摘要
第一部分ERCC1基因的多态性和肺癌的铂类药物化疗疗效及毒副作用的关联研究
肺癌是肿瘤治疗中的难点之一,肺癌患者的总生存率较低。其中化疗的有效率仅为18-40%,而影响化疗疗效的主要原因之一是耐药性,其中又以铂类耐药占重要地位,铂类药物的药理作用就是通过引起DNA交联或形成DNA加合物,抑制DNA复制而杀死肿瘤细胞。而细胞中的NER修复通路则有可能降低铂类的疗效。
其中ERCC1是NER通路中的主效基因,通过与XPF组成复合体的形式负责5'的核苷酸切除,它的上调表达提高DRC,明显降低以铂类药物为基础的化疗疗效。该基因的T19007C位点是研究得较热门的一个SNP位点,我们采用Massarray对样本中的209名NSCLC患者的该位点进行了分型,并进行统计分析。
在对该位点和疗效的关联分析中,任何遗传模型下均未显示两者之间的关联。
在对化疗毒副作用作用的关联分析中,发现显性遗传模型下该位点与肠胃毒副作用存在关联。(TT+CT vs CC,P=0.047,优势比(OR)=3.311,95%置信区间(CI):1.015～10.796)。
本部分研究分析了ERCC1的较热门的SNP位点与化疗疗效及毒副作用的统计学关系。研究结果可作为下一步扩大样本量并在不同药物中开展的关联分析提供依据。
第二部分ERCC1基因T19007C(rs11615)的多态性和铂类药物化疗疗效的meta-分析
ERCC1(错配切除交叉互补修复酶)是NER修复复合物中的一个功能单位,行使DNA链的5'切除修复。另外,所选取的T19007C位点为同义突变位点,不涉及氨基酸的改变,但有可能影响密码子利用效率,从而对疗效发挥影响。
以往对ERCC1 T19007C及化疗疗效所进行的关联分析结果存在冲突。
我们在此对所有的合格单项研究汇总进行meta-分析。总体来说,T19007等位基因突变(555份有效组病例和595份无效组病例)并不表现出对化疗的显著耐药性。(P=0.732,优势比(OR)=0.950;95%置信区间(CI):0.707-1.276,P_(异质性)=0.017)。在所有遗传模型下进行的meta-分析也未显示出显著的与疗效的关联。而单项研究间存在异质性。需要对更大的人群样本进行更进一步的研究,以更加清晰地阐明ERCC1的T19007C位点在不同癌中的地位和作用。
PartⅠThe association study of ERCC1 polymorphism and chemotherapy response/toxicity of lung cancer
The survival rate of lung-cancer patients still remained low.The response rate of chemotherapy is about 18-40%,the factor which affects the chemotherapy response is drug resistance,especially platinum drug.The drug mechanism is that DNA adducts was formed to kill tumor cells.And the NER pathway may greatly reduced the effects of platinum drugs.
ERCC1 is one of the maineffect genes of NER,excising nucleotide by forming complex with XPF.Its up-regulating increases DRC,and obviousely reduces chemotherapy response.The T19007C site is a "hot spot" SNP,which was genotyped with Massarray.
No association was found under any genetic model in the study on chemotherapy response,in this study including 209 NSCLC patients.
We found this SNP was associated with gastrointestinal toxicity only under recessive genetic model(TT+CT vs CC).(P=0.047,odds ratio(OR)=3.311;95%confidence interval(CI):1.015～10.796).
In sum,this part specialized in one of the popular SNPs of ERCC1,and its statistic relationship of chemotherapy response and toxicity.The present results may supply clue for the further study based on larger sample treated with different drugs.
PartⅡAmeta-analysis of ERCC1 T19007C(rs11615) and chemotherapy response
ERCC1(excision repair cross complementation group 1) is a subunit of the nucleotide excision repair complex,which can perform DNA strand incision correction of DNA damage.
Association studies on the ERCC1 polymorphisms(T19007C) in platinum-based chemotherapy of cancer had shown conflicting results.
We performed a meta-analysis from all eligible studies to assess the purported associations.Overall,the T19007 allele(555 responders and 595 non-responders) showed no significant effect on chemotherapy resistance compared to 19007C allele(P=0.732,odds ratio(OR)=0.950;95%confidence interval(CI):0.707-1.276, P_(heterogeneity)=0.017) in all subjects.Meta-analysis under any genetic contrasts did not reveal significant association of T19007C to drug resistance of chemotherapy in all subjects.Significant between-study heterogeneity existed in T19007C.More studies based on larger population should be required to further evaluate the role of ERCC1 T19007C polymorphisms in different cancer.
引文
1.Sancar,A.,DNA repair in humans.Annual Review of Genetics,1995.29:p.69-105.
2.Wood,R.D.,Nucleotide excision repair in mammalian cells.Journal of Biological Chemistry,1997.272(38):p.23465-23468.
3.Lindahl,T.and R.D.Wood,Quality control by DNA repair.Science,1999.286(5446):p.1897-1905.
4.Frazier,M.L.,et al.,Age-associated risk of cancer among individuals with N-acetyltransferase 2(NAT2) mutations and mutations in DNA mismatch repair genes.Cancer Research,2001.61(4):p.1269-1271.
5.Little,M.P.,et al.,Risks of brain tumour following treatment for cancer in childhood:Modification by genetic factors,radiotherapy and chemotherapy.International Journal of Cancer,1998.78(3):p.269-275.
6.Roddam,P.L.,et al.,Genetic variants of NHEJ DNA ligase Ⅳ can affect the risk of developing multiple myeloma,a tumour characterised by aberrant class switch recombination.Journal of Medical Genetics,2002.39(12):p.900-905.
7.Carlson,C.S.,et al.,Selecting a maximally informative set of single-nucleotide polymorphisms for association analyses using linkage disequilibrium.American Journal of Human Genetics,2004.74(1):p.106-120.
8.Botstein D.and N.Risch,Discovering genotypes underlying human phenotypes:past successes for mendelian disease,future approaches for complex disease.Nature Genetics,2003.33:p.228-237.
9.Dempke,W.,et al.,Preferential repair of the N-ras gene in K 562cells after exposure to cisplatin.Anti-Cancer Drugs,1999.10(6):p.545-549.
10.Zhen,W.P.,et al.,INCREASED GENE-SPECIFIC REPAIR OF CISPLATIN INTERSTRAND CROSS-LINKS IN CISPLATIN-RESISTANT HUMAN OVARIAN-CANCER CELL-LINES.Molecular and Cellular Biology,1992.12(9):p.3689-3698.
11.Reed,E.,Platinum-DNA adduct,nucleotide excision repair and platinum based anti-cancer chemotherapy.Cancer Treatment Reviews,1998.24(5):p.331-344.
12.Dabholkar,M.,et al.,MESSENGER-RNA LEVELS OF XPAC AND ERCC1 IN OVARIAN-CANCER TISSUE CORRELATE WITH RESPONSE TO PLATINUM-BASED CHEMOTHERAPY.Journal of Clinical Investigation,1994.94(2):p.703-708.
13.Yu,J.J.,et al.,Comparison of two human ovarian carcinoma cell lines(A2780/CP70 and MCAS) that are equally resistant to platinum,but differ at codon 118 of the ERCC1 gene.International Journal of Oncology,2000.16(3):p.555-560.
14.Dabholkar,M.,et al.,ERCC1 AND ERCC2 EXPRESSION IN MALIGNANT-TISSUES FROM OVARIAN-CANCER PATIENTS.Journal of the National Cancer Institute,1992.84(19):p.1512-1517.
15.Rosell,R.,et al.,Applications of genomics in NSCLC.Lung Cancer,2005.50:p.S33-S40.
16.Huang,P.-Y.,et al.,[Correlation analysis among expression of ERCC-1,metallothionein,p53 and platinum resistance and prognosis in advanced non-small cell lung cancer].Ai Zheng,2004.23(7):p.845-50.
17.Rosell,R.,et al.,Nucleotide excision repair pathways involved in Cisplatin resistance in non-small-cell lung cancer.Cancer Control,2003.10(4):p.297-305.
18.Kang,S.,et al.,Association between excision repair cross-complementation group 1 polymorphism and clinical outcome of platinum-based chemotherapy in patients with epithelial ovarian cancer.Experimental and Molecular Medicine,2006.38(3):p.320-324.
19.Ryu,J.S.,et al.,Association between polymorphisms of ERCC1and XPD and survival in non-small-cell lung cancer patients treated with cisplatin combination chemotherapy.Lung Cancer,2004.44(3):p.311-316.
20.Siddik,Z.H.,Cisplatin:mode of cytotoxic action and molecular basis of resistance.Oncogene,2003.22(47):p.7265-7279.
21.Sancar A,R.J.,Nucleotide excision repair in E-coli and man:DNA Repair and Replication.Vol.69.2004.43-71.
22.Altaha,R.,et al.,Excision repair cross complementing-group 1:Gene expression and platinum resistance(Review).International Journal of Molecular Medicine,2004.14(6):p.959-970.
23.Vanduin,M.,et al.,MOLECULAR CHARACTERIZATION OF THE HUMAN EXCISION REPAIR GENE ERCC-1-CDNA CLONING AND AMINO-ACID HOMOLOGY WITH THE YEAST DNA-REPAIR GENE RAD10.Cell,1986.44(6):p.913-923.
24.Yu,J.J.,et al.,A nucleotide polymorphism in ERCC1 in human ovarian cancer cell lines and tumor tissues.Mutation Research-Genomics,1997.382(1-2):p.13-20.
25.Rabik,C.A.and M.E.Dolan,Molecular mechanisms of resistance and toxicity associated with platinating agents.Cancer Treatment Reviews,2007.33(1):p.9-23.
26.Grunberg,S.M.and P.J.Hesketh,DRUG-THERAPY- CONTROL OF CHEMOTHERAPY-INDUCED EMESIS.New England Journal of Medicine,1993.329(24):p.1790-1796.
27.Suk,R.,et al.,Polymorphisms in ERCC 1 and grade 3 or 4 toxicity in non-small cell lung cancer patients.Clinical Cancer Research,2005.11(4):p.1534-1538.
28.Bonk,T.and A.Humeny,MALDI-TOF-MS analysis of protein and DNA.Neuroscientist,2001.7(1):p.6-12.
29.Krull,I.S.,A.Sebag,and R.Stevenson,Specific applications of capillary electrochromatography to biopolymers,including proteins,nucleic acids,peptide mapping,antibodies,and so forth.Journal of Chromatography A,2000.887(1-2):p.137-163.
30.Akaike,H.,NEW LOOK AT STATISTICAL-MODEL IDENTIFICATION.leee Transactions on Automatic Control,1974.AC19(6):p.716-723.
31.Siciliano,M.J.,A.V.Carrano,and L.H.Thompson,CHROMOSOME-19 CORRECTS 2 COMPLEMENTING DNA-REPAIR MUTATIONS PRESENT IN CHO CELLS.Cytogenetics and Cell Genetics,1985.40(1-4):p.744-745.
32.Sijbers,A.M.,et al.,Mutational analysis of the human nucleotide excision repair gene ERCC1.Nucleic Acids Research,1996.24(17):p.3370-3380.
33.Park,C.H.and A.Sancar,FORMATION OF A TERNARY COMPLEX BY HUMAN XPA,ERCC1,AND ERCC4(XPF) EXCISION-REPAIR PROTEINS.Proceedings of the National Academy of Sciences of the United States of America,1994.91(11):p.5017-5021.
34.Weaver,D.A.,et al.,ABCC5,ERCC2,XPA and XRCC1 transcript abundance levels correlate with cisplatin chemoresistance in non-small cell lung cancer cell lines.Molecular Cancer,2005.4.
35.Rosell,R.,et al.,Genetic testing for chemotherapy in non-small cell lung cancer.Lung Cancer,2003.41:p.S97-S102.
36.Wang,Z.-Y.,et al.,Study on the expression of DNA excision repair biomarkers in cispatin-treated lung cancer cell line.Zhonghua Yufang Yixue Zazhi,2003.37(2):p.109-111.
1.Ruzzo,A.,et al.,Pharmacogenetic profiling and clinical outcome of patients with advanced gastric cancer treated with palliative chemotherapy.Journal of Clinical Oncology,2006.24(12):p.1883-1891.
2.Liu,D.X.,et al.,Impact of gene Polymorphisms on clinical outcome for stage Ⅳ melanoma patients treated with biochemotherapy:An exploratory study.Clinical Cancer Research,2005.11(3):p.1237-1246.
3.Viguier,J.,et al.,ERCC1 codon 118 polymorphism is a predictive factor for the tumor response to oxaliplatin/5-fluorouracil combination chemotherapy in patients with advanced colorectal cancer.Clinical Cancer Research,2005.11(17):p.6212-6217.
4.Isla,D.,et al.,Single nucleotide polymorphisms and outcome in docetaxel-cisplatin-treated advanced non-small-cell lung cancer.Annals of Oncology,2004.15(8):p.1194-1203.
5.Su,D.,et al.,Genetic polymorphisms and treatment response in advanced non-small cell lung cancer.Lung Cancer,2007.56(2):p.281-288.
6.Chung,H.H.,et al.,XRCC1 R399Q polymorphism is associated with response to platinum-based neoadjuvant chemotherapy in bulky cervical cancer.Gynecologic Oncology,2006.103(3):p.1031-1037.
7.Ryu,J.S.,et al.,Association between polymorphisms of ERCC1and XPD and survival in non-small-cell lung cancer patients treated with cisplatin combination chemotherapy.Lung Cancer,2004.44(3):p.311-316.
8.Steffensen KD,W.M.,Jeppesen U,Brandslund I,Jakobsen A,Prediction of response to chemotherapy by ERCC1immunohistochemistry and ERCC1 polymorphism in ovarian cancer.International Journal of Gynecological Cancer,2007.Oct 24.
9.Smith,S.,et al.,ERCC1 genotype and phenotype in epithelial ovarian cancer identify patients likely to benefif from paclitaxel treatment in addition to platinum-based therapy.Journal of Clinical Oncology,2007.25:p.5172-5179.
10.Tibaldi,C.,et al.,Correlation of CDA,ERCC1,and XPD polymorphisms with response and survival in gemcitabine/cisplatin-Treated advanced non-small cell lung cancer patients.Clinical Cancer Research,2008.14(6):p.1797-1803.
11.Hirschhorn,J.N.,et al.,A comprehensive review of genetic association studies.Genetics in Medicine,2002.4(2):p.45-61.
12.Zondervan,K.T.and L.R.Cardon,The complex interplay among factors that influence allelic association.Nature Reviews Genetics,2004.5(2):p.89-U14.
13.Munafo,M.R.and J.Flint,meta-analysis of genetic association studies.Trends in Genetics,2004.20(9):p.439-444.
14.Li,Y.,et al.,No association of ERCC1 C8092A and T19007C polymorphisms to cancer risk:a meta-analysis.Eur J Hum Genet,2007.15(9):p.967-73.
15.Wei,Q.,M.L.Frazier,and B.Levin,DNA repair:a double-edged sword.Journal Of The National Cancer Institute,2000.92(6):p.440-441.
16.Fox,M.and J.J.Roberts,Drug resistance and DNA repair.Cancer metastasis Reviews,1987.6(3):p.261-281.
17.SW Johnson,J.S.,PJ O'Dwyer Principles and Practice of Oncology.2001,Philadelphia,PA:Lippincott Williams and Wilkins.
18.Reed,E.,Platinum-DNA adduct,nucleotide excision repair and platinum based anti-cancer chemotherapy.Cancer Treatment Reviews,1998.24(5):p.331-344.
19.Zeng-Rong,N.,et al.,Elevated DNA repair capacity is associated with intrinsic resistance of lung cancer to chemotherapy.Cancer Res,1995.55(21):p.4760-4764.
20.Petitti,D.B.,meta-analysis,decision analysis,and cost-effectiveness analysis.1994,New York:Oxford University Press.
1.Sancar,A.,DNA repair in humans.Annual Review of Genetics,1995.29:p.69-105.
2.Wood,R.D.,Nucleotide excision repair in mammalian cells.Journal of Biological Chemistry,1997.272(38):p.23465-23468.
3.Lindahl,T.and R.D.Wood,Quality control by DNA repair.Science,1999.286(5446):p.1897-1905.
4.Frazier,M.L.,et al.,Age-associated risk of cancer among individuals with N-acetyltransferase 2(NAT2) mutations and mutations in DNA mismatch repair genes.Cancer Research,2001.61(4):p.1269-1271.
5.Little,M.P.,et al.,Risks of brain tumour following treatment for cancer in childhood:Modification by genetic factors,radiotherapy and chemotherapy.International Journal of Cancer,1998.78(3):p.269-275.
6.Roddam,P.L.,et al.,Genetic variants of NHEJ DNA ligase Ⅳ can affect the risk of developing multiple myeloma,a tumour characterised by aberrant class switch recombination.Journal of Medical Genetics,2002.39(12):p.900-905.
7.Ryu,J.S.,et al.,Association between polymorphisms of ERCC1 and XPD and survival in non-small-cell lung cancer patients treated with cisplatin combination chemotherapy.Lung Cancer,2004.44(3):p.311-316.
8.Suk,R.,et al.,Polymorphisms in ERCC1 and grade 3 or 4 toxicity in non-small cell lung cancer patients.Clinical Cancer Research,2005.11(4):p.1534-1538.
9.Li,Y.,et al.,No association of ERCC1 C8092A and T19007C polymorphisms to cancer risk:a meta-analysis.Eur J Hum Genet,2007.15(9):p.967-73.
10.de Boer,J.and J.H.J.Hoeijmakers,Nucleotide excision repair and human syndromes.Carcinogenesis,2000.21(3):p.453-460.
11.Taylor,E.M.,et al.,Xeroderma pigmentosum and trichothiodystrophy are associated with different mutations in the XPD(ERCC2) repair/transcription gene.Proceedings of the National Academy of Sciences of the United States of America,1997.94(16):p.8658-8663.
12.Yuan,P.,et al.,[Polymorphisms in nucleotide excision repair genes XPC and XPD and clinical responses to platinum-based chemotherapy in advanced non-small cell lung cancer].Zhonghua Yi Xue Za Zhi,2005.85(14):p.972-5.
13.Zatloukal,P.,et al.,Gemcitabine plus cisplatin vs.gemcitabine plus carboplatin in stage Ⅲb and Ⅳ non-small cell lung cancer:a phase Ⅲrandomized trial.Lung Cancer,2003.41(3):p.321-331.
14.Stoehlmacher,J.,et al.,A polymorphism of the XRCC1 gene predicts for response to platinum based treatment in advanced colorectal cancer.Anticancer Research,2001.21(4B):p.3075-3079.
15.Wang,Z.-H.,et al.,[Single nucleotide polymorphisms in XRCC1 and clinical response to platin-based chemotherapy in advanced non-small cell lung cancer],Ai Zheng,2004.23(8):p.865-8.
16.Yuan,P.,et al.,XRCC1 and XPD genetic polymorphisms predict clinical responses to platinum-based chemotherapy in advanced non-small cell lung cancer.Zhonghua Zhongliu Zazhi,2006.28(3):p.196-199.
17.Wei,J.,B.-r.Liu,and Y.-p.Wang,Advances in research on the association between single nucleotide polymorphisms of the DNA repair genes and resistance to platinum-based chemotherapy.Zhonghua Zhongliu Zazhi,2006.28(3):p.161-163.
18.Esteller,M.,et al.,Hypermethylation of the DNA repair gene O-6-methylguanine DNA methyltransferase and survival of patients with diffuse large B-cell lymphoma.Journal of the National Cancer Institute,2002.94(1):p.26-32.
19.Esteller,M.,et al.,Detection of aberrant promoter hypermethylation of tumor suppressor genes in serum DNA from non-small cell lung cancer patients.Cancer Research,1999.59(1):p.67-70.
20.Peltomaki,P.,et al.,Mutations predisposing to hereditary nonpolyposis colorectal cancer:Database and results of a collaborative study.Gastroenterology,1997.113(4):p.1146-1158.
21.Strathdee,G.,et al.,A role for methylation of the hMLH1 promoter in loss of hMLH1 expression and drug resistance in ovarian cancer.Oncogene,1999.18(14):p.2335-2341.
22.Humbert,O.,et al.,Mismatch repair and differential sensitivity of mouse and human cells to methylating agents.Carcinogenesis,1999.20(2):p.205-214.
23.Durant,S.T.,et al.,Dependence on RAD52 and RAD1 for anticancer drug resistance mediated by inactivation of mismatch repair genes.Current Biology,1999.9(1):p.51-54.
24.Umar,A.,et al.,Correction of hypermutability,N-methyl-N'-nitro-N-nitrosoguanidine resistance,and defective DNA mismatch repair by introducing chromosome 2 into human tumor cells with mutations in MSH2 and MSH6.Cancer Research,1997.57(18):p.3949-3955.
25.Ikeda,K.,et al.,Glutathione content is correlated with the sensitivity of lines of PC12 cells to cisplatin without a corresponding change in the accumulation of platinum.Molecular and Cellular Biochemistry,2001.219(1-2):p.51-56.
26.Sullivan,G.F.,et al.,Regulation of expression of the multidrug resistance protein MRP1 by p53 in human prostate cancer cells.Journal of Clinical Investigation,2000.105(9):p.1261-1267.
27.Baehr,O.,W.Wick,and M.Weller,Modulation of MDR/MRP by wild-type and mutant p53.Journal of Clinical Investigation,2001.107(5):p.643-646.
28.McDaid,H.M.,et al.,Eleutherobin:Defining a structure-activity profile and patterns of cross-resistance in taxol-resistant cell lines.Proceedings of the American Association for Cancer Research Annual Meeting,1999.40:p.623.
29.Gottesman,M.M.and I.Pastan,THE MULTIDRUG TRANSPORTER,A DOUBLE-EDGED SWORD.Journal of Biological Chemistry,1988.263(25):p.12163-12166.
30.Labroille,G.,et al.,Cytometric study of intracellular P-gp expression and reversal of drug resistance.Cytometry,1998.32(2):p.86-94.
31.Sparreboom,A.,et al.,Limited oral bioavailability and active epithelial excretion of paclitaxel(Taxol) caused by P-glycoprotein in the intestine.Proceedings of the National Academy of Sciences of the United States of America,1997.94(5):p.2031-2035.
32.Dicato,M.,et al.,Multidrug resistance:Molecular and clinical aspects.Cytokines Cellular & Molecular Therapy,1997.3(2):p.91-99.
33.Kavallaris,M.,The role of multidrug resistance-associated protein(MRP)expression in multidrug resistance.Anti-Cancer Drugs,1997.8(1):p.17-25.
34.Schiff,P.B.,J.Fant,and S.B.Horwitz,PROMOTION OF MICROTUBULE ASSEMBLY INVITRO BY TAXOL.Nature,1979.277(5698):p.665-667.
35.Bhattacharyya,B.and J.Wolff,INTERACTION OF 1-ANILINO-8-NAPHTHALENE SULFONATE WITH TUBULIN-SITE INDEPENDENT OF COLCHICINE-BINDING SITE.Archives of Biochemistry and Biophysics,1975.167(1):p.264-269.
36.Bhattacharya,R.and F.Cabral,A ubiquitous beta-tubulin disrupts microtubule assembly and inhibits cell proliferation.Molecular Biology of the Cell,2004.15(7):p.3123-3131.
37.Liu,B.,et al.,Mechanisms of taxotere-related drug resistance in pancreatic carcinoma.Journal of Surgical Research,2001.99(2):p.179-186.
38.Zhou,J.,et al.,Study of multi-drug resistant mechanisms in a taxol-resistant hepatocellular carcinoma QGY-TR 50 cell line.Biochemical and Biophysical Research Communications,2001.280(5):p.1237-1242.
39.Kamath,K.,et al.,beta Ⅲ-tubulin induces paclitaxel resistance in association with reduced effects on microtubule dynamic instability.Journal of Biological Chemistry,2005.280(13):p.12902-12907.
40.Kavallaris,M.,C.A.Burkhart,and S.B.Horwitz,Antisense oligonucleotides to class Ⅲ beta-tubulin sensitize drug-resistant cells to Taxol.British Journal of Cancer,1999.80(7):p.1020-1025.
41.Kavallaris,M.,et al.,Taxol-resistant epithelial ovarian tumors are associated with altered expression of specific beta-tubulin isotypes.Journal of Clinical Investigation,1997.100(5):p.1282-1293.
42.Banerjee,A.,et al.,INCREASED MICROTUBULE ASSEMBLY IN BOVINE BRAIN TUBULIN LACKING THE TYPE Ⅲ ISOTYPE OF BETA TUBULIN.Journal of Biological Chemistry,1990.265(3):p.1794-1799.
43.Rosell,R.,et al.,Transcripts in pretreatment biopsies from a three-arm randomized trial in metastatic non-small-cell lung cancer.Oncogene,2003.22(23):p.3548-3553.
44.Seve,E,et al.,Class Ⅲ beta-tubulin expression in tumor cells predicts response and outcome in patients with non-small cell lung cancer receiving paclitaxel.Molecular Cancer Therapeutics,2005.4(12):p.2001-2007.
45.Seve,P.,et al.,Class Ⅲ beta-tubulin is a marker of paclitaxel resistance in carcinomas of unknown primary site.Cancer Chemotherapy and Pharmacology,2007.60(1):p.27-34.
46.Paradiso,A.,et al.,Biomarkers predictive for clinical efficacy of taxol-based chemotherapy in advanced breast cancer.Annals of Oncology,2005.16:p. 14-19.
47.Mozzetti,S.,et al.,Class Ⅲ beta-tubulin overexpression is a prominent mechanism of paclitaxel resistance in ovarian cancer patients.Clinical Cancer Research,2005.11(1):p.298-305.
48.Ferrandina,G.,et al.,Class Ⅲ beta-tubulin overexpression is a marker of poor clinical outcome in advanced ovarian cancer patients.Clinical Cancer Research,2006.12(9):p.2774-2779.
49.Krull,I.S.,A.Sebag,and R.Stevenson,Specific applications of capillary electrochromatography to biopolymers,including proteins,nucleic acids,peptide mapping,antibodies,and so forth.Journal of Chromatography A,2000.887(1-2):p.137-163.
50.Zhou,B.S.,et al.,Overexpression of transfected human ribonucleotide reductase M2 subunit in human cancer cells enhances their invasive potential.Clinical & Experimental Metastasis,1998.16(1):p.43-49.
51.Fan,H.Z.,C.Villegas,and J.A.Wright,Ribonucleotide reductase R2component is a novel malignancy determinant that cooperates with activated oncogenes to determine transformation and malignant potential.Proceedings of the National Academy of Sciences of the United States of America,1996.93(24):p.14036-14040.
52.Tonin,P.N.,et al.,CHROMOSOMAL ASSIGNMENT OF AMPLIFIED GENES IN HYDROXYUREA-RESISTANT HAMSTER-CELLS.Cytogenetics and Cell Genetics,1987.45(2):p.102-108.
53.Wright,J.A.,et al.,REGULATION AND DRUG-RESISTANCE MECHANISMS OF MAMMALIAN RIBONUCLEOTIDE REDUCTASE,AND THE SIGNIFICANCE TO DNA-SYNTHESIS.Biochemistry and Cell Biology-Biochimie Et Biologie Cellulaire,1990.68(12):p.1364-1371.
54.McClarty,G.A.,et al.,INCREASED FERRITIN GENE-EXPRESSION IS ASSOCIATED WITH INCREASED RIBONUCLEOTIDE REDUCTASE GENE-EXPRESSION AND THE ESTABLISHMENT OF HYDROXYUREA RESISTANCE IN MAMMALIAN-CELLS.Journal of Biological Chemistry,1990.265(13):p.7539-7547.
55.Davis,R.,et al.,PURIFICATION,CHARACTERIZATION,AND LOCALIZATION OF SUBUNIT INTERACTION AREA OF RECOMBINANT MOUSE RIBONUCLEOTIDE REDUCTASE R1 SUBUNIT.Journal of Biological Chemistry,1994.269(37):p.23171-23176.
56.Mann,G.J.,et al.,RIBONUCLEOTIDE REDUCTASE-M1 SUBUNIT IN CELLULAR PROLIFERATION,QUIESCENCE,AND DIFFERENTIATION.Cancer Research,1988.48(18):p.5151-5156.
57.Jordan,A.and P.Reichard,Ribonucleotide reductases.Annual Review of Biochemistry,1998.67:p.71-98.
58.Choy,B.K.,et al.,MOLECULAR MECHANISMS OF DRUG-RESISTANCE INVOLVING RIBONUCLEOTIDE REDUCTASE-HYDROXYUREA RESISTANCE IN A SERIES OF CLONALLY RELATED MOUSE-CELL LINES SELECTED IN THE PRESENCE OF INCREASING DRUG CONCENTRATIONS.Cancer Research,1988.48(8):p.2029-2035.
59.Engstrom,Y.,et al.,CELL CYCLE-DEPENDENT EXPRESSION OF MAMMALIAN RIBONUCLEOTIDE REDUCTASE-DIFFERENTIAL REGULATION OF THE 2 SUBUNITS.Journal of Biological Chemistry,1985.260(16):p.9114-9116.
60.Goan,Y.G.,et al.,Overexpression of ribonucleotide reductase as a mechanism of resistance to 2,2-difluorodeoxycytidine in the human KB cancer cell line.Cancer Research,1999.59(17):p.4204-4207.
61.Dumontet,C.,et al.,Common resistance mechanisms to deoxynucleoside analogues in variants of the human erythroleukaemic line K562.British Journal of Haematology,1999.106(1):p.78-85.
