SCE/cell differences were defined by student's t-test. A difference of P≤0.05 was considered significant.
, http://www.100md.com
2 Results
2.1 Comparison of P21, SCE/cell between exposed group and control group Both P21 level and SCE/cell frequency were significantly higher in exposed group than those in control group and the differences were significant (P<0.001). The results were provided in Tab 1.
Tab 1 P21, SCE/cell differences
between exposed group and control group (
±s) Group, 百拇医药
n
P21
SCE/cell
Exposure group
25
3 774.2±1494.2*
11.43±2.11**
Control group
12
1 270.7±632.7
6.37±0.59
, 百拇医药
* P<0.001， indicates that P21 and SCE/cell of exposure group were significantly elevated compared with the control group as determined by student′s t-test2.2 Comparison of P21, SCE/cell among different working environments Among workers exposed to COV, both mean P21 level and mean SCE/cell in workers in an occupation of coke oven top site were remarkably higher than those in other type of working environments. The differences were significant (Tab 2).
Tab 2 P21,SCE/cell differences
, 百拇医药
in different working environment (
±s) Work-typen
P21
SCE/cell
Furnace top
11
4 377.5±1 632.7*
13.51±1.76**
Other site
, 百拇医药 14
3 300.1±1 233.3
10.07±0.44
* P<0.05 , ** P<0.001, indicates that both P21 and SCE/cell were significantly higher in furnace top workers than those in other working environments as determined by student′s t-test2.3 The differences of P21 level and SCE/cell frequency between smokers and nonsmokers in workers exposed to COV Stratum analysis was performed to compare the smokers and nonsmokers in workers exposed to COV (Tab 3). No significant difference in either P21 level or SCE/cell was found between smokers and nonsmokers (P>0.05, respectively).
, 百拇医药
Tab 3 P21,SCE/cell differences between
smokers and nonsmokers in workers exposed to COV (
±s) Groupn
P21
SCE/cell
Smokers
14
3 945.4±1 883.8
13.10±2.34
, 百拇医药
Nonsmokers
11
3 556.3± 807.4
10.89±4.56
3 Discussion
SCE is DNA exchange product formed in DNA synthesis cycle[4] and may be associated with DNA strand breakages. SCE frequency reflects DNA repair after injury in DNA synthesis cycle. SCE is a sensitive index[7] for detection of DNA injury in occupational workers. The SCE may be used as a useful method to screen high-risk population who may have a high risk to carcinoma. The results of the present study have showed that the SCE in exposed workers was significantly higher than that in normal control, indicating that COV has a strong genotoxic effect. SCE can be used as a useful index in workers' physical examination each year and as a biomarker for earlier cancer detection in exposed workers.
, http://www.100md.com
It is generally believed that carcinogenesis is associated with DNA damage and mutation, oncogene activation and antioncogene deficiency[8] . The ras oncogene and its related product P21, were extensively studied as possible biomarkers for earlier cancer detection. It has been demonstrated that the ras has a close relationship with occupational cancers, especially cancers of the lung[8]. The product of ras gene is a protein with a molecular of 21 000 daltons. The ras P21 is similar to G protein[10,11] in its structure and function. P21 is considered be a signal transconduction protein. This protein is the internal part of the cytoplasmic membrane[12,13]. While the exact mechanism for the malignant transformation of the normal cell is not yet known, it has been suggested that the qualitative or quantitative changes in the expression of ras oncogene may play an important role in the cancer development. The P21 levels showed overexpression when ras oncogene occured. Since P21 oncoprotein can be secreted to extracellular domain[14], the P21 can be detected in the serum of occupational workers associated high-risk population. Due to the fact that the elevation of serum P21 levels occur prior to the clinical development of lung cancer[15], it could potentially be an important biomarker for screening lung cancer in high-risk population.
, http://www.100md.com
The results obtained in the present studyed show that P21 levels were significantly higher among 25 cases of COV in exposed group than those in normal group(P<0.001). An important feature in workers occupationally exposed to COV is that these workers are located at different locations within a factory. There are different lung cancer mortalities among them. It has been shown that the mortality of lung cancer is associated with the site according to the sequence of oven top, oven side and non-coke oven[16]. The results obtained on COV workers indicated that both P21 levels and SCE frequency in workers around the oven top were higher than those in other sites. The levels of P21 change in response to carcinogens such as coke oven volatiles and can provide an important clue concerning the mechanism of COV-induced carcinogenesis.
, http://www.100md.com
Smoking as a high-risk factor of lung cancer attracts a world-wide attention. In this study, we did not observe any significant difference in P21 and SCE between smokers and non-smokers of workers exposed to COV. It is possible that the effects resulted from exposed to COV was much stronger than those of smoking. Thus, the smoking effect may not be apparent[17].
SCE is the product of DNA repair after DNA injury. It can reflect the events of genetic end point to mutagens or genotoxic agents as well as carcinogens. The method to detect SCE is simple and easily available. This method may become useful for screening occupational lung cancer of high-risk population. P21 oncogene is a protein of ras gene and can be used as a biomarker for earlier cancer development.
, 百拇医药
All of the cytogenetic and bio-molecular markers were significantly increased in the exposed vs control group. It is concluded that occupational exposure of workers to COV resulted in an increased levels of both SCE/cell and P21. The frequency of both SCE and the P21 levels were found to be related to exposure to carcinogenic PAHs.
基金项目：河南省自然科学基金资助项目 97330001,984020300
作者简介：吴逸明：男，55岁，教授，博士生导师，研究方向：肺癌的病因、预防和早期诊断，References
, 百拇医药
[1]Wu YM, Chen C, Yang TZ, et al. Historical cohort study on malignant tumor in workers exposed to coal tar pitch in a carbon black factory. J Henan Med Univ, 1990, 25(1):50
[2]Poncy JL, Fritsch P, Masse R. Evolution of sister chromatid exchange (SCE) in rat bone marrow cells as a function of time after 2 Gy of whole-body neutron irradiation. Mutat Res, 1988,202(1):45
[3]Soderkvisf P, Axelson O. On the use of molecular biology date in occupational and environmental epidemiology. JOEM, 1995, 37(1):84
, 百拇医药
[4]Huang XS, Cheng XC. Experimental methods on environmental chemical substances. Hangzhou: Zhejiang Scientific and Technical Publishing House, 1985.185
[5]Ausubel FM, Brent R, Kingaton RE, et al. Short protocols in molecular biology. the 2nd edition. New York: John Wiley & Sons , 1990.69
[6]曾晓菲，蒋学之，王簃兰.接触氯甲醚工人血清中ras癌基因产物P21蛋白的检测.中华劳动卫生与职业病杂志，1993，11(5)：273
[7]Kalina I,Brezi P, Gsjdoov D,et al.Cytogenetic monitoring in coke oven workers. Mutant Res, 1998,417(1):9
, http://www.100md.com
[8]Frzier ME,Lindbery KA, Mueller DM, et al. Oncogene involvement in plutonium induced carcinogenesis. Int J Rad Biol, 1986,49:542
[9]Bos JL. ras oncogenes as tools to study tumor development. Contrib Oncol, 1990,39:44
[10]Cross M, Dexser TM. Growth factors in development transformation and tumorigenesis. Cell, 1991,64:27
[11]Cantley LC,Auger KR, Capenter C, et al. Oncogenes and signals transconduction. Cell, 1991,64:281
, http://www.100md.com
[12]Barbaid M. Ras gene. Am Rev Biochem, 1987,56:779
[13]Buse JE, Sefton EM. Direct identification of palmitic acid as the lipid attached to ras P21. Mol Cell Biol,1986,6(11):116
[14]Brandt-Rauf PW. The molecular epidemiology of oncoproteins. Scand J Work Environ Health, 1992,18:546
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