联合检测外周血VEGF、MT与晚期肺癌疗效及预后判断的相关性研究
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摘要
目的：探讨联合检测晚期肺癌患者外周血血管内皮生长因子(vascular endothelial growth factor, VEGF)和金属硫蛋白(Metallothionein, MT)与肺癌病理类型、淋巴结转移情况、疗效、预后判断之间的关系。方法：实验分为肺癌组(33例晚期肺癌患者)和对照组(30例健康者)；采用双抗体夹心(ABC-ELISA)法测定两组血清VEGF和MT的含量；实时定量逆转录聚合酶链反应(RT-PCR)法检测两组外周血单个核细胞VEGF mRNA和MT mRNA的表达情况。结果：对照组血清VEGF、MT含量分别为(174.3±60.1) pg/ml、(5.7±2.8) ng/ml,肺癌组患者化疗前VEGF、MT含量分别为(401.2±142.4) pg/ml、(13.9±6.0) ng/ml,肺癌组患者化疗前血清VEGF及MT均明显高于对照组(P<0.01)。对照组外周血VEGF mRNA、MT mRNA的表达分别为(48.8±24.1)、(95.0±30.3),肺癌组患者化疗前外周血VEGF mRNA、MT mRNA分别为(209.6±90.3)、(184.2±103.2),肺癌组患者化疗前外周血VEGF mRNA、MT mRNA的表达均明显高于对照组(P<0.01)。肺癌组患者化疗后VEGF蛋白水平低于化疗前(P<0.05),而外周血VEGF mRNA化疗前后无差异性(P>0.05)；外周血MT蛋白及mRNA治疗前后亦无差异性(P>0.05)。VEGF与MT的蛋白及基因水平表达与晚期肺癌患者性别、病理类型、淋巴结有无转移及疗效均无相关性,差异无统计学意义(P>0.05)。肺癌组VEGF及MT阳性率分别为78.8%及63.6%,两种肿瘤标志物联合检测阳性率上升为91%。血清VEGF与MT测定值之间无相关性。结论：血清VEGF与MT联合检测可提高阳性率,但二者之间无相关性。VEGF、MT联合检测与晚期肺癌患者性别、病理类型、淋巴结有无转移、疗效及预后均无相关性。
Objective:To investigate the relationship between the combined detection of Peripheral Blood vascular endothelial growth factor (VEGF), metallothionein(MT) and pathological type, lymph node metastasis, efficacy and prognosis and other factors in Patients with advanced lung cancer. Methods:The study were divided into lung cancer group (33 patients with advanced lung cancer patients) and control group (30 healthy people).The serum VEGF and MT levels were measured by ABC-ELISA double antibody sandwich method in the two groups. Peripheral blood mononuclear cells expression of VEGF mRNA and MT mRNA were measured by Reverse transcription polymerase chain reaction (RT-PCR). Results:Serum VEGF and MT normal expression level were (174.3±60.1) pg/ml and (5.7±2.8) ng/ml, VEGF and MT expression level in Lung cancer patients before treatment were (401.2±142.4) pg/ml and (13.9±6.0) ng/ml, Serum VEGF and MT expression level in patients with lung cancers before chemotherapy were significantly higher than normal group (P<0.01). Peripheral blood VEGF mRNA and MT mRNA in normal group were (48.8±24.1) and (95.0±30.3) VEGF mRNA and MT mRNA in Lung cancer patients before chemotherapy expression level were (209.6±90.3) and (184.2±103.2), MT mRNA and VEGF mRNA in Lung cancer patients before chemotherapy was significantly higher than normal group. Serum VEGF levels in lung cancer patients after chemotherapy were Less than the before (P <0.05). However, VEGF mRNA in Peripheral Blood before and after the chemotherapy of advanced lung cancer have no difference (P> 0.05); MT protein and mRNA in peripheral blood before and after the chemotherapy of advanced lung cancer have no differences (P> 0.05).VEGF and MT have no correlation with gender, pathological type, lymph node metastasis and efficacy, the differences have not statistically significant (P> 0.05).The positive rates of VEGF and MT in lung cancer patients were 78.8% and 63.6%.There were no correlation between the measured value of serum VEGF and MT. Conclusion: Combined detection of serum VEGF and MT can improve the positive rate, while there were no correlation between the two indexes. VEGF and MT have no correlation with gender, pathological type, lymph node metastasis , efficacy and prognosis in advanced lung cancer.
Objective:To investigate the relationship between the combined detection of Peripheral Blood vascular endothelial growth factor (VEGF), metallothionein(MT) and pathological type, lymph node metastasis, efficacy and prognosis and other factors in Patients with advanced lung cancer. Methods:The study were divided into lung cancer group (33 patients with advanced lung cancer patients) and control group (30 healthy people).The serum VEGF and MT levels were measured by ABC-ELISA double antibody sandwich method in the two groups. Peripheral blood mononuclear cells expression of VEGF mRNA and MT mRNA were measured by Reverse transcription polymerase chain reaction (RT-PCR). Results:Serum VEGF and MT normal expression level were (174.3±60.1) pg/ml and (5.7±2.8) ng/ml, VEGF and MT expression level in Lung cancer patients before treatment were (401.2±142.4) pg/ml and (13.9±6.0) ng/ml, Serum VEGF and MT expression level in patients with lung cancers before chemotherapy were significantly higher than normal group (P<0.01). Peripheral blood VEGF mRNA and MT mRNA in normal group were (48.8±24.1) and (95.0±30.3) VEGF mRNA and MT mRNA in Lung cancer patients before chemotherapy expression level were (209.6±90.3) and (184.2±103.2), MT mRNA and VEGF mRNA in Lung cancer patients before chemotherapy was significantly higher than normal group. Serum VEGF levels in lung cancer patients after chemotherapy were Less than the before (P <0.05). However, VEGF mRNA in Peripheral Blood before and after the chemotherapy of advanced lung cancer have no difference (P> 0.05); MT protein and mRNA in peripheral blood before and after the chemotherapy of advanced lung cancer have no differences (P> 0.05).VEGF and MT have no correlation with gender, pathological type, lymph node metastasis and efficacy, the differences have not statistically significant (P> 0.05).The positive rates of VEGF and MT in lung cancer patients were 78.8% and 63.6%.There were no correlation between the measured value of serum VEGF and MT. Conclusion: Combined detection of serum VEGF and MT can improve the positive rate, while there were no correlation between the two indexes. VEGF and MT have no correlation with gender, pathological type, lymph node metastasis , efficacy and prognosis in advanced lung cancer.
引文
[1]陈公琰,洪璇.血管内皮生长因子与肺癌的关系[J].中华肿瘤杂志,2005,27(8)：449-451.
[2]Moldovan N I. Angiogenesis, lpenfant terrible of vascular biology is coming of age[J]. J CellMolMed,2005,9 (4):775-794.
[3]Hanahan, D, Weinberg,RA. The hallmarks of cancer[J].Cell 2000,100(1):57-70.
[4]Ferrara N. Vascular Endothelial Growth Factor as a Target for Anticancer Therapy [J]. The Oncologist,2004,1(9):2-10.
[5]Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis [J]. J Clin Oncol,2005,23(5):1011-1027.
[6]Ferrara N, Hillan KJ, Gerber HP, Novotny W. Discovery and development of bevacizumab,an anti-VEGF antibody for treating cancer[J].Nat Rev Drug Discov. 2004,3:391-400.
[7]Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch[J].Nat Rev Cancer 2003,3:401-10.
[8]Jain RK. Normalizing tumor vasculature with anti-angiogenic therapy:a new paradigm for combination therapy[J].Nat Med 2001,7:987-989.
[9]Jain RK. Normallization of tumor vasculature:An emerging concept in antiangiogenic therapy [J].Science 2005;307(5706):58-62.
[10]Gerber HP, Ferrara N. The role of VEGF in nomal and neoplastic hematopoiesis[J]. J Mol Med 2003; 81:20-31.
[11]王官成,白桂芝,袁江永.肝癌组织中MMP-9和VEGF的表达变化及意义[J].山东医药,2010；46：58-59.
[12]田峰,文道林,等.鼻咽癌患者血清中VEGF-C和CYFR21-1的表达及其与淋巴转移的关系[J].海南医学,2011,22(01)：11-12.
[13]卢先军,栗占三.大肠癌组织中VEGF、MMP-9表达和KI-67标记指数与大肠癌生物学行为的关系[J].中外健康文摘,2010,7(12)：75-77.
[14]姚文健,白玉,等.p27kip1和VEGF在非小细胞肺癌中的表达及其意义[J].医学信息,2011,24(1)：4-5.
[15]江秀娟,陈俊瑶,等.非小细胞肺癌与血清中2种相关因子含量关系[J].中国公共卫生,2010,26(7)：807-808.
[16]张真.血清CD44v6和VEGF表达水平与不能手术非小细胞肺癌同步放化疗的相关性研究[J].青岛大学,2009,2：128-207.
[17]陈敬,陈正堂,邹岚,等.非小细胞肺癌患者外周血VEGF、CK19mRNA、CEA和TSGF联合检测的意义[J].重庆医学,2004,7(33)：977-979.
[18]Haerslev T, Jacobsen GK, Zedeler K. The prognostic significance of im2 munohistochemically etectable metallothionein in primary breast carcinomas[J]. PMIS, 1995,103 (4):316-319.
[19]张伟,于颖彦.乳腺癌患者金属硫蛋白的表达与临床病理学的关系[J].外科理论与实践,2000,5(3)：178-180.
[20]吕新华,许浪,颜建辉,等.非小细胞肺癌中MT蛋白与P53表达的研究[J].中国医师杂志,2005,7(7)：912-914.
[21]王彦,吴焕明,肺癌中金属硫蛋白的表达及其与细胞增殖、凋亡的关系[J].中国组织化学与细胞化学杂志,2003,12(4)：393-398.
[22]许浪,张玉霞,孙远昌,等.非小细胞肺癌中MT蛋白的表达及意义[J].数理医药学杂志,2003,16(5)：403-405.
[23]李墨农,白岚,周荣祥,等.金属硫蛋白与血管内皮生长因子在前列腺癌中的表达及临床意义[J].中国全科医学,2009,20：1852-1853.
[24]中国抗癌协会肺癌专业委员会,2010中国肺癌临床指南[M].2010；17-19.
[25]陈智伟,廖美琳,等.WHO标准和RECIST标准评价肺癌化疗疗效的比较[J].循证医学,2004；6,(4)：83-106.
[26]Ide AG, Baker NH, Warren SL. Vascularization of the Brown-Peatce rabbit epithelioma transplant as seen in the transparent ear chamber[J], Am J Roentgenol,1939, 42:891-899.
[27]late KH, Breier G, Weich HA, Risau W. Vascular endothelial growth factor is a potential tumor angiogenesis factor in human gliomas in vivo[J].Nature 1992;359:845-848.
[28]Carmeliet P, Jain RK. Angiogenesis in cancer and other disease[J]. Nature,2000, 407:249—257.
[29]尹春华,刘丝荪,刘页玲,等.金属硫蛋白在宫颈癌中的表达及临床意义[J].江西医学院学报,2006,46(6)：74-76.
[30]许浪,张玉霞,等.非小细胞肺癌中MT蛋白的表达及意义[J].数理医药学杂志,2003,16(5)：403-404.
[31]徐建芳,周彩存,等.非小细胞肺癌VEGF的表达与临床相关性[J].中国癌症杂志,2002,12(6)：509-515.
[32]金阳,陶晓南,等.非小细胞肺癌患者血清VEGF水平和外周血CK19 mRNA的表达[J].中国病理生理杂志,2007,23(10)：2031—203.
[33]郭鹏.肿瘤生物节律治疗[J].肿瘤预防与治疗,2010,6(23)：518-523.
[34]任迎春,李翔九,等.血管内皮生长因子表达与肺癌预后的相关性研究[J].中华结核和呼吸感染,1999,9(22)：538.
[35]曾军杰,李颖妍,等.VEGF COX-2表达对肺腺癌预后生存期影响[J].医药论坛杂志,2007,4(28)：29-33.
[36]杨博.Her-1、Her-2、P53、Ki-67、VEGF在非小细胞肺癌中的表达及其对预后的影响[D].军医进修学院学位论文,2009.
[1]赵丽微,杨淑艳,方青,等.VEGF表达的调节及与肿瘤的相关研究[J].吉林医药学院学报,2007(3)：167-169.
[2]Haerslev T, Jacobsen GK, Zedeler K. The prognostic significance of immunohisto-chemically etectable metallothionein in primary breast carcinomas [J]. APMIS,1995,103 (4):316-319.
[3]Neufeld G, Cohen T, Stela G, et al. Vascular endothelial growth factor (VEGF) and its receptors[J]. FASEB J,1999,13:9-22.
[4]Shalabi F, Rossant J, Yamaguchi TP, et al. Failure of blood island formation and vasculogenesis in Flkl deficient mice[J]. Nature,1995,376:62-66.
[5]刘莉,胡宝成,张玉静,等.血管内皮生长因子受体——结构与功能[J].生理科学进展,2000,3(31)：269-272.
[6]李晓娟,纪淑红,等.综述VEGF的结构特征及生物学功能[J].中华临床医学研究杂志2007,2(3)：388。
[7]陈敬,陈正堂,邹岚,等,非小细胞肺癌患者外周血VEGF、CK19mRNA、CEA和TSGF联合检测的意义[J].重庆医学,2004,7(3),977-979.
[8]Dziegiel P, Jelen M, Muszczynska B, et al. Role of metallothionein expression in non-small cell lung carcinomas [J]. ROcz Akad Med Bialymst,2004,49(1):43-45.
[9]Janssen AM, van Duijn W, Kubben F, et al. Prognostic significance of metallothionein in human gastrointestinal cancer [J]. Clin Cancer Res,2002,8: 1889-1896.
[10]Jin R, Bay BH, Chow VT, et al. Metallothionein 1E mRNA is highly expressed in oestrogen receptor-negative human invasive ductal breast cancer[J]. Br J Cancer,2000, 83:319-323.
[11]安建平,王海娟,韩沛平,等.金属硫蛋白生理功能的研究进展[J].天水师范学院学报,2005,25(2)：34-38.
[12]Janssen AM, van Duijn W, Kubben F, et al. Prognostic significance of metallothionein in human gastrointestinal cancer. Clin Cancer Res,2002,8:1889-1896.
[13]Abdel—Mageed AB, Agrawal KC. Activation of nuclear factor kappaB:potential role in metallothionein-mediated mitogenic response. Cancer Res,1998,58:2335-2338.
[14]Kondo Y,Kuo SM Lazo JS.Interleuk in B mediated MT inductiong and oytoprotectiong against Cd and CDDP[J].J Pharm acol Exp Ther,1994,270:1313-1318.
[15]Kondo Y,Woo ES,Michalska AE,et al.Metallothionein null cells have increased sensitivity to anticancer drugs[J].Cancer Res,1995,55(10):2021-2023.
[16]邢树礼,王洪光,赵帅,等.金属硫蛋白的功能及应用前景[J].生物技术通报,2008,2：45-47.
[17]吕新华,等.MT在肿瘤组织中的表达研究进展[J].湘南学院学报(自然科学版),2005,7(2)：72-73.
[18]Mahboobi H, Viarengo A, Colangelo D,et al. Effect of metal-based anticancer drugs on wild type and metallotlrionein null cell lines[J]. Biometals,2003,16(3):403-409.
[19]Min K S, Morishita F, Tetsuchikawahara N,et al. Induction of hepatic and renal metallothionein synthesis by ferric nitrilotriacetate in mice:the role of MT as an antioxidant [J]. Toxicol Appl Pharmacol,2005,204(1):9-17.
[20]Rossman TG, Goncharova El. Spontaneous mutagenesis in mammalian cells is caused mainly by oxidative events and can be blocked by antioxidants and metallothinein[J]. Mutat Res,1998,402:103-110.
[2l]Lewin B, Genes VI[M]. Oxford UniversityPress, Incz, New York.1997,849-850.
[22]Goulding H, Jasani B, Pereira H, et al. Metallothionein exp ression in human breast cancer [J]. Br J Cancer,1995,72:968-972.
[23]苏华,等.耐药标志物金属硫蛋白在乳腺癌中的表达[J].张家口医学院学报,2004,21(1)：41-42.
[24]苏勇,等.放疗前中后鼻咽癌组织金属硫蛋白表达变化及其意义[J].广东医学,2003,11(24)：1189-1191.
[25]李天,等.宫颈癌中金属硫蛋白的表达及其与细胞增殖、凋亡的关系[J].华中科技大学学报(医学版),2006,6(35)：768-770.
[2]Moldovan N I. Angiogenesis, lpenfant terrible of vascular biology is coming of age[J]. J CellMolMed,2005,9 (4):775-794.
[3]Hanahan, D, Weinberg,RA. The hallmarks of cancer[J].Cell 2000,100(1):57-70.
[4]Ferrara N. Vascular Endothelial Growth Factor as a Target for Anticancer Therapy [J]. The Oncologist,2004,1(9):2-10.
[5]Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis [J]. J Clin Oncol,2005,23(5):1011-1027.
[6]Ferrara N, Hillan KJ, Gerber HP, Novotny W. Discovery and development of bevacizumab,an anti-VEGF antibody for treating cancer[J].Nat Rev Drug Discov. 2004,3:391-400.
[7]Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch[J].Nat Rev Cancer 2003,3:401-10.
[8]Jain RK. Normalizing tumor vasculature with anti-angiogenic therapy:a new paradigm for combination therapy[J].Nat Med 2001,7:987-989.
[9]Jain RK. Normallization of tumor vasculature:An emerging concept in antiangiogenic therapy [J].Science 2005;307(5706):58-62.
[10]Gerber HP, Ferrara N. The role of VEGF in nomal and neoplastic hematopoiesis[J]. J Mol Med 2003; 81:20-31.
[11]王官成,白桂芝,袁江永.肝癌组织中MMP-9和VEGF的表达变化及意义[J].山东医药,2010；46：58-59.
[12]田峰,文道林,等.鼻咽癌患者血清中VEGF-C和CYFR21-1的表达及其与淋巴转移的关系[J].海南医学,2011,22(01)：11-12.
[13]卢先军,栗占三.大肠癌组织中VEGF、MMP-9表达和KI-67标记指数与大肠癌生物学行为的关系[J].中外健康文摘,2010,7(12)：75-77.
[14]姚文健,白玉,等.p27kip1和VEGF在非小细胞肺癌中的表达及其意义[J].医学信息,2011,24(1)：4-5.
[15]江秀娟,陈俊瑶,等.非小细胞肺癌与血清中2种相关因子含量关系[J].中国公共卫生,2010,26(7)：807-808.
[16]张真.血清CD44v6和VEGF表达水平与不能手术非小细胞肺癌同步放化疗的相关性研究[J].青岛大学,2009,2：128-207.
[17]陈敬,陈正堂,邹岚,等.非小细胞肺癌患者外周血VEGF、CK19mRNA、CEA和TSGF联合检测的意义[J].重庆医学,2004,7(33)：977-979.
[18]Haerslev T, Jacobsen GK, Zedeler K. The prognostic significance of im2 munohistochemically etectable metallothionein in primary breast carcinomas[J]. PMIS, 1995,103 (4):316-319.
[19]张伟,于颖彦.乳腺癌患者金属硫蛋白的表达与临床病理学的关系[J].外科理论与实践,2000,5(3)：178-180.
[20]吕新华,许浪,颜建辉,等.非小细胞肺癌中MT蛋白与P53表达的研究[J].中国医师杂志,2005,7(7)：912-914.
[21]王彦,吴焕明,肺癌中金属硫蛋白的表达及其与细胞增殖、凋亡的关系[J].中国组织化学与细胞化学杂志,2003,12(4)：393-398.
[22]许浪,张玉霞,孙远昌,等.非小细胞肺癌中MT蛋白的表达及意义[J].数理医药学杂志,2003,16(5)：403-405.
[23]李墨农,白岚,周荣祥,等.金属硫蛋白与血管内皮生长因子在前列腺癌中的表达及临床意义[J].中国全科医学,2009,20：1852-1853.
[24]中国抗癌协会肺癌专业委员会,2010中国肺癌临床指南[M].2010；17-19.
[25]陈智伟,廖美琳,等.WHO标准和RECIST标准评价肺癌化疗疗效的比较[J].循证医学,2004；6,(4)：83-106.
[26]Ide AG, Baker NH, Warren SL. Vascularization of the Brown-Peatce rabbit epithelioma transplant as seen in the transparent ear chamber[J], Am J Roentgenol,1939, 42:891-899.
[27]late KH, Breier G, Weich HA, Risau W. Vascular endothelial growth factor is a potential tumor angiogenesis factor in human gliomas in vivo[J].Nature 1992;359:845-848.
[28]Carmeliet P, Jain RK. Angiogenesis in cancer and other disease[J]. Nature,2000, 407:249—257.
[29]尹春华,刘丝荪,刘页玲,等.金属硫蛋白在宫颈癌中的表达及临床意义[J].江西医学院学报,2006,46(6)：74-76.
[30]许浪,张玉霞,等.非小细胞肺癌中MT蛋白的表达及意义[J].数理医药学杂志,2003,16(5)：403-404.
[31]徐建芳,周彩存,等.非小细胞肺癌VEGF的表达与临床相关性[J].中国癌症杂志,2002,12(6)：509-515.
[32]金阳,陶晓南,等.非小细胞肺癌患者血清VEGF水平和外周血CK19 mRNA的表达[J].中国病理生理杂志,2007,23(10)：2031—203.
[33]郭鹏.肿瘤生物节律治疗[J].肿瘤预防与治疗,2010,6(23)：518-523.
[34]任迎春,李翔九,等.血管内皮生长因子表达与肺癌预后的相关性研究[J].中华结核和呼吸感染,1999,9(22)：538.
[35]曾军杰,李颖妍,等.VEGF COX-2表达对肺腺癌预后生存期影响[J].医药论坛杂志,2007,4(28)：29-33.
[36]杨博.Her-1、Her-2、P53、Ki-67、VEGF在非小细胞肺癌中的表达及其对预后的影响[D].军医进修学院学位论文,2009.
[1]赵丽微,杨淑艳,方青,等.VEGF表达的调节及与肿瘤的相关研究[J].吉林医药学院学报,2007(3)：167-169.
[2]Haerslev T, Jacobsen GK, Zedeler K. The prognostic significance of immunohisto-chemically etectable metallothionein in primary breast carcinomas [J]. APMIS,1995,103 (4):316-319.
[3]Neufeld G, Cohen T, Stela G, et al. Vascular endothelial growth factor (VEGF) and its receptors[J]. FASEB J,1999,13:9-22.
[4]Shalabi F, Rossant J, Yamaguchi TP, et al. Failure of blood island formation and vasculogenesis in Flkl deficient mice[J]. Nature,1995,376:62-66.
[5]刘莉,胡宝成,张玉静,等.血管内皮生长因子受体——结构与功能[J].生理科学进展,2000,3(31)：269-272.
[6]李晓娟,纪淑红,等.综述VEGF的结构特征及生物学功能[J].中华临床医学研究杂志2007,2(3)：388。
[7]陈敬,陈正堂,邹岚,等,非小细胞肺癌患者外周血VEGF、CK19mRNA、CEA和TSGF联合检测的意义[J].重庆医学,2004,7(3),977-979.
[8]Dziegiel P, Jelen M, Muszczynska B, et al. Role of metallothionein expression in non-small cell lung carcinomas [J]. ROcz Akad Med Bialymst,2004,49(1):43-45.
[9]Janssen AM, van Duijn W, Kubben F, et al. Prognostic significance of metallothionein in human gastrointestinal cancer [J]. Clin Cancer Res,2002,8: 1889-1896.
[10]Jin R, Bay BH, Chow VT, et al. Metallothionein 1E mRNA is highly expressed in oestrogen receptor-negative human invasive ductal breast cancer[J]. Br J Cancer,2000, 83:319-323.
[11]安建平,王海娟,韩沛平,等.金属硫蛋白生理功能的研究进展[J].天水师范学院学报,2005,25(2)：34-38.
[12]Janssen AM, van Duijn W, Kubben F, et al. Prognostic significance of metallothionein in human gastrointestinal cancer. Clin Cancer Res,2002,8:1889-1896.
[13]Abdel—Mageed AB, Agrawal KC. Activation of nuclear factor kappaB:potential role in metallothionein-mediated mitogenic response. Cancer Res,1998,58:2335-2338.
[14]Kondo Y,Kuo SM Lazo JS.Interleuk in B mediated MT inductiong and oytoprotectiong against Cd and CDDP[J].J Pharm acol Exp Ther,1994,270:1313-1318.
[15]Kondo Y,Woo ES,Michalska AE,et al.Metallothionein null cells have increased sensitivity to anticancer drugs[J].Cancer Res,1995,55(10):2021-2023.
[16]邢树礼,王洪光,赵帅,等.金属硫蛋白的功能及应用前景[J].生物技术通报,2008,2：45-47.
[17]吕新华,等.MT在肿瘤组织中的表达研究进展[J].湘南学院学报(自然科学版),2005,7(2)：72-73.
[18]Mahboobi H, Viarengo A, Colangelo D,et al. Effect of metal-based anticancer drugs on wild type and metallotlrionein null cell lines[J]. Biometals,2003,16(3):403-409.
[19]Min K S, Morishita F, Tetsuchikawahara N,et al. Induction of hepatic and renal metallothionein synthesis by ferric nitrilotriacetate in mice:the role of MT as an antioxidant [J]. Toxicol Appl Pharmacol,2005,204(1):9-17.
[20]Rossman TG, Goncharova El. Spontaneous mutagenesis in mammalian cells is caused mainly by oxidative events and can be blocked by antioxidants and metallothinein[J]. Mutat Res,1998,402:103-110.
[2l]Lewin B, Genes VI[M]. Oxford UniversityPress, Incz, New York.1997,849-850.
[22]Goulding H, Jasani B, Pereira H, et al. Metallothionein exp ression in human breast cancer [J]. Br J Cancer,1995,72:968-972.
[23]苏华,等.耐药标志物金属硫蛋白在乳腺癌中的表达[J].张家口医学院学报,2004,21(1)：41-42.
[24]苏勇,等.放疗前中后鼻咽癌组织金属硫蛋白表达变化及其意义[J].广东医学,2003,11(24)：1189-1191.
[25]李天,等.宫颈癌中金属硫蛋白的表达及其与细胞增殖、凋亡的关系[J].华中科技大学学报(医学版),2006,6(35)：768-770.