胃癌铂类疗效预测分子的研究及重楼复方对化疗相关基因表达的调节作用
|
摘要
[目的]探讨铂类化疗药物相关基因在胃癌含奥沙利铂辅助化疗中的疗效预测价值以及重楼复方(Chong Lou Fu Fang,CLFF)与胃癌常用化疗药物体外协同抗肿瘤作用。
[方法]荧光定量RT-PCR法测定化疗药物相关基因表达水平；采用TaqMan探针real-timePCR方法和直接测序法对ERCC1第118位密码子,XRCC1第399位密码子,XPD第751位密码子和GSTP1第105位密码子进行多态性分析；分析ERCC1基因表达水平及各基因型与接受含奥沙利铂方案辅助化疗的胃癌患者生存时间之间的关系。MTT法检测细胞增殖能力；基于中位效应原则的联合指数法评估重楼复方与各化疗药物对胃癌细胞系SGC-7901和BGC-823的交互作用；Annexin-V-FITC和PI双染色法检测细胞凋亡率。
[结果]
1、75例胃癌患者术后新鲜组织ERCC1基因表达水平检测结果显示中位值为7.32(0.50-147.03)；75例胃癌患者中52例接受术后改良FOLFOX4方案辅助化疗至少6周期,23例只接受手术治疗。单因素分析提示在辅助化疗组中,ERCC1低表达患者较高表达患者RFS和OS均显著延长(中位RFS分别为18和7月,P=0.001;中位OS分别为27和11月,P=0.001),在单纯手术组中,ERCC1高表达患者较低表达患者RFS和OS均显著延长(中位RFS分别为33和12月,P=0.038；中位OS分别为43和21月,P=0.004)；多因素Cox风险模型分析提示在含奥沙利铂辅助化疗组中,肿瘤组织ERCC1高表达可能是RFS和OS的不良预后因素,但在单纯手术组中,肿瘤组织ERCC1高表达却可能是OS的良好预后因素。
2、126例接受术后改良FOLFOX4方案辅助化疗的胃癌患者基因型分析显示野生纯合子,杂合子和突变纯合子频率在ERCC1-118中为64.29%,28.57%和7.14%；在XRCC1-399中为56.35%,38.89%,和4.76%；在XPD-751中为84.92%,15.08%和0,以及在GSTP1-105中为68.25%,30.60%和3.97%。单因素分析显示ERCC1-118,XRCC1-399和GSTP1-105单核苷酸多态性对患者无复发生存时间和总生存时间均有预测价值。就无复发生存时间而言，ERCC1-118T/T和C/T基因型患者中位生存时间为5个月,C/C基因型患者为45个月；XRCC1-399 A/A和A/G基因型患者M-RFS为47个月,G/G基因型患者为8个月;GSTP1-105 G/G和A/G基因型患者M-RFS为47个月,A/A基因型患者为12个月。就总生存时间而言,ERCC1-118T/T和C/T基因型患者中位生存时间(MST)为15个月,C/C基因型患者中位生存时间不能确定；XRCC1-399A/A和A/G基因型患者中位生存时间不能确定,G/G基因型患者MST为18个月；GSTP1-105 G/G和A/G基因型患者MST尚不能确定,A/A基因型患者为21个月。多因素Cox风险模型分析提示ERCC1-118基因型对无复发生存时间(P<0.001,HR=2.362；CI95%：1.458-3.827)和总生存时间(P=0.001；HR=2.388；CI 95%：1.448-3.937)均具有预测价值,而XRCC1-399基因型仅对无复发生存时间有预测价值,XRCC1-399 A/A和A/G基因型患者疾病复发风险显著降低(P=0.031；HR=0.569；CI 95%：0.341-0.949)。
3、重楼复方与5-FU在较宽抑制率范围内产生协同抗肿瘤作用(在SGC-7901细胞系中为20-95%抑制率范围,在BGC-823细胞中为5-65%抑制率范围),而与奥沙利铂和多西紫杉醇均在低浓度范围内产生协同抗肿瘤作用(两株细胞中均在<50%的抑制率范围内),联合指数<1。
4、凋亡分析显示重楼复方与各药以协同作用方式诱导肿瘤细胞凋亡。CLFF,5-氟尿嘧啶,奥沙利铂和多西紫杉醇单药作用48h后细胞凋亡率在SGC-7901细胞中分别为(8.4±6.8),(24.6±4.6),(9.7±3.7)和(29.6±5.9)%,在BGC-823细胞中分别为(6.7±1.7),(12.6±3.8),(11.3±1.3)和(6.6±1.2)%。CLFF与5-氟尿嘧啶,奥沙利铂和多西紫杉醇联合作用48h后细胞凋亡率在SGC-7901细胞中分别为(80.5±12.9),(32.5±5.7)和(63.2±6.2)%,在BGC-823细胞中分别为(66.1±6.4),(48.6±3.1)和(33.5±9.6)%。
5、重楼复方单独或分别与5-FU、奥沙利铂和多西紫杉醇联合作用后,SGC-7901和BGC-823细胞中化疗药物相关基因TS、ERCC1 (Excision repair cross-complementation 1)、β-tublinⅢ和Tau mRNA表达水平均显著下调,而化疗药单药不能下调化疗相关基因表达水平。重楼复方单独作用24小时后,上述各基因表达水平在SGC-7901细胞系中下调至(0.30±0.03)、(0.32±0.02)、(0.31±0.03)和(0.28±0.02)倍,在BGC-823细胞中下调至(0.46±0.03)、(0.46±0.02)、(0.44±0.04)和(0.56±0.07)倍。重楼复方分别联合5-FU、奥沙利铂和多西紫杉醇作用24h后,上述各基因表达水平在SGC-7901细胞系中下调至(0.55±0.02)、(0.48±0.03)、(0.59±0.04)和(0.43±0.02)倍,在BGC-823细胞中下调至(0.64±0.04)、(0.55±0.03)、(0.51±0.04)和(0.62±0.06)倍。
[结论]①肿瘤组织ERCC1低表达胃癌患者接受含奥沙利铂方案辅助化疗生存可能获益,但是ERCC1高表达可能是单纯手术患者的良好预后因子。②外周血ERCC1-118C/C基因型(野生型)和XRCC1-399A/G或G/G基因型(突变型)胃癌患者接受含奥沙利铂方案辅助化疗生存可能获益；③XRCC1-399和GSTP1-105基因多态性可能与含奥沙利铂方案化疗毒副反应相关；④重楼复方与5-氟尿嘧啶,奥沙利铂和多西紫杉醇有较好的体外协同抗肿瘤作用,可能与该复方与各化疗药协同诱导肿瘤细胞凋亡以及下调化疗相关基因表达水平有关。
[Objective] To explore the predictive values of platinum-related genes in gastric cancer treated with oxaliplatin-based chemotherapy and to explore the potentially synergistic effects of "Chong Lou Fu Fang" (CLFF) with chemotherapeutic agents commonly used in gastric cancer therapy in vitro.
[Methods] Expression of chemotherapeutic agents associated genes was measured by real time quantitative PCR. SNPs in ERCC1 Asp118Asp, XRCC1 Arg399Gln, XPD Lys751Gln and GSTP1 Ile105Val were assessed by 5'nuclease allelic discrimination assay (TaqMan) using real-time PCR and direct sequencing, The expression levels of ERCC1 and the genotypes of ERCC1 Asp118Asp, XRCC1 Arg399Gln, XPD Lys751Gln and GSTP1 Ile105Val were tested for an association with survivals in gastric cancer patients treated with oxaliplatin-based adjuvant chemotherapy regimen.The cell proliferation capacity was determined by the MTT assay. Interaction between CLFF and chemotherapeutic agents in human gastric cancer SGC-7901 and BGC-823 cell lines was evaluated using the combination index (CI) method based on the median-effect principle. Apoptosis rates of cancer cells were evaluated by means of flow cytometry.
[Results]
1. The ERCC1 expression analysis in all 75 patients indicated that the median value for ERCC1 was 7.32(range 0.50-147.03).Among 75 patients,52 cases received surgery followed by at least 6 cycles modified FOLFOX4 adjuvant chemotherapy, and 23 cases received surgery alone. Univariate analysis suggested that low ERCC1 levels had longer RFS and OS than those with high ERCC1 levels (median RFS,18 versus 7 months, P=0.001; MST,27 versus 11 months, P =0.001) in group received adjuvant chemotherapy, and high ERCC1 levels had longer RFS and OS than those with low ERCC1 levels (median RFS,33 versus 12 months, P=0.038; MST,43 versus 21 months, P=0.004) in group received surgery alone. Cox proportional hazards regression model multivariable analysis suggested that high ERCC1 expression is an independent prognostic marker of poor RFS (hazard ratio 2.16,95% confidence interval 1.09-4.25, P=0.026) and OS (hazard ratio 2.21,95% confidence interval 1.07-4.55, P=0.031) in oxaliplatin-based adjuvant settings, but remained significantly positive prognostic marker for OS (hazard ratio 0.17,95% confidence interval 0.04-0.71, P=0.015) in patients receiving surgery alone.
2.The genotype analysis in 126 gaseric cancer patients who received at least 6 cycles modified FOLFOX4 adjuvant chemotherapy indicated the frequencies for the homozygous wildtype allele, heterozygous and homozygous polymorphic variant:64.29%,28.57%, and 7.14% for ERCC1-118; 56.35%,38.89%, and 4.76% for XRCC1-399; 84.92%,15.08%,and 0 for XPD-751; and 68.25%,30.60%,and 3.97% for GSTP1-105. Univariate analysis indicated that the ERCC1-118, the XRCC1-399 and the GSTP1-105 SNPs showed the predictive values for RFS and OS. With regard to RFS, for ERCC1-118, the median RFS was 5 months for T/T and C/T cases and 45 months for C/C patients (P<0.001). For XRCC1-399, the median RFS was 47 months for A/A and A/G cases and 8 months for G/G patients (P=0.001), and For GSTP1-105, the median RFS was 47 months for G/G and A/G cases and 12 months for A/A patients (P<0.001). As for OS, the ERCC1-118, the XRCC1-399 and the GSTP1-105 SNPs also remained significant predictive value. For ERCC1-118, the MST was 15 months for T/T and C/T patients and no defined for C/C cases (P<0.001). For the XRCC1-399, the MST was 18 months for A/A patients and no defined for A/A and A/G patients P<0.001), and For GSTP1-105, the MST was no defined for G/G and A/G cases and 21 months for A/A patients (P=0.019). Cox proportional hazards regression model multivariable analysis suggested ERCC1-118 remained significant predictive value for RFS (P<0.001, HR=2.362; CI 95%:1.458-3.827) and OS (P=0.001; HR=2.388;CI 95%:1.448-3.937), and XRCC1-399 only remained significant predictive value for RFS, and XRCC1-399 (A/A+A/G) genotype could significantly decrease the recurrence hazard of the patients (P<0.001, HR=0.569; CI 95%:0.341-0.949).
3.The synergistic analysis indicated that CLFF had a synergistic effect on the cytotoxicity of 5-fluorouracil (5-FU) in a relative broad dose inhibition range (20-95% fraction affected in SGC-7901 cell lines and 5-65% fraction affected in BGC-823 cell lines), while the synergistic interaction between CLFF and oxaliplatin or docetaxel only existed in a low dose inhibition range (<50% fraction affected in both cell lines), CIs<1.
4. The apoptosis analysis indicated the combination of CLFF and 5-fluorouracil, oxaliplatin or docetaxel could also induce apoptosis in a synergistic manner. The percentages of the apoptotic cells (early apoptosis plus late apoptosis) induced by CLFF and 5-fluorouracil、oxaliplatin and docetaxel were (8.4+6.8)%, (24.6+4.6)%(9.7+3.7)%and (29.5+5.9)%in SGC-7901 cell lines and (6.7+1.4)%, (12.6+3.8)%(11.6+1.3)%, (6.6+1.2)%in BGC-823 cell lines, while the percentage of them induced by drug combination in both cell lines were increased to (80.5+12.9)%, (32.5+5.7)%and (63.2+6.2)%in SGC-7901 cells, respectively, and (66.1+6.4)%, (48.6+3.1)%and (33.5+9.6)%in BGC-823 cells, respectively.
5.The expression levels of ERCC1, TS, b-tubulinⅢand tau were significantly down-regulated after treatment with CLFF alone or CLFF combined with chemotherapeutic agents in SGC-7901 cell lines and BGC-823 cell lines. However, any of chemotherapeutic agents alone did not down-regulate their respective drug resistance-associated genes. TS、ERCC1、β-tublinⅢand Tau mRNA levels were markedly suppressed at (0.32±0.02)、(0.30±0.03)、(0.31±0.03)and (0.28±0.02) fold in SGC-7901 cell lines, respectively, and 0.46±0.03)、(0.46±0.02)、(0.44±0.04) and (0.56±0.07)fold in BGC-823 cell lines, respectively, by the presentation of CLFF for 24 h.At the same time, we found that the combination of CLFF and 5-FU, oxaliplatin and docetaxel for 24 h could downregulat the TS、ERCC1、β-tublinⅢand Tau mRNA levels to (0.55±0.02)、(0.48±0.03)、(0.59±0.04) and (0.43±0.02) fold in SGC-7901 cell lines, respectively, and (0.64±0.04)、(0.55±0.03)、(0.51±0.04) and (0.62±0.06) fold in BGC-823 cell lines, respectively.
[Conclusion] It seemed that gastric cancer patients with low levels of ERCC1 expression showed a great benefit from oxaliplatin-based adjuvant chemotherapy, while high levels of ERCC1 expression might be a positive prognostic marker for patients receiving surgery alone.On the other hand, gastric cancer patients harboring ERCC1-118C/C genotype and XRCC1-399A/G or G/G genotypes may better receive oxaliplatin-based adjuvant chemotherapy. XRCC1-399 and GSTP1-105 polymorph-isms may be associated with the toxicities of the oxaliplatin-based chemotherapy regimen.The combination of CLFF and 5-fluorouracil, oxaliplatin or docetaxel showed significant synergistic antitumor activity in both two gastric cancer cell lines. The possible mechanisms might be the synergistic apoptotic effect and the down-regulation of chemotherapeutic agents associated genes.
[方法]荧光定量RT-PCR法测定化疗药物相关基因表达水平；采用TaqMan探针real-timePCR方法和直接测序法对ERCC1第118位密码子,XRCC1第399位密码子,XPD第751位密码子和GSTP1第105位密码子进行多态性分析；分析ERCC1基因表达水平及各基因型与接受含奥沙利铂方案辅助化疗的胃癌患者生存时间之间的关系。MTT法检测细胞增殖能力；基于中位效应原则的联合指数法评估重楼复方与各化疗药物对胃癌细胞系SGC-7901和BGC-823的交互作用；Annexin-V-FITC和PI双染色法检测细胞凋亡率。
[结果]
1、75例胃癌患者术后新鲜组织ERCC1基因表达水平检测结果显示中位值为7.32(0.50-147.03)；75例胃癌患者中52例接受术后改良FOLFOX4方案辅助化疗至少6周期,23例只接受手术治疗。单因素分析提示在辅助化疗组中,ERCC1低表达患者较高表达患者RFS和OS均显著延长(中位RFS分别为18和7月,P=0.001;中位OS分别为27和11月,P=0.001),在单纯手术组中,ERCC1高表达患者较低表达患者RFS和OS均显著延长(中位RFS分别为33和12月,P=0.038；中位OS分别为43和21月,P=0.004)；多因素Cox风险模型分析提示在含奥沙利铂辅助化疗组中,肿瘤组织ERCC1高表达可能是RFS和OS的不良预后因素,但在单纯手术组中,肿瘤组织ERCC1高表达却可能是OS的良好预后因素。
2、126例接受术后改良FOLFOX4方案辅助化疗的胃癌患者基因型分析显示野生纯合子,杂合子和突变纯合子频率在ERCC1-118中为64.29%,28.57%和7.14%；在XRCC1-399中为56.35%,38.89%,和4.76%；在XPD-751中为84.92%,15.08%和0,以及在GSTP1-105中为68.25%,30.60%和3.97%。单因素分析显示ERCC1-118,XRCC1-399和GSTP1-105单核苷酸多态性对患者无复发生存时间和总生存时间均有预测价值。就无复发生存时间而言，ERCC1-118T/T和C/T基因型患者中位生存时间为5个月,C/C基因型患者为45个月；XRCC1-399 A/A和A/G基因型患者M-RFS为47个月,G/G基因型患者为8个月;GSTP1-105 G/G和A/G基因型患者M-RFS为47个月,A/A基因型患者为12个月。就总生存时间而言,ERCC1-118T/T和C/T基因型患者中位生存时间(MST)为15个月,C/C基因型患者中位生存时间不能确定；XRCC1-399A/A和A/G基因型患者中位生存时间不能确定,G/G基因型患者MST为18个月；GSTP1-105 G/G和A/G基因型患者MST尚不能确定,A/A基因型患者为21个月。多因素Cox风险模型分析提示ERCC1-118基因型对无复发生存时间(P<0.001,HR=2.362；CI95%：1.458-3.827)和总生存时间(P=0.001；HR=2.388；CI 95%：1.448-3.937)均具有预测价值,而XRCC1-399基因型仅对无复发生存时间有预测价值,XRCC1-399 A/A和A/G基因型患者疾病复发风险显著降低(P=0.031；HR=0.569；CI 95%：0.341-0.949)。
3、重楼复方与5-FU在较宽抑制率范围内产生协同抗肿瘤作用(在SGC-7901细胞系中为20-95%抑制率范围,在BGC-823细胞中为5-65%抑制率范围),而与奥沙利铂和多西紫杉醇均在低浓度范围内产生协同抗肿瘤作用(两株细胞中均在<50%的抑制率范围内),联合指数<1。
4、凋亡分析显示重楼复方与各药以协同作用方式诱导肿瘤细胞凋亡。CLFF,5-氟尿嘧啶,奥沙利铂和多西紫杉醇单药作用48h后细胞凋亡率在SGC-7901细胞中分别为(8.4±6.8),(24.6±4.6),(9.7±3.7)和(29.6±5.9)%,在BGC-823细胞中分别为(6.7±1.7),(12.6±3.8),(11.3±1.3)和(6.6±1.2)%。CLFF与5-氟尿嘧啶,奥沙利铂和多西紫杉醇联合作用48h后细胞凋亡率在SGC-7901细胞中分别为(80.5±12.9),(32.5±5.7)和(63.2±6.2)%,在BGC-823细胞中分别为(66.1±6.4),(48.6±3.1)和(33.5±9.6)%。
5、重楼复方单独或分别与5-FU、奥沙利铂和多西紫杉醇联合作用后,SGC-7901和BGC-823细胞中化疗药物相关基因TS、ERCC1 (Excision repair cross-complementation 1)、β-tublinⅢ和Tau mRNA表达水平均显著下调,而化疗药单药不能下调化疗相关基因表达水平。重楼复方单独作用24小时后,上述各基因表达水平在SGC-7901细胞系中下调至(0.30±0.03)、(0.32±0.02)、(0.31±0.03)和(0.28±0.02)倍,在BGC-823细胞中下调至(0.46±0.03)、(0.46±0.02)、(0.44±0.04)和(0.56±0.07)倍。重楼复方分别联合5-FU、奥沙利铂和多西紫杉醇作用24h后,上述各基因表达水平在SGC-7901细胞系中下调至(0.55±0.02)、(0.48±0.03)、(0.59±0.04)和(0.43±0.02)倍,在BGC-823细胞中下调至(0.64±0.04)、(0.55±0.03)、(0.51±0.04)和(0.62±0.06)倍。
[结论]①肿瘤组织ERCC1低表达胃癌患者接受含奥沙利铂方案辅助化疗生存可能获益,但是ERCC1高表达可能是单纯手术患者的良好预后因子。②外周血ERCC1-118C/C基因型(野生型)和XRCC1-399A/G或G/G基因型(突变型)胃癌患者接受含奥沙利铂方案辅助化疗生存可能获益；③XRCC1-399和GSTP1-105基因多态性可能与含奥沙利铂方案化疗毒副反应相关；④重楼复方与5-氟尿嘧啶,奥沙利铂和多西紫杉醇有较好的体外协同抗肿瘤作用,可能与该复方与各化疗药协同诱导肿瘤细胞凋亡以及下调化疗相关基因表达水平有关。
[Objective] To explore the predictive values of platinum-related genes in gastric cancer treated with oxaliplatin-based chemotherapy and to explore the potentially synergistic effects of "Chong Lou Fu Fang" (CLFF) with chemotherapeutic agents commonly used in gastric cancer therapy in vitro.
[Methods] Expression of chemotherapeutic agents associated genes was measured by real time quantitative PCR. SNPs in ERCC1 Asp118Asp, XRCC1 Arg399Gln, XPD Lys751Gln and GSTP1 Ile105Val were assessed by 5'nuclease allelic discrimination assay (TaqMan) using real-time PCR and direct sequencing, The expression levels of ERCC1 and the genotypes of ERCC1 Asp118Asp, XRCC1 Arg399Gln, XPD Lys751Gln and GSTP1 Ile105Val were tested for an association with survivals in gastric cancer patients treated with oxaliplatin-based adjuvant chemotherapy regimen.The cell proliferation capacity was determined by the MTT assay. Interaction between CLFF and chemotherapeutic agents in human gastric cancer SGC-7901 and BGC-823 cell lines was evaluated using the combination index (CI) method based on the median-effect principle. Apoptosis rates of cancer cells were evaluated by means of flow cytometry.
[Results]
1. The ERCC1 expression analysis in all 75 patients indicated that the median value for ERCC1 was 7.32(range 0.50-147.03).Among 75 patients,52 cases received surgery followed by at least 6 cycles modified FOLFOX4 adjuvant chemotherapy, and 23 cases received surgery alone. Univariate analysis suggested that low ERCC1 levels had longer RFS and OS than those with high ERCC1 levels (median RFS,18 versus 7 months, P=0.001; MST,27 versus 11 months, P =0.001) in group received adjuvant chemotherapy, and high ERCC1 levels had longer RFS and OS than those with low ERCC1 levels (median RFS,33 versus 12 months, P=0.038; MST,43 versus 21 months, P=0.004) in group received surgery alone. Cox proportional hazards regression model multivariable analysis suggested that high ERCC1 expression is an independent prognostic marker of poor RFS (hazard ratio 2.16,95% confidence interval 1.09-4.25, P=0.026) and OS (hazard ratio 2.21,95% confidence interval 1.07-4.55, P=0.031) in oxaliplatin-based adjuvant settings, but remained significantly positive prognostic marker for OS (hazard ratio 0.17,95% confidence interval 0.04-0.71, P=0.015) in patients receiving surgery alone.
2.The genotype analysis in 126 gaseric cancer patients who received at least 6 cycles modified FOLFOX4 adjuvant chemotherapy indicated the frequencies for the homozygous wildtype allele, heterozygous and homozygous polymorphic variant:64.29%,28.57%, and 7.14% for ERCC1-118; 56.35%,38.89%, and 4.76% for XRCC1-399; 84.92%,15.08%,and 0 for XPD-751; and 68.25%,30.60%,and 3.97% for GSTP1-105. Univariate analysis indicated that the ERCC1-118, the XRCC1-399 and the GSTP1-105 SNPs showed the predictive values for RFS and OS. With regard to RFS, for ERCC1-118, the median RFS was 5 months for T/T and C/T cases and 45 months for C/C patients (P<0.001). For XRCC1-399, the median RFS was 47 months for A/A and A/G cases and 8 months for G/G patients (P=0.001), and For GSTP1-105, the median RFS was 47 months for G/G and A/G cases and 12 months for A/A patients (P<0.001). As for OS, the ERCC1-118, the XRCC1-399 and the GSTP1-105 SNPs also remained significant predictive value. For ERCC1-118, the MST was 15 months for T/T and C/T patients and no defined for C/C cases (P<0.001). For the XRCC1-399, the MST was 18 months for A/A patients and no defined for A/A and A/G patients P<0.001), and For GSTP1-105, the MST was no defined for G/G and A/G cases and 21 months for A/A patients (P=0.019). Cox proportional hazards regression model multivariable analysis suggested ERCC1-118 remained significant predictive value for RFS (P<0.001, HR=2.362; CI 95%:1.458-3.827) and OS (P=0.001; HR=2.388;CI 95%:1.448-3.937), and XRCC1-399 only remained significant predictive value for RFS, and XRCC1-399 (A/A+A/G) genotype could significantly decrease the recurrence hazard of the patients (P<0.001, HR=0.569; CI 95%:0.341-0.949).
3.The synergistic analysis indicated that CLFF had a synergistic effect on the cytotoxicity of 5-fluorouracil (5-FU) in a relative broad dose inhibition range (20-95% fraction affected in SGC-7901 cell lines and 5-65% fraction affected in BGC-823 cell lines), while the synergistic interaction between CLFF and oxaliplatin or docetaxel only existed in a low dose inhibition range (<50% fraction affected in both cell lines), CIs<1.
4. The apoptosis analysis indicated the combination of CLFF and 5-fluorouracil, oxaliplatin or docetaxel could also induce apoptosis in a synergistic manner. The percentages of the apoptotic cells (early apoptosis plus late apoptosis) induced by CLFF and 5-fluorouracil、oxaliplatin and docetaxel were (8.4+6.8)%, (24.6+4.6)%(9.7+3.7)%and (29.5+5.9)%in SGC-7901 cell lines and (6.7+1.4)%, (12.6+3.8)%(11.6+1.3)%, (6.6+1.2)%in BGC-823 cell lines, while the percentage of them induced by drug combination in both cell lines were increased to (80.5+12.9)%, (32.5+5.7)%and (63.2+6.2)%in SGC-7901 cells, respectively, and (66.1+6.4)%, (48.6+3.1)%and (33.5+9.6)%in BGC-823 cells, respectively.
5.The expression levels of ERCC1, TS, b-tubulinⅢand tau were significantly down-regulated after treatment with CLFF alone or CLFF combined with chemotherapeutic agents in SGC-7901 cell lines and BGC-823 cell lines. However, any of chemotherapeutic agents alone did not down-regulate their respective drug resistance-associated genes. TS、ERCC1、β-tublinⅢand Tau mRNA levels were markedly suppressed at (0.32±0.02)、(0.30±0.03)、(0.31±0.03)and (0.28±0.02) fold in SGC-7901 cell lines, respectively, and 0.46±0.03)、(0.46±0.02)、(0.44±0.04) and (0.56±0.07)fold in BGC-823 cell lines, respectively, by the presentation of CLFF for 24 h.At the same time, we found that the combination of CLFF and 5-FU, oxaliplatin and docetaxel for 24 h could downregulat the TS、ERCC1、β-tublinⅢand Tau mRNA levels to (0.55±0.02)、(0.48±0.03)、(0.59±0.04) and (0.43±0.02) fold in SGC-7901 cell lines, respectively, and (0.64±0.04)、(0.55±0.03)、(0.51±0.04) and (0.62±0.06) fold in BGC-823 cell lines, respectively.
[Conclusion] It seemed that gastric cancer patients with low levels of ERCC1 expression showed a great benefit from oxaliplatin-based adjuvant chemotherapy, while high levels of ERCC1 expression might be a positive prognostic marker for patients receiving surgery alone.On the other hand, gastric cancer patients harboring ERCC1-118C/C genotype and XRCC1-399A/G or G/G genotypes may better receive oxaliplatin-based adjuvant chemotherapy. XRCC1-399 and GSTP1-105 polymorph-isms may be associated with the toxicities of the oxaliplatin-based chemotherapy regimen.The combination of CLFF and 5-fluorouracil, oxaliplatin or docetaxel showed significant synergistic antitumor activity in both two gastric cancer cell lines. The possible mechanisms might be the synergistic apoptotic effect and the down-regulation of chemotherapeutic agents associated genes.
引文
1.孙秀娣,牧人,周有尚,等.中国胃癌死亡率20年变化情况分析及其发展趋势预测[J].中华肿瘤杂志,2004,26(1)：4-8.
2. Wesolowski R;Is there a role for second-line chemotherapy in advanced gastric cancer [J]? Lancet Oncol.2009,10(9):903-912.
3. Overman MJ, Kazmi SM, Jhamb J, et al.Weekly docetaxel, cisplatin, and 5-fluorouracil as initial therapy for patients with advanced gastric and esophageal cancer[J]. Cancer.2010,116(6):1446-1453
4.Chon HJ, Rha SY, Im CK, et al.Docetaxel versus Paclitaxel Combined with 5-FU and Leucovorin in Advanced Gastric Cancer:Combined Analysis of Two Phase Ⅱ Trials[J].Cancer Res Treat.2009, 41(4):196-204.
5.Yamamoto K, Fujiwara Y, Nishida T, et al.Induction chemotherapy with docetaxel,5-FU and CDDP (DFP) for advanced gastric cancer[J].Anticancer Res.2009;29(10):4211-4215.
6.Louvet C, Andre T, Tigaud JM, et al. Phase Ⅱ study of oxaliplatin, fluorouracil, and folinic acid in locally advanced or metastatic gastric cancer patients [J]. J Clin Oncol 2002;20:4543-4548.
7.De Vita F, Orditura M, Matano E, et al.A phase Ⅱ study of biweekly oxaliplatin plus infusional 5-fluorouracil and folinic acid (FOLFOX-4) as first-line treatment of advanced gastric cancer patients [J]. Br J Cancer 2005; 92:1644-1649.
8.A1-Batran SE, Atmaca A, Hegewisch-Becker S, et al. Phase Ⅱ trial of biweekly infusional fluorouracil, folinic acid, and oxaliplatin in patients with advanced gastric cancer [J]. J Clin Oncol 2004;22:658-663.
9. Lordick F, Lorenzen S, Stollfuss J, et al. Phase Ⅱ study of weekly oxaliplatin plus infusional fluorouracil and folinic acid (FUFOX regimen) as first-line treatment in metastatic gastric cancer [J]. Br J Cancer 2005; 93:190-194.
10.Cavanna L, Artioli F, Codignola C, et al. Oxaliplatin in combination with 5-fluorouracil (5-FU) and leucovorin (LV) in patients with metastatic gastric cancer (MGC) [J]. Am J Clin Oncol 2006;29:371-375.
11.Mauer AM, Kraut EH, Krauss SA, et al. Phase Ⅱ trial of oxaliplatin, leucovorin and fluorouracil in patients with advanced carcinoma of the esophagus [J]. Ann Oncol 2005; 16:1320-1325.
12.Efferth T, Volm M. Pharmacogenetics for individualized cancer chemotherapy.Pharmacol Ther,2005,107 (2):155-176.
13.Fakhrejahani E, Miyamoto A, Tanigawa N. Correlation between thymidylate synthase and dihydropyrimidine dehydrogenase mRNA level and in vitro chemosensitivity to 5-fluorouracil, in relation to differentiation in gastric cancer. Cancer Chemother Pharmacol [J].2007 Aug; 60(3):437-446.
14.Wang W, Cassidy J, OBrien V, et al.Mechanistic and PredictiveProfiling of 5-Fluorouracil Resistance in Human Cancer Cells[J].Cancer Res 2004,64:8167-8176.
15.Terashima M, lrinoda T, Fujiwara H, et al.Roles of Thymidylate Synthase and Dihydropyrimidine Dehydrogenase in TumorProgression and Sensitivity to 5-FIuorouracil in Humsn Gastric Cancer[J].Anticancer Res 2002,22:761-768.
16.Nishina T, Hyodo I, Miyaike J, et al. The ratio of Thymidine Phosphorylase to Dihydropyrimidine Dehydrogenase in Tumour Tissues of Patients with Metastatic Gastric Cancer is Predictive of the Clinical Response to 5-DFUR[J]. Eur J Caneer,2004,40(10):1566-1571.
17.Park DJ and Lenz HJ. Determinants of chemosensitivity in gastric cancer. Curr Opin Pharmacol.2006, 6:337-344.
18.Ahaha R,Liang X.Yu JJ,et al.Excision RepairCrossComple-menting-group 1:Gene Expression and Platinum Resistance[J].Int J Mol Med,2004,14(6):959-970.
19.Garcia-Campelo R,Alonso-Curbera G,Anton Aparicio LM,et al.Pharmacogenomics in Lung caner:an Analysis of DNA Repair Gene Expression in Patients Treated with Platinunl-hased Chemotherapy[J].Expert Opin Pharmacother.2005,6(12):2015-2026.
20.Gossage L, Madhusudan S. Current Status of Excision Repair Cross Complementing-group 1(ERCC1)in Cancer[J].Cancer Tteat Rev,2007,33(6):565-577.
21.Selvakumaran M, Pisarcik DA, Bao R, et al.Enhanced cisplatin cytotoxicity by disturbing the nucleotide excision repair pathway in ovarian cancer cell lines[J].Cancer Res.2003,15;63(6):1311-1316.
22.Youn CK, Kim MH, Cho HJ, et al.Oncogenic H-Ras Up-regulate a Expression of ERCC1 to Protect Cells from Platinum-based Anticancer Agents[J].Cancer Res,2004,64(14):4849-4857.
23 Ruzzo A,Graziano F, Loupakis F.et al. Pharmacogenetic Profiling in Patients with Advanced Colorectal Cancer Treated with First-line FOLFOX-4 Cherootherapy[J].J Clin Oncol,2007,25(10):1247-1254.
24.Kwon HC, Roh MS, Oh SY, et al.Prognostic Value of Expression of ERCC1, Thymidylate Synthase and Glutathione S Transferase PI for 5-FluorouraciI/Oxaliplatin Chemotherapy in Advanced Gastric Cancer[J].Ann Oncol,2007,18:504-509.
25.Wei J, Zou Z, Qian X,et al. ERCC1 mRNA levels and survival of advanced gastric cancer patients treated with a modified FOLFOX regimen [J]. Br J Cancer.2008; 98 (8):1398-1402.
26.Nishina T, Matsubara J, Toshikazu M, et al.Clinical Significanoe of Dihydropyrimidine DPD), Epidermal Growth Factor Receptor(EGFR), and Excision Repair Cross-complementing Gene1(ERCC1)Gene Expression of Tumor Tissue in Patients with Advanced Gastric Cancer[J]. ASCO Meeting Abstracts,2007,25 (18):4629.
27.Liu B, Wei J, Zou Z, et al. Polymorphism of XRCC1 predicts overall survival of gastric cancer patients receiving oxaliplatin-based chemotherapy in Chinese population[J].Eur J Hum Genet.2007 Oct; 15 (10):1049-1053
28.McLeod HL, Sargent DJ, Marsh S, et al.Ramanathan RK,Williamson S, Findlay B, Thibo eau S, Petersen G, Goldberg R:Pharmacogenetic analysis of systemic toxicity and response after 5-fluorouracil (5FU)/CPT-11,5FU/oxaliplatin (oxal),or CPT-11/oxal therapy for advanced colorectal cancer (CRC):Results from an intergroup trial[J] [abstract 1013]. Proc Am SocClin Oncol 2003,22:253.
29.Stoehlmacher J, Park DJ, Zhang W, et al.Association between glutathione S-transferase P1, T1, and M1 genetic polymorphism and survival of patients with metastatic colorectal cance r [J].J Natl Cancer Inst.2002 Jun 19;94(12):936-942.
30. Seve P, Dumontet C.Is class Ⅲ beta-tubulin a predictive factor in patients receiving tubulin-binding agents [J]? Lancet Oncol.2008 Feb;9(2):168-175.
31. Rouzier R, Rajan R, Wagner P, et al.Microtubule-associated protein tau:a marker of paclitaxel sensitivity in breast cancer[J].Proc Natl Acad Sci U S A.2005 Jun 7; 102(23):8315-8320.
32. Nogales E, Wolf SG, Downing KH.Structure of the alpha beta tubulin dimer by electron crystallography [J]. Nature.1998 Jan 8;391(6663):199-203. Erratum in:Nature 1998;393(6681):191:
33. Kavallaris M, Burkhart CA, Horwitz SB. Antisense oligonucleotides to class III beta-tubulin sensitize drug-resistant cells to Taxol [J].Br J Cancer.1999 Jun;80(7):1020-1025.
34. Ranganathan S, Benetatos CA, Colarusso PJ, et al. Altered beta-tubulin isotype expression in paclitaxel-resistant human prostate carcinoma cells [J].Br J Cancer.1998; 77(4):562-526.
35. Pusztai L.Markers predicting clinical benefit in breast cancer from microtubule-targeting agents [J].Ann Oncol 2007; 18(Suppl 12):xii15-20.
1.王艳,吴玉波,张永恒.猪苓多糖对顺铂增效作用及其毒性的影响[J].中医药研究,1996(5)：60-61.
2.高志明,叶启霞,张予,等.冬凌草甲素增强顺铂抗肿瘤活性的研究[J].中国癌症杂志,1993(3)：140-142.
3.徐淑萍,孙国平,王华,等.丹皮酚增强顺铂对人肝癌细胞SMMC-7721的增殖抑制作用[J].安徽医科大学学报,2006；14(1)：63-65.
4.薛妍,刘宝瑞,慕利梅.姜黄素和阿霉素联合应用对人肝癌细胞SMMC-7721抑制作用的研究[J].肿瘤研究与临床,2000；12(6)：372-374.
5.林溪,许建华,柯丹如.姜黄素与阿霉素联合用药的体外抗肿瘤作用[J].中国药理学通报2000；16(5)：522-525.
6.曾晖,邹冰,谭慧珍,等.苦参碱联合氟尿嘧啶抑制人胃癌裸鼠移植瘤的生长作用及机制[J],广州中医药大学学报,2006；23(2)：164-167.
7.黄云虹,张胜华,甄瑞贤,等.积雪草试诱导肿瘤细胞凋亡及增强长春新碱的抗肿瘤作用[J].癌症2004；23(12)：1599-1604.
8.徐萌,周蓓.汉防己甲素逆转肺癌化疗耐药和凋亡抗性的实验研究[J].新中医2006；38(6)：90-91.
9.李贵海,刘明霞,孙付军,等.粉防己碱对获得性多药耐药小鼠S180肿瘤细胞P170, LRP, TOPOⅡ表达的调控[J].中国中药杂志2005；30(16)：1280-1282.
10.滕晔,钟华,顾春红,等.槲皮素逆转柔红霉素在耐药细胞株内的异常分布[J].上海医学,2003；26(6)：292-294.
11.Takara K,Horibe S,et al.Effects of 19 herbal extracts on the sensitivity topaxlitaxel or 5-fluorouracil in hela cells[J].Biol Pharm Bull 2005;28(1):138-142.
12.武姗姗,高文远,段宏泉,等.重楼化学成分和药理作用研究进展[J].中草药,2004,35(3)：344-347.
13.许玲.益肺抗瘤饮对肺癌转移及免疫功能的影响[J].中国中西医结合杂志,1997,17(7)：401-403.
14.金炜东,陈孝平,蔡红娇.重楼提取物对HepG2细胞的毒性作用[J].华中科技大学学报,2006,35(1)：103-104.
15.季申,周坛树,张锦哲.中药重楼和云南白药中抗肿瘤细胞毒活性物质Gracillin的测定[J].中成药,2001,23(3)：212-214.
16. Chen CX, Zhou JI. Two new seroid sapogenins of Paris polyphylla var. yunnanensis [J].Acta B of Yunnan, 1992,14(1):111-113.
17. Singh SB, Raghunath SI.Furostanolsaponins from Parispolyphylla:Stuctures of polyphyllin C, D, E, and F[J].Phy tochemistry,1982,21(12):2079.
18.Xu XM, Zhong ZC. Studies on chemical constituents of Paris polyphylla var.chinenses[J]. Chin Tradit Herb Drugs,1988,19 (6):242-249.
19.刘明.中药连翘药理作用的研究近况[J].现代医药卫生,2007,23(16)：2438-2439.
20.李倩,冯卫生.连翘的化学成分研究进展[J].河南中医学院学报,2005,20(117)：78-80.
21.焦红军.党参的药理作用及其临床应用[J].临床医学,2005,25(4)：92-93
1. Leung WK, Wu MS, Kakugawa Y, et al. Screening for gastric cancer in Asia:current evidence and practice [J]. Lancet Oncol 2008;9:279-87.
2. Macdonald JS.Treatment of localized gastric cancer [J]. Semin Oncol 2004;31 (4):566-73.
3.Carrato A, Gallego-Plazas J, Guillen-Ponce C. Adjuvant therapy of resected gastric cancer is necessary[J]. Semin Oncol 2005;32:S105-8.
4.Louvet C, Andre T, Tigaud JM, et al. Phase Ⅱ study of oxaliplatin, fluorouracil, and folinic acid in locally advanced or metastatic gastric cancer patients[J]. J Clin Oncol 2002;20:4543-8.
5.De Vita F, Orditura M, Matano E, et al.A phase Ⅱ study of biweekly oxaliplatin plus infusional 5-fluorouracil and folinic acid (FOLFOX-4) as first-line treatment of advanced gastric cancer patients [J].Br J Cancer 2005;92:1644-9.
6. Al-Batran SE, Atmaca A, Hegewisch-Becker S, et al. Phase Ⅱ trial of biweekly infusional fluorouracil, folinic acid, and oxaliplatin in patients with advanced gastric cancer [J]. J Clin Oncol 2004; 22:658-63.
7. Lordick F, Lorenzen S, Stollfuss J, et al. Phase Ⅱ study of weekly oxaliplatin plus infusional fluorouracil and folinic acid (FUFOX regimen) as first-line treatment in metastatic gastric cancer [J]. Br J Cancer 2005; 93:190-4.
8.Cavanna L, Artioli F, Codignola C, et al.Oxaliplatin in combination with 5-fluorouracil (5-FU) and leucovorin (LV) in patients with metastatic gastric cancer (MGC)[J]. Am J Clin Oncol 2006; 29:371-5.
9. Mauer AM, Kraut EH, Krauss SA, et al. Phase Ⅱ trial of oxaliplatin, leucovorin and fluorouracil in patients with advanced carcinoma of the esophagus[J]. Ann Oncol 2005; 16:1320-5.
10. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method[J]. Methods,2001,25(4):402-408
11.Van Cutsem E. The treatment of advanced gastric cancer:new findings on the activity of the taxanes[J]. The Oncologist,2004,9:9-15.
12.Vamdhachary GR, Ajani JA. Gastric cancer[J]. Clin Adv Hcmatol Oncol.2005,3:118-24.
13.Ajani JA. Evolving chemotherapy for advanced gastric caneer[J]. The Oncologist,2005,10:49-58.
14. Schnall S, Macdonald JS.Mitomycin therapy in gastric cancer [J].Oncology.1993 Apr,50 (1):70-77.
15. David J Park and Heinz-Josef Lenz. Determinants of chemosensitivity in gastric cancer [J]. Curr Opin Pharmacol.2006,6:337-344.
16. Mamenta EL, Poma EE, Kaufmann WK, Delmastro DA, Grady HL, Chaney SG. Enhanced replicative bypass of platinum-DNA adducts in cisplatin-resistant human ovarian carcinoma cell lines [J]. Cancer Res 1994;54:3500-3505.
17. Extra JM, Espie M, Calvo F, Ferme C, Mignot L, Marty M. Phase Ⅰ study of oxaliplatin in patients with advanced cancer [J]. Cancer Chemother Pharmacol 1990;25:299-303.
18.Sharif S, O'Connell MJ, Yothers G, Lopa S, Wolmark N. FOLFOX and FLOX regimens for the adjuvant treatment of resected stage Ⅱ and Ⅲ colon cancer[J]. Cancer Invest 2008; 26:956-963.
19.Park DJ, Determinants of chemosensitivity in gastric cancer [J].Curr Opin Pharmacol. 2006V6N4:337-344;
20. Toffoli G. Pharmacogenomics and stomach cancer[J]. Pharmacogenomics.2004,5(6):627-641.
21. Gossage L, Madhusudan S.Current Status of Excision Repair Cross Complemen ting-group 1 (ERCC1) in Cancer [J].Cancer Tteat Rev,2007.33(6):565-577.
22.Tripsianes K, Folkers G, Ab E, et al. The structure of the human ERCC1/XPF interaction domains reveals a complementary role for the two proteins in nucleotide excision repair.Structure [J].2005 Dec; 13 (12):1849-1858.
23. Selvakumaran M, Pisarcik DA, Bao R, et al.Enhanced cisplatin cytotoxicity by disturbing the nucleotide excision repair pathway in ovarian cancer cell lines [J].Cancer Res.2003 Mar 15;63 (6):1311-1316.
24. Chang IY, Youn CK, Kim HB, et al. Oncogenic H-Ras up-regulates expression of Ku80 to protect cells from gamma-ray irradiation in NIH3T3 cells[J].Cancer Res.2005 Aug 1;65(15):6811-9.
25.Olaussen KA, Dunant A, Fouret P,et al.DNA Repair by ERCC1 in Non-smail-cell Lung Cancer and Cisplatin-based Adjuvant Chemotherapy[J]. N Engl J Med,2006,355(10):983-991.
26.Ceppi P.Volante M,Novella S,et al.ERCCI and RRM1 Gene Expressions but not EGFR Ale Predictive of Shorter Survival in Advanced Non-small-cell Lung Cancer Treated with Cisplatin and Gemcitabine[J].Ann Oneol,2006,17(12):1818-1825.
27.Altaha R,Liang X,Yu J J,et al.Excision Repair Cross Complementing-group l:Gene Expression and Platinum Resistance [J].Int J Mol Med,2004;14(6):959-970.
28.Kang S,Ju W,Kim JW,et al.Association between Excision Repair Cross Complementation group 1 Polymorphism and Clinical outcome of Platinum-based Chemotherapy in Patients with Epithelial Ovarian Cancer[J].Exp Mol Med,2006,38 (3)1320-1324.
29. Su D, Ma S, Liu P, et al. Genetic polymorphisms and Treatment Response in Advanced Non-small-cell lung Cancer[J].Lung Cancer,2007,56(2)1281-288.
30. Matsubara J, Nishina T, Yamada Y, et al. Impacts of excision repair cross-complementing gene 1 (ERCC1), dihydropyrimidine dehydrogenase, and epidermal growth factor receptor on the outcomes of patients with advanced gastric cancer [J]. Br J Cancer 2008;98:832-839.
31. Kwon HC, Roh MS, Oh SY, et al. Prognostic value of expression of ERCC1, thymidylate synthase, and glutathione S-transferase P1 for 5-fluorouracil/oxaliplatin chemotherapy in advanced gastric cancer [J]. Ann Oncol 2007;18:504-509.
32. Wei J, Zou Z, Qian X,et al. ERCC1 mRNA levels and survival of advanced gastric cancer patients treated with a modified FOLFOX regimen [J]. Br J Cancer.2008;98 (8):1398-1402.
33. Kim JS, Kim MA, Kim TM, et al. Biomarker analysis in stage Ⅲ-Ⅳ (M0) gastric cancer patients who received curative surgery followed by adjuvant 5-fluorouracil and cisplatin chemotherapy:epidermal growth factor receptor (EGFR) associated with favourable survival [J]. Br J Cancer 2009; 100:732-738.
34. Napieralski R, Ott K, Kremer M, et al. Combined GADD45A and thymidine phosphorylase expression levels predict response and survival of neoadjuvant-treated gastric cancer patients [J]. Clin Cancer Res 2005; 11:3025-3031.
35.Olaussen KA, Dunant A, Fouret P, et al. DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy [J]. N Engl J Med 2006;355:983-991.
36.Lee KH, Min HS, Han SW, et al. ERCC1 expression by immunohistochemistry and EGFR mutations in resected non-small cell lung cancer [J]. Lung Cancer 2008; 60:401-407.
37.Simon GR, Sharma S, Cantor A, et al. ERCC1 expression is a predictor of survival in resected patients with non-small cell lung cance [J]r. Chest 2005;127:978-983.
1.Louvet C, Andre T, Tigaud JM, et al. Phase Ⅱ study of oxaliplatin, fluorouracil, and folinic acid in locally advanced or metastatic gastric cancer patients. J Clin Oncol 2002;20:4543-4548.
2. De Vita F, Orditura M, Matano E, et al. A phase Ⅱ study of biweekly oxaliplatin plus infusional 5-fluorouracil and folinic acid (FOLFOX-4) as first-line treatment of advanced gastric cancer patients [J]. Br J Cancer 2005;92:1644-1649.
3. Al-Batran SE, Atmaca A, Hegewisch-Becker S, et al. Phase Ⅱ trial of biweekly infusional fluorouracil, folinic acid, and oxaliplatin in patients with advanced gastric cancer[J]. J Clin Oncol 2004;22:658-663.
4. Lordick F, Lorenzen S, Stollfuss J, et al. Phase Ⅱ study of weekly oxaliplatin plus infusional fluorouracil and folinic acid (FUFOX regimen) as first-line treatment in metastatic gastric cancer [J]. Br J Cancer 2005;93: 190-194.
5.Cavanna L, Artioli F, Codignola C, et al. Oxaliplatin in combination with 5-fluorouracil (5-FU) and leucovorin (LV) in patients with metastatic gastric cancer (MGC) [J]. Am J Clin Oncol 2006;29:371-375.
6. Mauer AM, Kraut EH, Krauss SA, et al. Phase Ⅱ trial of oxaliplatin, leucovorin and fluorouracil in patients with advanced carcinoma of the esophagus[J]. Ann Oncol 2005;16:1320-1325.
7.Macdonald JS, Smalley SR, Benedetti J, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction[J]. N Engl J Med 2001,345:725-730.
8. Efferth T,Volm M.Pharmacogeneties for individualized cancer chemotherapy[J].Pharmacol Ther,2005, 107(2):155
9.LaFramboise T.Weir BA, Zhao X,et al.Allele-spe-cific amplification in cancer revealed by SNP array analysis[J].PLoS Comput Bid,2005,(6):e65.
10. Park DJ and Lenz HJ. Determinants of chemosensitivity in gastric cancer [J].Curr Opin Pharmacol.2006,6：337-344.
11.Mamenta EL, Poma EE, Kaufmann WK, et al. Enhanced replicative bypass of platinum-DNA adducts in cisplatin-resistant human ovarian carcinoma cell lines [J]. Cancer Res 1994;54:3500-350
12. Extra JM, Espie M, Calvo F, et al. Phase Ⅰ study of oxaliplatin in patients with advanced cance r [J]. Cancer Chemother Pharmacol 1990;25:299-303.
13. Park DJ, Stoehlmacher J, Zhang W, et al. A Xeroderma pigmentosum group D gene polymorphism predicts clinical outcome to platinum-based chemotherapy in patients with advanced colorectal cancer [J].Cancer Res.2001 Dec 15;61(24):8654-8658.
14.Ryu JS, Hong YC, Han HS, et al. Association between polymorphisms of ERCC1 and XPD and survival in non-small-cell lung cancer patients treated with cisplatin combination chemotherapy[J].Lung Cancer,2004,44(3):311-316.
15.Gurubhagavatula S,Liu G,Park,et al.XPD and XRCC1 genetic polymorphisms are prognostic factors in advanced non-small-cell lung cancer patients treated with platinum chemotherapy[J].J Clin Oncol,2004,22 (13):2594-2599.
16.Stoehlmacher J, Ghaderi V, Iobal S, et al.A polymorphism of the XRCC1 gene predicts for response to platinum based treatment in advanced colorectal cancer[J].Anticancer Res.2001 Jul-Aug;21(4B):3075-3079.
17.Stoehlmacher J, Park DJ, Zhang W, et al.Association between glutathione S-transferase P1, T1, and M1 genetic polymorphism and survival of patients with metastatic colorectal cance r [J].J Natl Cancer Inst.2002 Jun 19;94(12):936-942.
1.孙秀娣,牧人,周有尚,等.中国胃癌死亡率20年变化情况分析及其发展趋势预测[J].中华肿瘤杂志,2004,26(1)：4-8.
2.Richardson, M A, Sanders, T, Palmer, J L, et al. Complementary/alternative medicine use ina comprehensive cancer center and the implications foroncology[J]. J Clin Oncol.2000,18(13):2505-2514.
3.Chou TC, Talalay P. Quantitative analysis of dose effect relationships:the combined effects of multiple drugs or enzyme inhibitors[J]. Adv Enzyme Regul 1984;22:27-55
4.Livak KJ, Schmittgen TD. Analysis of relative gene expression data-using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method[J]. Methods,2001,25(4):402-408
5.李传刚,李墨林,舒晓宏,等.四君子汤对小鼠膀胱癌化疗的减毒增效作用[J].中国中西医结合杂志2005；25(4)：354-357.
6.曹勇,张丹,郑广娟,等.补肾化瘀解毒方对小鼠肝癌H22的抑瘤增效作用[J].中药材,2004；27(1)：38-39.
7.Longley D B, Harkin D P, Johnston P G.5-fluorouracil:mechanisms of action and clinical strategies[J]. Nat Rev Cancer 2003;3(5):330-338.
8.孙燕,石远凯.临床肿瘤内科手册[M].人民出版社.2008,481.
9.Ando T, Ishiguro H, Kuwabara Y, et al.Relationship between expression of 5-fluorouracil metabolic enzymes and 5-fluorouracil sensitivity in esophageal carcinoma cell lines[J].Dis Esophagus. 2008;21(1):15-20.
10.Salonga D, Danenberg KD, Johnson M, et al. Colorectal tumors responding to 5-fluorouracil have low gene expression levels of dihydro-pyrimidine dehydrogenase, thymidylate synthase, and thymi-dine phosphorylase[J]. Clin Cancer Res.2000;25 (6):1322-1327.
11.Theisen J, Danenberg K, Ott K, et al.Predictors of response and survival for neo-adjuvant treated patients with esophageal adenocarcinoma[J]. Dis Esophagus.2008; 21 (7):601-606.
12.Park DJ, Lenz HJ. Determinants of chemosensitivity in gastric cancer[J].Curr Opin Pharmacol.2006; 6(4):337-344.
13.Wei J, Liu B, Wang L,et al. Synergistic interaction between tetrandrine and chemotherapeutic agents and influence of tetrandrine on chemotherapeutic agent-associated genes in human gastric cancer cell lines[J]. Cancer Chemother Pharmacol.2007;60 (5):703-711.
1.Louvet C, Andre T, Tigaud JM, et al. Phase Ⅱ study of oxaliplatin, fluorouracil, and folinic acid in locally advanced or metastatic gastric cancer patients[J]. J Clin Oncol 2002;20:4543-4543.
2.De Vita F, Orditura M, Matano E, et al. A phase Ⅱ study of biweekly oxaliplatin plus infusional 5-fluorouracil and folinic acid (FOLFOX-4) as first-line treatment of advanced gastric cancer patients [J].Br J Cancer 2005;92:1644-1649.
3.Al-Batran SE, Atmaca A, Hegewisch-Becker S, et al. Phase Ⅱ trial of biweekly infusional fluorouracil, folinic acid, and oxaliplatin in patients with advanced gastric cancer[J]. J Clin Oncol 2004;22:658-663.
4.Lordick F, Lorenzen S, Stollfuss J, et al. Phase Ⅱ study of weekly oxaliplatin plus infusional fluorouracil and folinic acid (FUFOX regimen) as first-line treatment in metastatic gastric cancer [J]. Br J Cancer 2005;93: 190-194.
5.Cavanna L, Artioli F, Codignola C, et al.Oxaliplatin in combination with 5-fluorouracil (5-FU) and leucovorin (LV) in patients with metastatic gastric cancer (MGC) [J]. Am J Clin Oncol 2006;29:371-375.
6.Mauer AM, Kraut EH, Krauss SA, et al. Phase Ⅱ trial of oxaliplatin, leucovorin and fluorouracil in patients with advanced carcinoma of the esophagus[J]. Ann Oncol 2005;16:1320-1325.
7.文磊.中药复方治疗胃癌的临床研究进展[J].辽宁中医药大学学报,2008,10：68-70.
8.Chou TC, Talalay P. Quantitative analysis of dose effect relationships:the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 1984;22:27-55
9. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method[J]. Methods,2001,25(4):402-408
10.李财宝,龚航军.149例胃癌术后化疗与中药综合治疗临床观察[J].上海中医药杂志,2002(2)：15-16.
11.王纪东,王丽亚,李夏昀.中西医结合治疗中晚期胃癌92例临床分析[J].现代中西医结合杂志,2004,13(17)：2281-2282.
12.暴宪斌,沈俊兰.参芪五味子片对进展期胃癌化疗患者的影响[J].中国中医药信息杂志,2004,11(11)：1004-1005.
13.陈郭君,薛曼朗,王先菊.脾肾方对晚期胃癌化疗中减毒作用的临床研究[J].湖北中医杂志,2001,23(7)：9-10.
14. Zhao JS, Li QD Q,Zou BB,et al.In vitro combination characterization of the new anticancer plant drug beta-elemene with taxanes against human lung carcinoma [J]. Int J Oncol.2007 (31)2:241-252
15. David J Park and Heinz-Josef Lenz.Determinants of chemosensitivity in gastric cancer [J]. Curr Opin Pharmacol.2006,6:337-344.
16. Bernstein C, Bernstein H, Payne CM, et al. DNA repair/proapoptotic dual-role proteins in five major DNA repair pathways:fail-safe protection against carcinogenesis.[J]. Murat Res,2002, 511(2):145-178.
17.Gillet LC,Scharer OD,Molecular mechanisms of mammalian global genome nucleotide excision repair[J].Chem Rev 2006,106:253-276.
18. Reardon JT, Sancar A, Nucleotide excision repair [J].Prog Nucleic Acid Res Mol Biol 2005,79:183-235.
18. Reed E. Platinum-DNA adduct,nucleotide excision repair and platinum based anti-cancer chemotherapy [J].Cancer Treat. Rev.1998;24:331-344.
19. Olaussen KA, Mountzios G, Soria JC.ERCC1 as-a risk stratifier in platinum-based chemotherapy for nonsmall-cell lung cancer [J]. Curr Opin Pulm Med.2007; 13 (4):284-289.
20. Wei J, Zou Z, Qian X,et al. ERCC1 mRNA levels and survival of advanced gastric cancer patients treated with a modified FOLFOX regimen [J].Br J Cancer.2008;98 (8):1398-1402.
21. Wei J, Liu B, Wang L, et al.Synergistic interaction between tetrandrine and chemotherapeutic agents and influence of tetrandrine on chemotherapeutic agent-associated genes in human gastric cancer cell lines [J].Cancer Chemother Pharmacol.2007 Oct;60(5):703-711.
22. Hayward RL, Macpherson JS, Cummings J, et al. Enhanced oxaliplatin-induced apoptosis following antisense Bcl-xl down-regulation is p53 and Bax dependent:Genetic evidence for specificity of the antisense effect[J].Mol Cancer Ther.2004;3(2):169-178
1.Overman MJ, Kazmi SM, Jhamb J, et al.Weekly docetaxel, cisplatin, and 5-fluorouracil as initial therapy for patients with advanced gastric and esophageal cancer[J].Cancer.2010,116(6):1446-1453
2.Chon HJ, Rha SY, Im CK, et al.Docetaxel versus Paclitaxel Combined with 5-FU and Leucovorin in Advanced Gastric Cancer:Combined Analysis of Two Phase II Trials[J].Cancer Res Treat.2009, 41(4):196-204.
3.Yamamoto K, Fujiwara Y, Nishida T, et al.Induction chemotherapy with docetaxel,5-FU and CDDP (DFP) for advanced gastric cancer[J].Anticancer Res.2009;29(10):4211-4215
4.Zhong H, Zhang Y, Ma S, et al.Docetaxel plus oxaliplatin (DOCOX) as a second-line treatment after failure of fluoropyrimidine and platinum in Chinese patients with advanced gastric cancer[J].Anticancer Drugs.2008 Nov;19(10):1013-1018
5.Kim YH, Seo HY, Jeen YT,et al. Phase Ⅰ dose escalation study of docetaxel with a fixed dose of S-1 in combination chemotherapy for advanced gastric cancer.Cancer Chemother Pharmacol[J].2009 Jan;63(2):253-260.
6.Park SR, Kim HK, Kim CG, et al.Phase Ⅰ/Ⅱ study of S-1 combined with weekly docetaxel in patients with metastatic gastric carcinoma[J].Br J Cancer.2008 Apr 22;98(8):1305-1311.
7.Chou TC, Talalay P. Quantitative analysis of dose effect relationships:the combined effects of multiple drugs or enzyme inhibitors [J]. Adv Enzyme Regul 1984;22:27-55.
8. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method[J]. Methods,2001,25 (4):402-408.
9.Crown J,O'Leary M.The taxanes:An update[J].Lancet,2000.355:1176-1178.
lO.Sulkes A, Smyth J, Sessa C, et al. Docetaxel (Taxotere) in advanced gastric cancer:results of a phase II clinical trial EORTC Early Clinical Trials Group [J]. Br J Cancer.1994,70(2):380-383.
11.Ajani JA, Fodor MB, Tjulandin SA, et al. Phase Ⅱ multi-institutional randomized trial of docetaxel plus cisplatin with or without fluorouracil in patients with untreated, advanced gastric, or gastroesophageal adenocarcinoma[J]. J clin Oncol,2005,23(24):5660-5667.
12. Zhao JS, Li QD Q, Zou BB, et al.In vitro combination characterization of the new anticancer plant drug beta-elemene with taxanes against human lung carcinoma [J]. Int J Oncol.2007 (31)2:241-52.
13.曹勇,张丹,郑广娟,等.补肾化瘀解毒方对小鼠肝癌H22的抑瘤增效作用[J].中药材2004；27(1)：38-39.
14.郑昱,刘宝瑞,邹玺.土元乳液对胃癌化疗药物增效作用的体外研究[J],中国临床药理学与治疗 学,2006(11)3：354-356.
15.李财宝,龚航军.149例胃癌术后化疗与中药综合治疗临床观察[J].上海中医药杂志,2002(2)：15.
16.王纪东,王丽亚,李夏昀.中西医结合治疗中晚期胃癌92例临床分析[J].现代中西医结合杂志,2004.13(17)：2281.
17.陈郭君,薛曼朗,王先菊,脾肾方对晚期胃癌化疗中减毒作用的临床研究[J].湖北中医杂志,2001,23(7)：9-10.
18.Hasegawa S,Miyoshi Y,Egawa C,et al.Prediction of response to docetaxel by quantitative analysis of Class Ⅰ and Ⅲ beta-tubulin isotype mRNA expressi'on in human breast cancers[J]. Clinical Cancer Research,2003,9:2992.
19.Miyoshi Y,Ando A,Takamura Y,et al.Prediction of response to docetaxel by CYP3A4 mRNA expression in breast cancer tissues[J].Int J Cancer,2002,97(1):129-132.
20.Seve P,Dumontet C.Is class Ⅲ beta-tubulin a predictive factor in patients receiving tubulin-binding agents? [J] Lancet Oncol 2008;9:168-175.
21.Pusztai L. Markers predicting clinical benefit in breast cancer from microtubule-targeting agents [J]. Ann Oncol 2007; 18(Suppl 12):xiil5-20.
22.Rouzier R, Rajan R, Wagner P, et al.Microtubule-associated protein tau:a marker of paclitaxel sensitivity in breast cancer[J]. Proc Natl Acad Sci USA 2005;102:8315-8320.
23.Fabbri F,Carloni S,Brigliadori G,et al.Sequential events of apoptosis involving docetaxel. a microtuble interfering agent:acytometric study[J].BMC Cell Biol 2006,7:6.
1.吴雪卿.补益中药抗癌作用研究进展[J].湖南中医药导报,1999,5(9)：10-13.
2.苏勉诚,戴梅,吕晓英,等.中药复方癌宁对人胃腺癌细胞凋亡基因表达的影响[J].中药材.2002,25(8)：563-566.
3.杨勤建,雷良蔚,潘希雄,等.中药复方香龙散诱导人胃腺癌细胞凋亡的研究[J].湖北中医学院学报,1999,1(1)：43-45.
4.孙宏丹,贾莉,孟秀香,等.复方中药诱导Burkitt's淋巴瘤Raja细胞凋亡作用的研究[J].白血病·淋巴瘤,2002,11(2)：84-86.
5.陈志奎,林礼务,王艳,等.瘤内注射复方中药“99-克星”的活性组分抗肝癌作用及机制[J].中华医学超声杂志,2006,10(3)：266-268.
6.黄新苏,陈福,许锦阶.复方中药“克瘤宁”对人食管癌的抗癌作用及其机理研究[J].河北医学.2006,12(3)：193-195.
7.谭德明,刘作金,吴勇,等.“肝癌一号”对裸鼠人肝癌移植瘤生长的抑制作用及机制研究[J].重庆医学,2007,36(14)：1391-1394.
8.刘坚,谢红东,李瀚,等.中药复方搏癌丸对人肝癌细胞周期及bax、bcl-2、p53基因表达调控的影响[J].中西医结合肝病杂志,2004,14(3)：152-155.
9.郑瑾,刘强,王宗仁,等.活血化淤中药复方诱导K562细胞凋亡[J].第四军医大学学报,2003,24(5)：247-249.
10.金春峰,王守岩,蔡玉文,等.中药复方诱导肿瘤细胞凋亡的研究述评[J].辽宁中医学院学报,2004,6(3)：233-234.
11.罗晶,郭焱,勾敏慧,等.人参养荣汤对小鼠免疫功能的调节[J].中国现代医学杂志,2002,12(5)：27-281.
12.戴馨仪,陈林香,周岱翰,等.清金得生片抗肿瘤机理研究[J].中药新药与临床药理,2002,13(6)：360-3621.
13.王美,秦筱梅.中药复方JHL 抗肿瘤作用研究[J].青岛大学医学院学报,2004,40(2)：110-111.
14.杨文修.大承气汤对内毒素刺激巨噬细胞分泌肿瘤坏死因子的抑制作用[J].中国中西医结合外科杂志,2001,7(6):390-3921.
15.张运芳,李俊,金涌,等.芪加合剂对荷瘤小鼠体液免疫功能的影响[J].安徽医科大学学报,2000,35(2)：118-1201.
16.杨志强,王润田,等.中药复方抑瘤饮影响荷S180瘤小鼠免疫功能的动态研究[J].现代免疫学,2006,26(1)：64-68.
17.郑红刚,朴炳奎,林洪生,等.中药复方肺瘤平膏对树突状细胞功能影响的拆方研究[J].北京中医药大学学报,2007,30(8)：525-528,549.
18.李伟,胡凯文,苏伟.浙贝母散剂逆转急性白血病多药耐药的临床研究[J].北京中医药大学学报,2004,27(1)：63-65.
19.徐力,王明艳,许冬青.三物加白散加味方影响肿瘤多药耐药基因表达实验研究[J].上海中医药杂志,2005,39(8)：59-60.
20.姚祖仁,王亚非,姚祖培.肺腺癌多药耐药细胞株SPCA1/ADM的建立及中药方剂提取物A2的逆转作用研究[J].中医药研究,2001,17(4)：404324.
21.冯正权,郭勇,朱广希.复方三根制剂逆转多药耐药的实验研究[J].中国肿瘤,2003,12(6)：370-371.17.于广梅,郭继龙.中药及其有效成分抑制肿瘤血管生长的研究近况[J].山东中医杂志,2003,22(11)：694-6951.
22.田菲,贾英杰,陈军,等1肺一丸对肺癌血管生成及转移影响的实验研究[J].天津中医药,2003,20(5)：56-581.
23.施京红,刘德传,吴仕九,等1清香散对湿热型肝癌模型大鼠细胞凋亡、肿瘤血管生成的影响[J].陕西中医,2004,25(1)：84-861.
24.赵凤鸣,王明艳,吴海涛等.两首滋阴方药对环磷酰胺诱发的微核的抑制作用[J].福建中医药,1998(4)：91.
25.戴恩来,赵健雄,朱玉真,等.扶正抑瘤汤对肿瘤细胞周期主端粒酶影响的实验研究[J].中国中西医结合杂志,2001,21(10)：760-762.
26.王玉荣,王泽时.加味四君子汤诱导小鼠肿瘤细胞凋亡的实验研究[J].山西中医学院学报,2004,5(1)：16-18.
27.顾锦华,张伟,李锋.复方龙葵胶囊抗肿瘤作用及其对肿瘤细胞周期分布的影响[J].时珍国医国药,2006,17(12)2463-2464.
28.陈少全,陈菊祥,毛裕民,等.基因表达谱芯片在筛选胃腺癌相关基因中的应用[J].第二军医大学学报.2001,22(6)：523-525.
29.王顺启,陈力,倪虹,等.中药复方H3C-1对肝癌细胞SMMC-7721基因表达的影响[J].药物生物技术,2008,15(3)：176-179.
30.高鹏,许运明,峁俊卿,等.扶正消瘤液对肿瘤患者生活质量影响的临床研究[J].现代肿瘤医学,2003,11(4)：263-2641.
31.张义泽,李兴菊,宋丽华.中药在恶性肿瘤化疗中的减毒增效作用研究[J].山东中医杂志,1998,17(11)：488-4891.
32.朱海洪,姜国盛.中药内外治疗中晚期肝癌38例[J].中医杂志,2002,43：6109-6111.
33.李春青,李泽宇,李新.复方苦参注射液联合化疗治疗晚期消化道肿瘤的近期疗效观察[J].现代肿瘤医学,2006,14(14)：986-987.
2. Wesolowski R;Is there a role for second-line chemotherapy in advanced gastric cancer [J]? Lancet Oncol.2009,10(9):903-912.
3. Overman MJ, Kazmi SM, Jhamb J, et al.Weekly docetaxel, cisplatin, and 5-fluorouracil as initial therapy for patients with advanced gastric and esophageal cancer[J]. Cancer.2010,116(6):1446-1453
4.Chon HJ, Rha SY, Im CK, et al.Docetaxel versus Paclitaxel Combined with 5-FU and Leucovorin in Advanced Gastric Cancer:Combined Analysis of Two Phase Ⅱ Trials[J].Cancer Res Treat.2009, 41(4):196-204.
5.Yamamoto K, Fujiwara Y, Nishida T, et al.Induction chemotherapy with docetaxel,5-FU and CDDP (DFP) for advanced gastric cancer[J].Anticancer Res.2009;29(10):4211-4215.
6.Louvet C, Andre T, Tigaud JM, et al. Phase Ⅱ study of oxaliplatin, fluorouracil, and folinic acid in locally advanced or metastatic gastric cancer patients [J]. J Clin Oncol 2002;20:4543-4548.
7.De Vita F, Orditura M, Matano E, et al.A phase Ⅱ study of biweekly oxaliplatin plus infusional 5-fluorouracil and folinic acid (FOLFOX-4) as first-line treatment of advanced gastric cancer patients [J]. Br J Cancer 2005; 92:1644-1649.
8.A1-Batran SE, Atmaca A, Hegewisch-Becker S, et al. Phase Ⅱ trial of biweekly infusional fluorouracil, folinic acid, and oxaliplatin in patients with advanced gastric cancer [J]. J Clin Oncol 2004;22:658-663.
9. Lordick F, Lorenzen S, Stollfuss J, et al. Phase Ⅱ study of weekly oxaliplatin plus infusional fluorouracil and folinic acid (FUFOX regimen) as first-line treatment in metastatic gastric cancer [J]. Br J Cancer 2005; 93:190-194.
10.Cavanna L, Artioli F, Codignola C, et al. Oxaliplatin in combination with 5-fluorouracil (5-FU) and leucovorin (LV) in patients with metastatic gastric cancer (MGC) [J]. Am J Clin Oncol 2006;29:371-375.
11.Mauer AM, Kraut EH, Krauss SA, et al. Phase Ⅱ trial of oxaliplatin, leucovorin and fluorouracil in patients with advanced carcinoma of the esophagus [J]. Ann Oncol 2005; 16:1320-1325.
12.Efferth T, Volm M. Pharmacogenetics for individualized cancer chemotherapy.Pharmacol Ther,2005,107 (2):155-176.
13.Fakhrejahani E, Miyamoto A, Tanigawa N. Correlation between thymidylate synthase and dihydropyrimidine dehydrogenase mRNA level and in vitro chemosensitivity to 5-fluorouracil, in relation to differentiation in gastric cancer. Cancer Chemother Pharmacol [J].2007 Aug; 60(3):437-446.
14.Wang W, Cassidy J, OBrien V, et al.Mechanistic and PredictiveProfiling of 5-Fluorouracil Resistance in Human Cancer Cells[J].Cancer Res 2004,64:8167-8176.
15.Terashima M, lrinoda T, Fujiwara H, et al.Roles of Thymidylate Synthase and Dihydropyrimidine Dehydrogenase in TumorProgression and Sensitivity to 5-FIuorouracil in Humsn Gastric Cancer[J].Anticancer Res 2002,22:761-768.
16.Nishina T, Hyodo I, Miyaike J, et al. The ratio of Thymidine Phosphorylase to Dihydropyrimidine Dehydrogenase in Tumour Tissues of Patients with Metastatic Gastric Cancer is Predictive of the Clinical Response to 5-DFUR[J]. Eur J Caneer,2004,40(10):1566-1571.
17.Park DJ and Lenz HJ. Determinants of chemosensitivity in gastric cancer. Curr Opin Pharmacol.2006, 6:337-344.
18.Ahaha R,Liang X.Yu JJ,et al.Excision RepairCrossComple-menting-group 1:Gene Expression and Platinum Resistance[J].Int J Mol Med,2004,14(6):959-970.
19.Garcia-Campelo R,Alonso-Curbera G,Anton Aparicio LM,et al.Pharmacogenomics in Lung caner:an Analysis of DNA Repair Gene Expression in Patients Treated with Platinunl-hased Chemotherapy[J].Expert Opin Pharmacother.2005,6(12):2015-2026.
20.Gossage L, Madhusudan S. Current Status of Excision Repair Cross Complementing-group 1(ERCC1)in Cancer[J].Cancer Tteat Rev,2007,33(6):565-577.
21.Selvakumaran M, Pisarcik DA, Bao R, et al.Enhanced cisplatin cytotoxicity by disturbing the nucleotide excision repair pathway in ovarian cancer cell lines[J].Cancer Res.2003,15;63(6):1311-1316.
22.Youn CK, Kim MH, Cho HJ, et al.Oncogenic H-Ras Up-regulate a Expression of ERCC1 to Protect Cells from Platinum-based Anticancer Agents[J].Cancer Res,2004,64(14):4849-4857.
23 Ruzzo A,Graziano F, Loupakis F.et al. Pharmacogenetic Profiling in Patients with Advanced Colorectal Cancer Treated with First-line FOLFOX-4 Cherootherapy[J].J Clin Oncol,2007,25(10):1247-1254.
24.Kwon HC, Roh MS, Oh SY, et al.Prognostic Value of Expression of ERCC1, Thymidylate Synthase and Glutathione S Transferase PI for 5-FluorouraciI/Oxaliplatin Chemotherapy in Advanced Gastric Cancer[J].Ann Oncol,2007,18:504-509.
25.Wei J, Zou Z, Qian X,et al. ERCC1 mRNA levels and survival of advanced gastric cancer patients treated with a modified FOLFOX regimen [J]. Br J Cancer.2008; 98 (8):1398-1402.
26.Nishina T, Matsubara J, Toshikazu M, et al.Clinical Significanoe of Dihydropyrimidine DPD), Epidermal Growth Factor Receptor(EGFR), and Excision Repair Cross-complementing Gene1(ERCC1)Gene Expression of Tumor Tissue in Patients with Advanced Gastric Cancer[J]. ASCO Meeting Abstracts,2007,25 (18):4629.
27.Liu B, Wei J, Zou Z, et al. Polymorphism of XRCC1 predicts overall survival of gastric cancer patients receiving oxaliplatin-based chemotherapy in Chinese population[J].Eur J Hum Genet.2007 Oct; 15 (10):1049-1053
28.McLeod HL, Sargent DJ, Marsh S, et al.Ramanathan RK,Williamson S, Findlay B, Thibo eau S, Petersen G, Goldberg R:Pharmacogenetic analysis of systemic toxicity and response after 5-fluorouracil (5FU)/CPT-11,5FU/oxaliplatin (oxal),or CPT-11/oxal therapy for advanced colorectal cancer (CRC):Results from an intergroup trial[J] [abstract 1013]. Proc Am SocClin Oncol 2003,22:253.
29.Stoehlmacher J, Park DJ, Zhang W, et al.Association between glutathione S-transferase P1, T1, and M1 genetic polymorphism and survival of patients with metastatic colorectal cance r [J].J Natl Cancer Inst.2002 Jun 19;94(12):936-942.
30. Seve P, Dumontet C.Is class Ⅲ beta-tubulin a predictive factor in patients receiving tubulin-binding agents [J]? Lancet Oncol.2008 Feb;9(2):168-175.
31. Rouzier R, Rajan R, Wagner P, et al.Microtubule-associated protein tau:a marker of paclitaxel sensitivity in breast cancer[J].Proc Natl Acad Sci U S A.2005 Jun 7; 102(23):8315-8320.
32. Nogales E, Wolf SG, Downing KH.Structure of the alpha beta tubulin dimer by electron crystallography [J]. Nature.1998 Jan 8;391(6663):199-203. Erratum in:Nature 1998;393(6681):191:
33. Kavallaris M, Burkhart CA, Horwitz SB. Antisense oligonucleotides to class III beta-tubulin sensitize drug-resistant cells to Taxol [J].Br J Cancer.1999 Jun;80(7):1020-1025.
34. Ranganathan S, Benetatos CA, Colarusso PJ, et al. Altered beta-tubulin isotype expression in paclitaxel-resistant human prostate carcinoma cells [J].Br J Cancer.1998; 77(4):562-526.
35. Pusztai L.Markers predicting clinical benefit in breast cancer from microtubule-targeting agents [J].Ann Oncol 2007; 18(Suppl 12):xii15-20.
1.王艳,吴玉波,张永恒.猪苓多糖对顺铂增效作用及其毒性的影响[J].中医药研究,1996(5)：60-61.
2.高志明,叶启霞,张予,等.冬凌草甲素增强顺铂抗肿瘤活性的研究[J].中国癌症杂志,1993(3)：140-142.
3.徐淑萍,孙国平,王华,等.丹皮酚增强顺铂对人肝癌细胞SMMC-7721的增殖抑制作用[J].安徽医科大学学报,2006；14(1)：63-65.
4.薛妍,刘宝瑞,慕利梅.姜黄素和阿霉素联合应用对人肝癌细胞SMMC-7721抑制作用的研究[J].肿瘤研究与临床,2000；12(6)：372-374.
5.林溪,许建华,柯丹如.姜黄素与阿霉素联合用药的体外抗肿瘤作用[J].中国药理学通报2000；16(5)：522-525.
6.曾晖,邹冰,谭慧珍,等.苦参碱联合氟尿嘧啶抑制人胃癌裸鼠移植瘤的生长作用及机制[J],广州中医药大学学报,2006；23(2)：164-167.
7.黄云虹,张胜华,甄瑞贤,等.积雪草试诱导肿瘤细胞凋亡及增强长春新碱的抗肿瘤作用[J].癌症2004；23(12)：1599-1604.
8.徐萌,周蓓.汉防己甲素逆转肺癌化疗耐药和凋亡抗性的实验研究[J].新中医2006；38(6)：90-91.
9.李贵海,刘明霞,孙付军,等.粉防己碱对获得性多药耐药小鼠S180肿瘤细胞P170, LRP, TOPOⅡ表达的调控[J].中国中药杂志2005；30(16)：1280-1282.
10.滕晔,钟华,顾春红,等.槲皮素逆转柔红霉素在耐药细胞株内的异常分布[J].上海医学,2003；26(6)：292-294.
11.Takara K,Horibe S,et al.Effects of 19 herbal extracts on the sensitivity topaxlitaxel or 5-fluorouracil in hela cells[J].Biol Pharm Bull 2005;28(1):138-142.
12.武姗姗,高文远,段宏泉,等.重楼化学成分和药理作用研究进展[J].中草药,2004,35(3)：344-347.
13.许玲.益肺抗瘤饮对肺癌转移及免疫功能的影响[J].中国中西医结合杂志,1997,17(7)：401-403.
14.金炜东,陈孝平,蔡红娇.重楼提取物对HepG2细胞的毒性作用[J].华中科技大学学报,2006,35(1)：103-104.
15.季申,周坛树,张锦哲.中药重楼和云南白药中抗肿瘤细胞毒活性物质Gracillin的测定[J].中成药,2001,23(3)：212-214.
16. Chen CX, Zhou JI. Two new seroid sapogenins of Paris polyphylla var. yunnanensis [J].Acta B of Yunnan, 1992,14(1):111-113.
17. Singh SB, Raghunath SI.Furostanolsaponins from Parispolyphylla:Stuctures of polyphyllin C, D, E, and F[J].Phy tochemistry,1982,21(12):2079.
18.Xu XM, Zhong ZC. Studies on chemical constituents of Paris polyphylla var.chinenses[J]. Chin Tradit Herb Drugs,1988,19 (6):242-249.
19.刘明.中药连翘药理作用的研究近况[J].现代医药卫生,2007,23(16)：2438-2439.
20.李倩,冯卫生.连翘的化学成分研究进展[J].河南中医学院学报,2005,20(117)：78-80.
21.焦红军.党参的药理作用及其临床应用[J].临床医学,2005,25(4)：92-93
1. Leung WK, Wu MS, Kakugawa Y, et al. Screening for gastric cancer in Asia:current evidence and practice [J]. Lancet Oncol 2008;9:279-87.
2. Macdonald JS.Treatment of localized gastric cancer [J]. Semin Oncol 2004;31 (4):566-73.
3.Carrato A, Gallego-Plazas J, Guillen-Ponce C. Adjuvant therapy of resected gastric cancer is necessary[J]. Semin Oncol 2005;32:S105-8.
4.Louvet C, Andre T, Tigaud JM, et al. Phase Ⅱ study of oxaliplatin, fluorouracil, and folinic acid in locally advanced or metastatic gastric cancer patients[J]. J Clin Oncol 2002;20:4543-8.
5.De Vita F, Orditura M, Matano E, et al.A phase Ⅱ study of biweekly oxaliplatin plus infusional 5-fluorouracil and folinic acid (FOLFOX-4) as first-line treatment of advanced gastric cancer patients [J].Br J Cancer 2005;92:1644-9.
6. Al-Batran SE, Atmaca A, Hegewisch-Becker S, et al. Phase Ⅱ trial of biweekly infusional fluorouracil, folinic acid, and oxaliplatin in patients with advanced gastric cancer [J]. J Clin Oncol 2004; 22:658-63.
7. Lordick F, Lorenzen S, Stollfuss J, et al. Phase Ⅱ study of weekly oxaliplatin plus infusional fluorouracil and folinic acid (FUFOX regimen) as first-line treatment in metastatic gastric cancer [J]. Br J Cancer 2005; 93:190-4.
8.Cavanna L, Artioli F, Codignola C, et al.Oxaliplatin in combination with 5-fluorouracil (5-FU) and leucovorin (LV) in patients with metastatic gastric cancer (MGC)[J]. Am J Clin Oncol 2006; 29:371-5.
9. Mauer AM, Kraut EH, Krauss SA, et al. Phase Ⅱ trial of oxaliplatin, leucovorin and fluorouracil in patients with advanced carcinoma of the esophagus[J]. Ann Oncol 2005; 16:1320-5.
10. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method[J]. Methods,2001,25(4):402-408
11.Van Cutsem E. The treatment of advanced gastric cancer:new findings on the activity of the taxanes[J]. The Oncologist,2004,9:9-15.
12.Vamdhachary GR, Ajani JA. Gastric cancer[J]. Clin Adv Hcmatol Oncol.2005,3:118-24.
13.Ajani JA. Evolving chemotherapy for advanced gastric caneer[J]. The Oncologist,2005,10:49-58.
14. Schnall S, Macdonald JS.Mitomycin therapy in gastric cancer [J].Oncology.1993 Apr,50 (1):70-77.
15. David J Park and Heinz-Josef Lenz. Determinants of chemosensitivity in gastric cancer [J]. Curr Opin Pharmacol.2006,6:337-344.
16. Mamenta EL, Poma EE, Kaufmann WK, Delmastro DA, Grady HL, Chaney SG. Enhanced replicative bypass of platinum-DNA adducts in cisplatin-resistant human ovarian carcinoma cell lines [J]. Cancer Res 1994;54:3500-3505.
17. Extra JM, Espie M, Calvo F, Ferme C, Mignot L, Marty M. Phase Ⅰ study of oxaliplatin in patients with advanced cancer [J]. Cancer Chemother Pharmacol 1990;25:299-303.
18.Sharif S, O'Connell MJ, Yothers G, Lopa S, Wolmark N. FOLFOX and FLOX regimens for the adjuvant treatment of resected stage Ⅱ and Ⅲ colon cancer[J]. Cancer Invest 2008; 26:956-963.
19.Park DJ, Determinants of chemosensitivity in gastric cancer [J].Curr Opin Pharmacol. 2006V6N4:337-344;
20. Toffoli G. Pharmacogenomics and stomach cancer[J]. Pharmacogenomics.2004,5(6):627-641.
21. Gossage L, Madhusudan S.Current Status of Excision Repair Cross Complemen ting-group 1 (ERCC1) in Cancer [J].Cancer Tteat Rev,2007.33(6):565-577.
22.Tripsianes K, Folkers G, Ab E, et al. The structure of the human ERCC1/XPF interaction domains reveals a complementary role for the two proteins in nucleotide excision repair.Structure [J].2005 Dec; 13 (12):1849-1858.
23. Selvakumaran M, Pisarcik DA, Bao R, et al.Enhanced cisplatin cytotoxicity by disturbing the nucleotide excision repair pathway in ovarian cancer cell lines [J].Cancer Res.2003 Mar 15;63 (6):1311-1316.
24. Chang IY, Youn CK, Kim HB, et al. Oncogenic H-Ras up-regulates expression of Ku80 to protect cells from gamma-ray irradiation in NIH3T3 cells[J].Cancer Res.2005 Aug 1;65(15):6811-9.
25.Olaussen KA, Dunant A, Fouret P,et al.DNA Repair by ERCC1 in Non-smail-cell Lung Cancer and Cisplatin-based Adjuvant Chemotherapy[J]. N Engl J Med,2006,355(10):983-991.
26.Ceppi P.Volante M,Novella S,et al.ERCCI and RRM1 Gene Expressions but not EGFR Ale Predictive of Shorter Survival in Advanced Non-small-cell Lung Cancer Treated with Cisplatin and Gemcitabine[J].Ann Oneol,2006,17(12):1818-1825.
27.Altaha R,Liang X,Yu J J,et al.Excision Repair Cross Complementing-group l:Gene Expression and Platinum Resistance [J].Int J Mol Med,2004;14(6):959-970.
28.Kang S,Ju W,Kim JW,et al.Association between Excision Repair Cross Complementation group 1 Polymorphism and Clinical outcome of Platinum-based Chemotherapy in Patients with Epithelial Ovarian Cancer[J].Exp Mol Med,2006,38 (3)1320-1324.
29. Su D, Ma S, Liu P, et al. Genetic polymorphisms and Treatment Response in Advanced Non-small-cell lung Cancer[J].Lung Cancer,2007,56(2)1281-288.
30. Matsubara J, Nishina T, Yamada Y, et al. Impacts of excision repair cross-complementing gene 1 (ERCC1), dihydropyrimidine dehydrogenase, and epidermal growth factor receptor on the outcomes of patients with advanced gastric cancer [J]. Br J Cancer 2008;98:832-839.
31. Kwon HC, Roh MS, Oh SY, et al. Prognostic value of expression of ERCC1, thymidylate synthase, and glutathione S-transferase P1 for 5-fluorouracil/oxaliplatin chemotherapy in advanced gastric cancer [J]. Ann Oncol 2007;18:504-509.
32. Wei J, Zou Z, Qian X,et al. ERCC1 mRNA levels and survival of advanced gastric cancer patients treated with a modified FOLFOX regimen [J]. Br J Cancer.2008;98 (8):1398-1402.
33. Kim JS, Kim MA, Kim TM, et al. Biomarker analysis in stage Ⅲ-Ⅳ (M0) gastric cancer patients who received curative surgery followed by adjuvant 5-fluorouracil and cisplatin chemotherapy:epidermal growth factor receptor (EGFR) associated with favourable survival [J]. Br J Cancer 2009; 100:732-738.
34. Napieralski R, Ott K, Kremer M, et al. Combined GADD45A and thymidine phosphorylase expression levels predict response and survival of neoadjuvant-treated gastric cancer patients [J]. Clin Cancer Res 2005; 11:3025-3031.
35.Olaussen KA, Dunant A, Fouret P, et al. DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy [J]. N Engl J Med 2006;355:983-991.
36.Lee KH, Min HS, Han SW, et al. ERCC1 expression by immunohistochemistry and EGFR mutations in resected non-small cell lung cancer [J]. Lung Cancer 2008; 60:401-407.
37.Simon GR, Sharma S, Cantor A, et al. ERCC1 expression is a predictor of survival in resected patients with non-small cell lung cance [J]r. Chest 2005;127:978-983.
1.Louvet C, Andre T, Tigaud JM, et al. Phase Ⅱ study of oxaliplatin, fluorouracil, and folinic acid in locally advanced or metastatic gastric cancer patients. J Clin Oncol 2002;20:4543-4548.
2. De Vita F, Orditura M, Matano E, et al. A phase Ⅱ study of biweekly oxaliplatin plus infusional 5-fluorouracil and folinic acid (FOLFOX-4) as first-line treatment of advanced gastric cancer patients [J]. Br J Cancer 2005;92:1644-1649.
3. Al-Batran SE, Atmaca A, Hegewisch-Becker S, et al. Phase Ⅱ trial of biweekly infusional fluorouracil, folinic acid, and oxaliplatin in patients with advanced gastric cancer[J]. J Clin Oncol 2004;22:658-663.
4. Lordick F, Lorenzen S, Stollfuss J, et al. Phase Ⅱ study of weekly oxaliplatin plus infusional fluorouracil and folinic acid (FUFOX regimen) as first-line treatment in metastatic gastric cancer [J]. Br J Cancer 2005;93: 190-194.
5.Cavanna L, Artioli F, Codignola C, et al. Oxaliplatin in combination with 5-fluorouracil (5-FU) and leucovorin (LV) in patients with metastatic gastric cancer (MGC) [J]. Am J Clin Oncol 2006;29:371-375.
6. Mauer AM, Kraut EH, Krauss SA, et al. Phase Ⅱ trial of oxaliplatin, leucovorin and fluorouracil in patients with advanced carcinoma of the esophagus[J]. Ann Oncol 2005;16:1320-1325.
7.Macdonald JS, Smalley SR, Benedetti J, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction[J]. N Engl J Med 2001,345:725-730.
8. Efferth T,Volm M.Pharmacogeneties for individualized cancer chemotherapy[J].Pharmacol Ther,2005, 107(2):155
9.LaFramboise T.Weir BA, Zhao X,et al.Allele-spe-cific amplification in cancer revealed by SNP array analysis[J].PLoS Comput Bid,2005,(6):e65.
10. Park DJ and Lenz HJ. Determinants of chemosensitivity in gastric cancer [J].Curr Opin Pharmacol.2006,6：337-344.
11.Mamenta EL, Poma EE, Kaufmann WK, et al. Enhanced replicative bypass of platinum-DNA adducts in cisplatin-resistant human ovarian carcinoma cell lines [J]. Cancer Res 1994;54:3500-350
12. Extra JM, Espie M, Calvo F, et al. Phase Ⅰ study of oxaliplatin in patients with advanced cance r [J]. Cancer Chemother Pharmacol 1990;25:299-303.
13. Park DJ, Stoehlmacher J, Zhang W, et al. A Xeroderma pigmentosum group D gene polymorphism predicts clinical outcome to platinum-based chemotherapy in patients with advanced colorectal cancer [J].Cancer Res.2001 Dec 15;61(24):8654-8658.
14.Ryu JS, Hong YC, Han HS, et al. Association between polymorphisms of ERCC1 and XPD and survival in non-small-cell lung cancer patients treated with cisplatin combination chemotherapy[J].Lung Cancer,2004,44(3):311-316.
15.Gurubhagavatula S,Liu G,Park,et al.XPD and XRCC1 genetic polymorphisms are prognostic factors in advanced non-small-cell lung cancer patients treated with platinum chemotherapy[J].J Clin Oncol,2004,22 (13):2594-2599.
16.Stoehlmacher J, Ghaderi V, Iobal S, et al.A polymorphism of the XRCC1 gene predicts for response to platinum based treatment in advanced colorectal cancer[J].Anticancer Res.2001 Jul-Aug;21(4B):3075-3079.
17.Stoehlmacher J, Park DJ, Zhang W, et al.Association between glutathione S-transferase P1, T1, and M1 genetic polymorphism and survival of patients with metastatic colorectal cance r [J].J Natl Cancer Inst.2002 Jun 19;94(12):936-942.
1.孙秀娣,牧人,周有尚,等.中国胃癌死亡率20年变化情况分析及其发展趋势预测[J].中华肿瘤杂志,2004,26(1)：4-8.
2.Richardson, M A, Sanders, T, Palmer, J L, et al. Complementary/alternative medicine use ina comprehensive cancer center and the implications foroncology[J]. J Clin Oncol.2000,18(13):2505-2514.
3.Chou TC, Talalay P. Quantitative analysis of dose effect relationships:the combined effects of multiple drugs or enzyme inhibitors[J]. Adv Enzyme Regul 1984;22:27-55
4.Livak KJ, Schmittgen TD. Analysis of relative gene expression data-using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method[J]. Methods,2001,25(4):402-408
5.李传刚,李墨林,舒晓宏,等.四君子汤对小鼠膀胱癌化疗的减毒增效作用[J].中国中西医结合杂志2005；25(4)：354-357.
6.曹勇,张丹,郑广娟,等.补肾化瘀解毒方对小鼠肝癌H22的抑瘤增效作用[J].中药材,2004；27(1)：38-39.
7.Longley D B, Harkin D P, Johnston P G.5-fluorouracil:mechanisms of action and clinical strategies[J]. Nat Rev Cancer 2003;3(5):330-338.
8.孙燕,石远凯.临床肿瘤内科手册[M].人民出版社.2008,481.
9.Ando T, Ishiguro H, Kuwabara Y, et al.Relationship between expression of 5-fluorouracil metabolic enzymes and 5-fluorouracil sensitivity in esophageal carcinoma cell lines[J].Dis Esophagus. 2008;21(1):15-20.
10.Salonga D, Danenberg KD, Johnson M, et al. Colorectal tumors responding to 5-fluorouracil have low gene expression levels of dihydro-pyrimidine dehydrogenase, thymidylate synthase, and thymi-dine phosphorylase[J]. Clin Cancer Res.2000;25 (6):1322-1327.
11.Theisen J, Danenberg K, Ott K, et al.Predictors of response and survival for neo-adjuvant treated patients with esophageal adenocarcinoma[J]. Dis Esophagus.2008; 21 (7):601-606.
12.Park DJ, Lenz HJ. Determinants of chemosensitivity in gastric cancer[J].Curr Opin Pharmacol.2006; 6(4):337-344.
13.Wei J, Liu B, Wang L,et al. Synergistic interaction between tetrandrine and chemotherapeutic agents and influence of tetrandrine on chemotherapeutic agent-associated genes in human gastric cancer cell lines[J]. Cancer Chemother Pharmacol.2007;60 (5):703-711.
1.Louvet C, Andre T, Tigaud JM, et al. Phase Ⅱ study of oxaliplatin, fluorouracil, and folinic acid in locally advanced or metastatic gastric cancer patients[J]. J Clin Oncol 2002;20:4543-4543.
2.De Vita F, Orditura M, Matano E, et al. A phase Ⅱ study of biweekly oxaliplatin plus infusional 5-fluorouracil and folinic acid (FOLFOX-4) as first-line treatment of advanced gastric cancer patients [J].Br J Cancer 2005;92:1644-1649.
3.Al-Batran SE, Atmaca A, Hegewisch-Becker S, et al. Phase Ⅱ trial of biweekly infusional fluorouracil, folinic acid, and oxaliplatin in patients with advanced gastric cancer[J]. J Clin Oncol 2004;22:658-663.
4.Lordick F, Lorenzen S, Stollfuss J, et al. Phase Ⅱ study of weekly oxaliplatin plus infusional fluorouracil and folinic acid (FUFOX regimen) as first-line treatment in metastatic gastric cancer [J]. Br J Cancer 2005;93: 190-194.
5.Cavanna L, Artioli F, Codignola C, et al.Oxaliplatin in combination with 5-fluorouracil (5-FU) and leucovorin (LV) in patients with metastatic gastric cancer (MGC) [J]. Am J Clin Oncol 2006;29:371-375.
6.Mauer AM, Kraut EH, Krauss SA, et al. Phase Ⅱ trial of oxaliplatin, leucovorin and fluorouracil in patients with advanced carcinoma of the esophagus[J]. Ann Oncol 2005;16:1320-1325.
7.文磊.中药复方治疗胃癌的临床研究进展[J].辽宁中医药大学学报,2008,10：68-70.
8.Chou TC, Talalay P. Quantitative analysis of dose effect relationships:the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 1984;22:27-55
9. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method[J]. Methods,2001,25(4):402-408
10.李财宝,龚航军.149例胃癌术后化疗与中药综合治疗临床观察[J].上海中医药杂志,2002(2)：15-16.
11.王纪东,王丽亚,李夏昀.中西医结合治疗中晚期胃癌92例临床分析[J].现代中西医结合杂志,2004,13(17)：2281-2282.
12.暴宪斌,沈俊兰.参芪五味子片对进展期胃癌化疗患者的影响[J].中国中医药信息杂志,2004,11(11)：1004-1005.
13.陈郭君,薛曼朗,王先菊.脾肾方对晚期胃癌化疗中减毒作用的临床研究[J].湖北中医杂志,2001,23(7)：9-10.
14. Zhao JS, Li QD Q,Zou BB,et al.In vitro combination characterization of the new anticancer plant drug beta-elemene with taxanes against human lung carcinoma [J]. Int J Oncol.2007 (31)2:241-252
15. David J Park and Heinz-Josef Lenz.Determinants of chemosensitivity in gastric cancer [J]. Curr Opin Pharmacol.2006,6:337-344.
16. Bernstein C, Bernstein H, Payne CM, et al. DNA repair/proapoptotic dual-role proteins in five major DNA repair pathways:fail-safe protection against carcinogenesis.[J]. Murat Res,2002, 511(2):145-178.
17.Gillet LC,Scharer OD,Molecular mechanisms of mammalian global genome nucleotide excision repair[J].Chem Rev 2006,106:253-276.
18. Reardon JT, Sancar A, Nucleotide excision repair [J].Prog Nucleic Acid Res Mol Biol 2005,79:183-235.
18. Reed E. Platinum-DNA adduct,nucleotide excision repair and platinum based anti-cancer chemotherapy [J].Cancer Treat. Rev.1998;24:331-344.
19. Olaussen KA, Mountzios G, Soria JC.ERCC1 as-a risk stratifier in platinum-based chemotherapy for nonsmall-cell lung cancer [J]. Curr Opin Pulm Med.2007; 13 (4):284-289.
20. Wei J, Zou Z, Qian X,et al. ERCC1 mRNA levels and survival of advanced gastric cancer patients treated with a modified FOLFOX regimen [J].Br J Cancer.2008;98 (8):1398-1402.
21. Wei J, Liu B, Wang L, et al.Synergistic interaction between tetrandrine and chemotherapeutic agents and influence of tetrandrine on chemotherapeutic agent-associated genes in human gastric cancer cell lines [J].Cancer Chemother Pharmacol.2007 Oct;60(5):703-711.
22. Hayward RL, Macpherson JS, Cummings J, et al. Enhanced oxaliplatin-induced apoptosis following antisense Bcl-xl down-regulation is p53 and Bax dependent:Genetic evidence for specificity of the antisense effect[J].Mol Cancer Ther.2004;3(2):169-178
1.Overman MJ, Kazmi SM, Jhamb J, et al.Weekly docetaxel, cisplatin, and 5-fluorouracil as initial therapy for patients with advanced gastric and esophageal cancer[J].Cancer.2010,116(6):1446-1453
2.Chon HJ, Rha SY, Im CK, et al.Docetaxel versus Paclitaxel Combined with 5-FU and Leucovorin in Advanced Gastric Cancer:Combined Analysis of Two Phase II Trials[J].Cancer Res Treat.2009, 41(4):196-204.
3.Yamamoto K, Fujiwara Y, Nishida T, et al.Induction chemotherapy with docetaxel,5-FU and CDDP (DFP) for advanced gastric cancer[J].Anticancer Res.2009;29(10):4211-4215
4.Zhong H, Zhang Y, Ma S, et al.Docetaxel plus oxaliplatin (DOCOX) as a second-line treatment after failure of fluoropyrimidine and platinum in Chinese patients with advanced gastric cancer[J].Anticancer Drugs.2008 Nov;19(10):1013-1018
5.Kim YH, Seo HY, Jeen YT,et al. Phase Ⅰ dose escalation study of docetaxel with a fixed dose of S-1 in combination chemotherapy for advanced gastric cancer.Cancer Chemother Pharmacol[J].2009 Jan;63(2):253-260.
6.Park SR, Kim HK, Kim CG, et al.Phase Ⅰ/Ⅱ study of S-1 combined with weekly docetaxel in patients with metastatic gastric carcinoma[J].Br J Cancer.2008 Apr 22;98(8):1305-1311.
7.Chou TC, Talalay P. Quantitative analysis of dose effect relationships:the combined effects of multiple drugs or enzyme inhibitors [J]. Adv Enzyme Regul 1984;22:27-55.
8. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method[J]. Methods,2001,25 (4):402-408.
9.Crown J,O'Leary M.The taxanes:An update[J].Lancet,2000.355:1176-1178.
lO.Sulkes A, Smyth J, Sessa C, et al. Docetaxel (Taxotere) in advanced gastric cancer:results of a phase II clinical trial EORTC Early Clinical Trials Group [J]. Br J Cancer.1994,70(2):380-383.
11.Ajani JA, Fodor MB, Tjulandin SA, et al. Phase Ⅱ multi-institutional randomized trial of docetaxel plus cisplatin with or without fluorouracil in patients with untreated, advanced gastric, or gastroesophageal adenocarcinoma[J]. J clin Oncol,2005,23(24):5660-5667.
12. Zhao JS, Li QD Q, Zou BB, et al.In vitro combination characterization of the new anticancer plant drug beta-elemene with taxanes against human lung carcinoma [J]. Int J Oncol.2007 (31)2:241-52.
13.曹勇,张丹,郑广娟,等.补肾化瘀解毒方对小鼠肝癌H22的抑瘤增效作用[J].中药材2004；27(1)：38-39.
14.郑昱,刘宝瑞,邹玺.土元乳液对胃癌化疗药物增效作用的体外研究[J],中国临床药理学与治疗 学,2006(11)3：354-356.
15.李财宝,龚航军.149例胃癌术后化疗与中药综合治疗临床观察[J].上海中医药杂志,2002(2)：15.
16.王纪东,王丽亚,李夏昀.中西医结合治疗中晚期胃癌92例临床分析[J].现代中西医结合杂志,2004.13(17)：2281.
17.陈郭君,薛曼朗,王先菊,脾肾方对晚期胃癌化疗中减毒作用的临床研究[J].湖北中医杂志,2001,23(7)：9-10.
18.Hasegawa S,Miyoshi Y,Egawa C,et al.Prediction of response to docetaxel by quantitative analysis of Class Ⅰ and Ⅲ beta-tubulin isotype mRNA expressi'on in human breast cancers[J]. Clinical Cancer Research,2003,9:2992.
19.Miyoshi Y,Ando A,Takamura Y,et al.Prediction of response to docetaxel by CYP3A4 mRNA expression in breast cancer tissues[J].Int J Cancer,2002,97(1):129-132.
20.Seve P,Dumontet C.Is class Ⅲ beta-tubulin a predictive factor in patients receiving tubulin-binding agents? [J] Lancet Oncol 2008;9:168-175.
21.Pusztai L. Markers predicting clinical benefit in breast cancer from microtubule-targeting agents [J]. Ann Oncol 2007; 18(Suppl 12):xiil5-20.
22.Rouzier R, Rajan R, Wagner P, et al.Microtubule-associated protein tau:a marker of paclitaxel sensitivity in breast cancer[J]. Proc Natl Acad Sci USA 2005;102:8315-8320.
23.Fabbri F,Carloni S,Brigliadori G,et al.Sequential events of apoptosis involving docetaxel. a microtuble interfering agent:acytometric study[J].BMC Cell Biol 2006,7:6.
1.吴雪卿.补益中药抗癌作用研究进展[J].湖南中医药导报,1999,5(9)：10-13.
2.苏勉诚,戴梅,吕晓英,等.中药复方癌宁对人胃腺癌细胞凋亡基因表达的影响[J].中药材.2002,25(8)：563-566.
3.杨勤建,雷良蔚,潘希雄,等.中药复方香龙散诱导人胃腺癌细胞凋亡的研究[J].湖北中医学院学报,1999,1(1)：43-45.
4.孙宏丹,贾莉,孟秀香,等.复方中药诱导Burkitt's淋巴瘤Raja细胞凋亡作用的研究[J].白血病·淋巴瘤,2002,11(2)：84-86.
5.陈志奎,林礼务,王艳,等.瘤内注射复方中药“99-克星”的活性组分抗肝癌作用及机制[J].中华医学超声杂志,2006,10(3)：266-268.
6.黄新苏,陈福,许锦阶.复方中药“克瘤宁”对人食管癌的抗癌作用及其机理研究[J].河北医学.2006,12(3)：193-195.
7.谭德明,刘作金,吴勇,等.“肝癌一号”对裸鼠人肝癌移植瘤生长的抑制作用及机制研究[J].重庆医学,2007,36(14)：1391-1394.
8.刘坚,谢红东,李瀚,等.中药复方搏癌丸对人肝癌细胞周期及bax、bcl-2、p53基因表达调控的影响[J].中西医结合肝病杂志,2004,14(3)：152-155.
9.郑瑾,刘强,王宗仁,等.活血化淤中药复方诱导K562细胞凋亡[J].第四军医大学学报,2003,24(5)：247-249.
10.金春峰,王守岩,蔡玉文,等.中药复方诱导肿瘤细胞凋亡的研究述评[J].辽宁中医学院学报,2004,6(3)：233-234.
11.罗晶,郭焱,勾敏慧,等.人参养荣汤对小鼠免疫功能的调节[J].中国现代医学杂志,2002,12(5)：27-281.
12.戴馨仪,陈林香,周岱翰,等.清金得生片抗肿瘤机理研究[J].中药新药与临床药理,2002,13(6)：360-3621.
13.王美,秦筱梅.中药复方JHL 抗肿瘤作用研究[J].青岛大学医学院学报,2004,40(2)：110-111.
14.杨文修.大承气汤对内毒素刺激巨噬细胞分泌肿瘤坏死因子的抑制作用[J].中国中西医结合外科杂志,2001,7(6):390-3921.
15.张运芳,李俊,金涌,等.芪加合剂对荷瘤小鼠体液免疫功能的影响[J].安徽医科大学学报,2000,35(2)：118-1201.
16.杨志强,王润田,等.中药复方抑瘤饮影响荷S180瘤小鼠免疫功能的动态研究[J].现代免疫学,2006,26(1)：64-68.
17.郑红刚,朴炳奎,林洪生,等.中药复方肺瘤平膏对树突状细胞功能影响的拆方研究[J].北京中医药大学学报,2007,30(8)：525-528,549.
18.李伟,胡凯文,苏伟.浙贝母散剂逆转急性白血病多药耐药的临床研究[J].北京中医药大学学报,2004,27(1)：63-65.
19.徐力,王明艳,许冬青.三物加白散加味方影响肿瘤多药耐药基因表达实验研究[J].上海中医药杂志,2005,39(8)：59-60.
20.姚祖仁,王亚非,姚祖培.肺腺癌多药耐药细胞株SPCA1/ADM的建立及中药方剂提取物A2的逆转作用研究[J].中医药研究,2001,17(4)：404324.
21.冯正权,郭勇,朱广希.复方三根制剂逆转多药耐药的实验研究[J].中国肿瘤,2003,12(6)：370-371.17.于广梅,郭继龙.中药及其有效成分抑制肿瘤血管生长的研究近况[J].山东中医杂志,2003,22(11)：694-6951.
22.田菲,贾英杰,陈军,等1肺一丸对肺癌血管生成及转移影响的实验研究[J].天津中医药,2003,20(5)：56-581.
23.施京红,刘德传,吴仕九,等1清香散对湿热型肝癌模型大鼠细胞凋亡、肿瘤血管生成的影响[J].陕西中医,2004,25(1)：84-861.
24.赵凤鸣,王明艳,吴海涛等.两首滋阴方药对环磷酰胺诱发的微核的抑制作用[J].福建中医药,1998(4)：91.
25.戴恩来,赵健雄,朱玉真,等.扶正抑瘤汤对肿瘤细胞周期主端粒酶影响的实验研究[J].中国中西医结合杂志,2001,21(10)：760-762.
26.王玉荣,王泽时.加味四君子汤诱导小鼠肿瘤细胞凋亡的实验研究[J].山西中医学院学报,2004,5(1)：16-18.
27.顾锦华,张伟,李锋.复方龙葵胶囊抗肿瘤作用及其对肿瘤细胞周期分布的影响[J].时珍国医国药,2006,17(12)2463-2464.
28.陈少全,陈菊祥,毛裕民,等.基因表达谱芯片在筛选胃腺癌相关基因中的应用[J].第二军医大学学报.2001,22(6)：523-525.
29.王顺启,陈力,倪虹,等.中药复方H3C-1对肝癌细胞SMMC-7721基因表达的影响[J].药物生物技术,2008,15(3)：176-179.
30.高鹏,许运明,峁俊卿,等.扶正消瘤液对肿瘤患者生活质量影响的临床研究[J].现代肿瘤医学,2003,11(4)：263-2641.
31.张义泽,李兴菊,宋丽华.中药在恶性肿瘤化疗中的减毒增效作用研究[J].山东中医杂志,1998,17(11)：488-4891.
32.朱海洪,姜国盛.中药内外治疗中晚期肝癌38例[J].中医杂志,2002,43：6109-6111.
33.李春青,李泽宇,李新.复方苦参注射液联合化疗治疗晚期消化道肿瘤的近期疗效观察[J].现代肿瘤医学,2006,14(14)：986-987.