Objective： Experimental evidence suggests that the overexpression of breast cancer-specific tumor suppressor protein 1 （BRCA1） gene enhances sensitivity to docetaxel and resistance to cisplatin and ribonucleotide r...Objective： Experimental evidence suggests that the overexpression of breast cancer-specific tumor suppressor protein 1 （BRCA1） gene enhances sensitivity to docetaxel and resistance to cisplatin and ribonucleotide reductase M1 （RRM1） gene overexpression enhances resistance to gemcitabine. To further examine the effect of BRCA1 and RRM1 mRNA levels on outcome in advanced non-small cell lung cancer （NSCLC）, we performed this non-randomized phase II clinical trial which tested the hypothesis that customized therapy would confer improved outcome over non-customized therapy. Methods： RNA was isolated from fresh tumor tissue. Patients received chemotherapy regimen based on their BRCA1 and RRM1 mRNA levels： both low-cisplatin plus gemcitabine （GP）; both high-vinorelbine plus cisplatin （NP）; BRCA1 low and RRM1 high-cisplatin plus docetaxel （TP）; BRCA1 high and RRM1 low-vinorelbine plus gemcitabine （GN）. Results： From Dec 2005 to Nov 2008, 94 metastatic and locally advanced NSCLC patients from our institute were enrolled in this study. The median age was 58 years old. Among them, 21 patients received GP, 30 patients received TP and 43 patients received NP chemotherapy. GP group had a higher response rate, and longer median time to progression （TTP） and median overall survival （OS） time than the other 2 groups. The response rates in the GP, TP and NP groups were 42.9%, 36.7% and 27.9%, respectively （P=0.568）. The median TTP was 5.6, 5.0, 4.8 months （P=0.975）, respectively, and the median OS time was 12.5, 11.0, 9.7 months （P=0.808）, respectively. Conclusion： Chemotherapy customized according to BRCA1 and RRM1 expression levels is associated with higher response rate and longer TTP and OS time in the GP group. This suggests that BRCA1 and RRM1 mRNA levels could be used as biomarkers in individual therapy in NSCLC.展开更多
乳腺癌是女性最常见的恶性肿瘤之一,在全球范围内,发病率呈逐年上升的趋势,在国内多个大中城市中,它已成为威胁女性健康的恶性肿瘤首位死因。BRCA1（breast cancer sus-ceptibility gene 1）是遗传性乳腺癌和卵巢癌的易感基因,Miki等[1]...乳腺癌是女性最常见的恶性肿瘤之一,在全球范围内,发病率呈逐年上升的趋势,在国内多个大中城市中,它已成为威胁女性健康的恶性肿瘤首位死因。BRCA1（breast cancer sus-ceptibility gene 1）是遗传性乳腺癌和卵巢癌的易感基因,Miki等[1]在1994年首次成功地将其定位和分离。经过国内外学者大量的研究发现，BRCAI的基因结构和功能异常与乳腺癌的发生发展有着密切的关系，可作为一种肿瘤抑制因子而发挥作用，是目前发现的与乳腺癌发生相关的关键的抑癌基因。展开更多
The BRCA1 （Breast Cancer Anti-estrogen resistance-I）, early-onset gene is expressed in cells of breast and other tissue and helps to repair damaged DNA or destroy cells in cases DNA cannot be repaired. When the BRCA...The BRCA1 （Breast Cancer Anti-estrogen resistance-I）, early-onset gene is expressed in cells of breast and other tissue and helps to repair damaged DNA or destroy cells in cases DNA cannot be repaired. When the BRCA1 gene is damaged, then the DNA is not repaired appropriately and this enhances the risk for cancer. Fluorescence and UV-visible thermal studies were performed for WT （wild type） and MT （mutant type targets） full systems. The target DNAs used were in the form of short oligonucleotides, genomic DNA. The probe system was used for detection of WT and SNP alleles of human BRCAI [（170-190, G---~T） and （290-310, G---~T）]. The Cy5 dye attached to a probe oligonucleotide （10-mer） undergoes a fluorescence intensity change on hybridisation of the probe to the WT compared to MT targets. Our results indicate that the system consisting of the target sequence and the one probe oligonucleotides bearing the Cy5 dye assemble correctly at the specified target. Once the full system （probe and target） is arranged under suitable conditions, a red-shift emission and change in fluorescence intensity are seen at a suitable wavelength. Thermal studies also showed significant differences in T,, between WT and MT. The results suggest that the differences in the fluorescence intensity at 665 nm and the spectrophotometric T,,,cs） for the WT and MT can be attributed to the type of binding of the probe to the target. The systems were sensitive to single nucleotide polymorphisms and this may help in high throughput applications in genetic testing and molecular diagnostics.展开更多
基金supported by grants from the key project of the Science and Technology Commission of Shanghai Municipality (No.06DZ19502)the project of the Science and Technology Commission of Shanghai Municipality (04DZ19109)
文摘Objective： Experimental evidence suggests that the overexpression of breast cancer-specific tumor suppressor protein 1 （BRCA1） gene enhances sensitivity to docetaxel and resistance to cisplatin and ribonucleotide reductase M1 （RRM1） gene overexpression enhances resistance to gemcitabine. To further examine the effect of BRCA1 and RRM1 mRNA levels on outcome in advanced non-small cell lung cancer （NSCLC）, we performed this non-randomized phase II clinical trial which tested the hypothesis that customized therapy would confer improved outcome over non-customized therapy. Methods： RNA was isolated from fresh tumor tissue. Patients received chemotherapy regimen based on their BRCA1 and RRM1 mRNA levels： both low-cisplatin plus gemcitabine （GP）; both high-vinorelbine plus cisplatin （NP）; BRCA1 low and RRM1 high-cisplatin plus docetaxel （TP）; BRCA1 high and RRM1 low-vinorelbine plus gemcitabine （GN）. Results： From Dec 2005 to Nov 2008, 94 metastatic and locally advanced NSCLC patients from our institute were enrolled in this study. The median age was 58 years old. Among them, 21 patients received GP, 30 patients received TP and 43 patients received NP chemotherapy. GP group had a higher response rate, and longer median time to progression （TTP） and median overall survival （OS） time than the other 2 groups. The response rates in the GP, TP and NP groups were 42.9%, 36.7% and 27.9%, respectively （P=0.568）. The median TTP was 5.6, 5.0, 4.8 months （P=0.975）, respectively, and the median OS time was 12.5, 11.0, 9.7 months （P=0.808）, respectively. Conclusion： Chemotherapy customized according to BRCA1 and RRM1 expression levels is associated with higher response rate and longer TTP and OS time in the GP group. This suggests that BRCA1 and RRM1 mRNA levels could be used as biomarkers in individual therapy in NSCLC.
文摘乳腺癌是女性最常见的恶性肿瘤之一,在全球范围内,发病率呈逐年上升的趋势,在国内多个大中城市中,它已成为威胁女性健康的恶性肿瘤首位死因。BRCA1（breast cancer sus-ceptibility gene 1）是遗传性乳腺癌和卵巢癌的易感基因,Miki等[1]在1994年首次成功地将其定位和分离。经过国内外学者大量的研究发现，BRCAI的基因结构和功能异常与乳腺癌的发生发展有着密切的关系，可作为一种肿瘤抑制因子而发挥作用，是目前发现的与乳腺癌发生相关的关键的抑癌基因。
文摘The BRCA1 （Breast Cancer Anti-estrogen resistance-I）, early-onset gene is expressed in cells of breast and other tissue and helps to repair damaged DNA or destroy cells in cases DNA cannot be repaired. When the BRCA1 gene is damaged, then the DNA is not repaired appropriately and this enhances the risk for cancer. Fluorescence and UV-visible thermal studies were performed for WT （wild type） and MT （mutant type targets） full systems. The target DNAs used were in the form of short oligonucleotides, genomic DNA. The probe system was used for detection of WT and SNP alleles of human BRCAI [（170-190, G---~T） and （290-310, G---~T）]. The Cy5 dye attached to a probe oligonucleotide （10-mer） undergoes a fluorescence intensity change on hybridisation of the probe to the WT compared to MT targets. Our results indicate that the system consisting of the target sequence and the one probe oligonucleotides bearing the Cy5 dye assemble correctly at the specified target. Once the full system （probe and target） is arranged under suitable conditions, a red-shift emission and change in fluorescence intensity are seen at a suitable wavelength. Thermal studies also showed significant differences in T,, between WT and MT. The results suggest that the differences in the fluorescence intensity at 665 nm and the spectrophotometric T,,,cs） for the WT and MT can be attributed to the type of binding of the probe to the target. The systems were sensitive to single nucleotide polymorphisms and this may help in high throughput applications in genetic testing and molecular diagnostics.
