Objective:To evaluate the predictive values of gene expressions of ribonucleotide reductase M1(RRM1) and breast cancer susceptibility gene 1(BRCA1) in peripheral blood from Chinese patients with non-small-cell lung ca...Objective:To evaluate the predictive values of gene expressions of ribonucleotide reductase M1(RRM1) and breast cancer susceptibility gene 1(BRCA1) in peripheral blood from Chinese patients with non-small-cell lung cancer(NSCLC) treated with gemcitabine plus platinum.Methods:Forty Chinese patients with advanced NSCLC were recruited and received gemcitabine 1200 mg/m 2 on Days 1 and 8 plus carboplatin AUC 5 on Day 1.RRM1 and BRCA1 expression levels in peripheral blood were detected by quantitative reverse transcription-polymerase chain reaction(RT-PCR) .Kaplan-Meier survival curve and log-rank test were performed to evaluate the correlation between gene expression and overall survival for these subjects.Results:No correlation was observed between gene expression of RRM1 and that of BRCA1(P>0.05) ,but there was a strong correlation between the expression of RRM1 and the response to chemotherapy(P=0.003) .Subjects with low RRM1 expression levels in peripheral blood had longer sur-vival time than those with high RRM1 expression levels(16.95 vs.12.76 months,log-rank 3.989,P=0.046) .However,no significant association between BRCA1 expression levels and survival time was found(16.80 vs.13.77 months,log-rank 0.830,P=0.362) .Conclusions:Patients with low RRM1 expression levels in peripheral blood have a greater response to chemotherapy and longer survival time.Advanced NSCLC patients with low RRM1 expression levels may benefit from gemcitabine plus platinum therapy.RRM1 mRNA expression in peripheral blood could be used to predict the prognosis of NSCLC treated by gemcitabine and platinum.展开更多
Fluorodeoxyglucose positron emission tomography/conlputed tomography （FDG PET/CT） is widely applied in non-small cell lung cancer （NSCLC）. The standardized uptake value （SUV）, a semi-quantitative index, plays an...Fluorodeoxyglucose positron emission tomography/conlputed tomography （FDG PET/CT） is widely applied in non-small cell lung cancer （NSCLC）. The standardized uptake value （SUV）, a semi-quantitative index, plays an essential role in NSCLC tbr diagnosis, staging, and efficacy evaklation. It has been px3posed that the SUV of tumors may correlate with the presence or absence of chemotherapy resistance-associated biomarkers based on studies that have displayed a close correlation between SUV and the expression levels of excision repair cross-complementary Group 1 （ERCC 1 ）1~1 and Tp53-induced glycolysis and apoptosis regulator.121 FDG avidity of NSCLC and ERCC 1 and ribonucleotide reductase subunit M 1 （RRM 1 ） levels have not been as extensively investigated. Based on these findings, we looked tbr correlations among metabolic parameters （SUVm,,. metabolic tumor volume [MTV], and total lesion glycolysis [TLG]） and ERCC1 and RRM1 expression in patients with NSCLC, to investigate whether FDG uptake reflects the presence or absence ofchemoresistance proteins （ERCC1 and RRM 1 ） within tumor cells.展开更多
Aim:Gemcitabine is a frontline agent for locally-advanced and metastatic pancreatic ductal adenocarcinoma(PDAC),but neither gemcitabine alone nor in combination produces durable remissions of this tumor type.We develo...Aim:Gemcitabine is a frontline agent for locally-advanced and metastatic pancreatic ductal adenocarcinoma(PDAC),but neither gemcitabine alone nor in combination produces durable remissions of this tumor type.We developed three PDAC patient-derived xenograft(PDX)models with gemcitabine resistance(gemR)acquired in vivo,with which to identify mechanisms of resistance relevant to drug exposure in vivo and to evaluate novel therapies.Methods:Mice bearing independently-derived PDXs received 100 mg/kg gemcitabine once or twice weekly.Tumors initially responded,but regrew on treatment and were designated gemR.We used immunohistochemistry to compare expression of proteins previously associated with gemcitabine resistance[ribonucleotide reductase subunit M1(RRM1),RRM2,human concentrative nucleoside transporter 1(hCNT1),human equilibrative nucleoside transporter 1(hENT1),cytidine deaminase(CDA),and deoxycytidine kinase(dCK)]in gemR and respective gemcitabine-naïve parental tumors.Results:Parental and gemR tumors did not differ in tumor cell morphology,amount of tumor-associated stroma,or expression of stem cell markers.No consistent pattern of expression of the six gemR marker proteins was observed among the models.Increases in RRM1 and CDA were consistent with in vitro-derived gemR models.However,rather than the expected decreases of hCNT1,hENT1,and dCK,gemR tumors expressed no change in or higher levels of these gemR marker proteins than parental tumors.Conclusion:These models are the first PDAC PDX models with gemcitabine resistance acquired in vivo.The data indicate that mechanisms identified in models with resistance acquired in vitro are unlikely to be the predominant mechanisms when resistance is acquired in vivo.Ongoing work focuses on characterizing unidentified mechanisms of gemR and on identifying agents with anti-tumor efficacy in these gemR models。展开更多
基金Project supported by the Science and Technology Planning Project of Zhejiang Province(No.2009C33165)the Medical Science Research Fund Scheme of Zhejiang Province(No.2008A060),China
文摘Objective:To evaluate the predictive values of gene expressions of ribonucleotide reductase M1(RRM1) and breast cancer susceptibility gene 1(BRCA1) in peripheral blood from Chinese patients with non-small-cell lung cancer(NSCLC) treated with gemcitabine plus platinum.Methods:Forty Chinese patients with advanced NSCLC were recruited and received gemcitabine 1200 mg/m 2 on Days 1 and 8 plus carboplatin AUC 5 on Day 1.RRM1 and BRCA1 expression levels in peripheral blood were detected by quantitative reverse transcription-polymerase chain reaction(RT-PCR) .Kaplan-Meier survival curve and log-rank test were performed to evaluate the correlation between gene expression and overall survival for these subjects.Results:No correlation was observed between gene expression of RRM1 and that of BRCA1(P>0.05) ,but there was a strong correlation between the expression of RRM1 and the response to chemotherapy(P=0.003) .Subjects with low RRM1 expression levels in peripheral blood had longer sur-vival time than those with high RRM1 expression levels(16.95 vs.12.76 months,log-rank 3.989,P=0.046) .However,no significant association between BRCA1 expression levels and survival time was found(16.80 vs.13.77 months,log-rank 0.830,P=0.362) .Conclusions:Patients with low RRM1 expression levels in peripheral blood have a greater response to chemotherapy and longer survival time.Advanced NSCLC patients with low RRM1 expression levels may benefit from gemcitabine plus platinum therapy.RRM1 mRNA expression in peripheral blood could be used to predict the prognosis of NSCLC treated by gemcitabine and platinum.
文摘Fluorodeoxyglucose positron emission tomography/conlputed tomography （FDG PET/CT） is widely applied in non-small cell lung cancer （NSCLC）. The standardized uptake value （SUV）, a semi-quantitative index, plays an essential role in NSCLC tbr diagnosis, staging, and efficacy evaklation. It has been px3posed that the SUV of tumors may correlate with the presence or absence of chemotherapy resistance-associated biomarkers based on studies that have displayed a close correlation between SUV and the expression levels of excision repair cross-complementary Group 1 （ERCC 1 ）1~1 and Tp53-induced glycolysis and apoptosis regulator.121 FDG avidity of NSCLC and ERCC 1 and ribonucleotide reductase subunit M 1 （RRM 1 ） levels have not been as extensively investigated. Based on these findings, we looked tbr correlations among metabolic parameters （SUVm,,. metabolic tumor volume [MTV], and total lesion glycolysis [TLG]） and ERCC1 and RRM1 expression in patients with NSCLC, to investigate whether FDG uptake reflects the presence or absence ofchemoresistance proteins （ERCC1 and RRM 1 ） within tumor cells.
文摘Aim:Gemcitabine is a frontline agent for locally-advanced and metastatic pancreatic ductal adenocarcinoma(PDAC),but neither gemcitabine alone nor in combination produces durable remissions of this tumor type.We developed three PDAC patient-derived xenograft(PDX)models with gemcitabine resistance(gemR)acquired in vivo,with which to identify mechanisms of resistance relevant to drug exposure in vivo and to evaluate novel therapies.Methods:Mice bearing independently-derived PDXs received 100 mg/kg gemcitabine once or twice weekly.Tumors initially responded,but regrew on treatment and were designated gemR.We used immunohistochemistry to compare expression of proteins previously associated with gemcitabine resistance[ribonucleotide reductase subunit M1(RRM1),RRM2,human concentrative nucleoside transporter 1(hCNT1),human equilibrative nucleoside transporter 1(hENT1),cytidine deaminase(CDA),and deoxycytidine kinase(dCK)]in gemR and respective gemcitabine-naïve parental tumors.Results:Parental and gemR tumors did not differ in tumor cell morphology,amount of tumor-associated stroma,or expression of stem cell markers.No consistent pattern of expression of the six gemR marker proteins was observed among the models.Increases in RRM1 and CDA were consistent with in vitro-derived gemR models.However,rather than the expected decreases of hCNT1,hENT1,and dCK,gemR tumors expressed no change in or higher levels of these gemR marker proteins than parental tumors.Conclusion:These models are the first PDAC PDX models with gemcitabine resistance acquired in vivo.The data indicate that mechanisms identified in models with resistance acquired in vitro are unlikely to be the predominant mechanisms when resistance is acquired in vivo.Ongoing work focuses on characterizing unidentified mechanisms of gemR and on identifying agents with anti-tumor efficacy in these gemR models。
