胸苷酸合成酶预测胃癌化疗敏感性的研究

目的 探讨胃癌组织中TS的表达及其对胃癌DDP+5-Fu化疗敏感性的预测价值.方法 60例胃癌均接受2个周期DDP+5-Fu化疗.化疗方案:DDP 15～20 ms/(m2·d),静脉滴注,d1～5;5-Fu 375～500 mg/(m2·d),静脉滴注8h,d1～5.间隔4周后,进行第2个周期化疗.采用免疫组织化学S-P法检测胃癌组织中TS的表达.结果 60例胃癌中TS高表达者29例,化疗有效率34.5%(10/29),TS低表达者的化疗有效率为64.5%(20/31),两者比较差异具有统计学意义(P<0.05).结论 胃癌组织中TS表达水平对胃癌DDP+5-Fu化疗的敏感性具有一定预测价值.     

周剂量紫杉醇联合LFP方案治疗晚期食管癌的临床观察

目的 评价周剂量紫杉醇(PTX)联合氟脲嘧啶(5-Fu)、顺铂(DDP)和醛氢叶酸(CF)组成PLFP方案治疗晚期食管癌的临床疗效和毒副反应.方法 16例Ⅲ、Ⅳ期晚期食管癌,给予周剂量PTX LFP(CF 5-Fu DDP),即PTX 80 mg/m2,iv gtt qw,连续2周;DDP 80 mg/m2,iv gtt,d3-5;5-Fu 500 mg/m2,iv gtt,d1-5;CF 100 mg/次,iv gtt,在5-Fu前2 h内给药,d1-5,21 d为1周期,2周期后按UICC标准评价近期疗效和毒副反应.结果 全组16例,全都可评价疗效,总有效率56.3%,11例初治组有效率为63.6%,其中CR 1例.5例复治组有效率为40%.毒副反应主要为剂量限制性毒性,表现为Ⅱ～Ⅲ度为主的骨髓抑制.结论 周剂量紫杉醇联合氟脲嘧啶、顺铂和醛氢叶酸组成的PLFP方案可能是治疗晚期食管癌较好的化疗方案,值得进一步观察.     

胃癌患者血清DPD mRNA和TS mRNA表达对替吉奥疗效预测价值分析

目的 探讨进展期胃癌(advanced gastric carcinoma,AGC)患者二氢嘧啶脱氢酶(thymidine phosphorylase,DPD) mRNA和胸苷酸合成酶(thymidylate synthase,TS) mRNA表达与含替吉奥(S-1)方案化疗疗效的关系.方法 收集2012-09-01-2013-09-01苏州市相城人民医院收治经病理确诊的AGC患者40例,化疗前抽取外周血采用RT-PCR法检测DPD mRNA及TS mRNA表达水平,给予含S-1的方案:S-1(40 mg/m2,2次/d,口服14 d)+顺铂(DDP,75 mg/m2,静脉滴入,d1)化疗.分析DPD mRNA及TS mRNA表达与化疗疗效的关系.结果 RT-PCR检测结果显示,40例患者的DPD mRNA和TS mRNA表达相对于β-actin的相对数值分别为2.53±1.86和0.636±0.363.DPDmRNA和TS mRNA表达水平之间有显著相关性,r=0.68,P＜0.01.AGC患者外周血中DPD mRNA表达与Lauren分型显著相关,x2 =3.259,P=0.032.TS mRNA表达则与是否有远处转移显著相关,x2 =3.294,P=0.040. DPDmR-NA及TS mRNA均是表达越高患者疗效越差,表达越低患者疗效越好,r=0.708,P＜0.01;r=0.728,P＜0.01.联合分析显示,DPD mRNA及TS mRNA同时低表达时疗效更好,x2 =13.23,P=0.004.结论 DPD mRNA及TS mRNA表达可单独或联合用于预测AGC患者对含S-1方案的化疗疗效,初步研究结果提示可以根据患者外周血DPD mRNA及TS mRNA表达来指导胃癌的个体化治疗.     

食管癌BRCA1和β-tubulin Ⅲ mRNA表达与紫杉类耐药性的临床研究

  目的  检测食管癌组织BRCA1、β-tubulin Ⅲ mRNA的表达,探讨与紫杉类耐药性的关系。  方法  收集36例晚期食管癌组织标本,采用RTq-PCR方法检测组织中BRCA1、β-tubulin Ⅲ mRNA表达,分析二者与紫杉类药物耐药性的关系。  结果  BRCA1相对于内参基因β-actin的中位值为6.27;β-tubulin Ⅲ相对于内参基因β-actin的中位值为4.44。以中位值作为cutoff值,36例标本根据cutoff值分为低表达组和高表达组。BRCA1高表达组的有效率66.7%（12/18）稍高于低表达组55.6%（10/18）,但二者差异无统计学意义（P=0.733）。β-tubulin Ⅲ低表达组的有效率83.3%（15/18）显著高于高表达组38.9%（7/18）,差异有统计学意义（P=0.015）。  结论  BRCA1 mRNA表达水平与紫杉类药物敏感性差异无统计学意义。β-tubulin Ⅲ mRNA表达水平与紫杉类药物敏感性之间存在相关性。提示β-tubulin Ⅲ可以作为紫杉烷类药物在晚期食管癌中疗效的预测因子。      

长春瑞滨联合顺铂、亚叶酸钙/5-氟脲嘧啶治疗晚期食管癌

目的:观察长春瑞滨(NVB)联合亚叶酸钙(CF)、5-氟脲嘧啶(5-Fu)和顺铂(DDP)方案治疗晚期食管癌的近期疗效和毒性反应.方法:NVB 25mg/m2静脉注入,第1、8天给药;CF 200 mg静滴,第2天～6天给药;5-Fu 500mg/m2静滴6小时,第2天～6天给药;DDP 35mg/m2静滴,第2天～4天给药.28天为一个周期,完成2周期化疗后评价疗效.结果:23例晚期食管癌患者中,完全缓解2例(8.7%),部分缓解10例(43.5%),总有效率为52.2%.毒副反应主要是骨髓抑制、胃肠道反应、静脉炎.结论:NVB联合DDP、CF及5-Fu方案治疗晚期食管癌疗效较好,毒副反应可以耐受,是一个较好的联合化疗方案.     

羟基喜树碱联合氟尿嘧啶顺铂治疗晚期食管癌的疗效观察

目的 观察HCPT＋DDP＋5-Fu方案治疗晚期食管癌的疗效。方法 本组晚期食管癌38例。HCPT6～8mg／m^2，d1～5，DDP60～80mg／m^2，d1，5-Fu0．6g／m^2，d1=5；21天或28天为1周期，每例至少完成3周期。结果 38例中无一例CR，18例PR，9例SD，11例PD，有效率47．3％。结论 HCPT＋DDP＋5-Fu方案治疗晚期食管癌有效，毒副反应能耐受。     

多西紫杉醇联合低剂量氟尿嘧啶持续静脉输注治疗中晚期食管癌的近期疗效观察

目的 观察国产多西紫杉醇联合低剂量氟尿嘧啶(5-Fu)持续静脉输注治疗中晚期食管癌的近期疗效和毒副反应.方法 20例中晚期食管癌患者行此方案化疗,多西紫杉醇40 mg/(m2·d),静脉滴注1 h,第1,8天;5-Fu 250 mg/(m2·d),低剂量持续泵静脉输注24 h,连用14 d.以上方案每4周为1周期,2周期观察近期疗效和毒副反应.结果 20例患者均可评价疗效,其中CR 1例,PR 10例,SD 5例,PD 4例,总有效率55.0%(11 / 20).主要毒副反应为骨髓抑制,非血液学毒性轻微.结论 多西紫杉醇联合5-Fu低剂量持续泵静脉输注治疗中晚期食管癌具有较好疗效,副反应轻,耐受性好.     

胃癌术后OXA+5-FU/LV联合DDP腹腔灌注辅助化疗疗效观察

目的:探讨OXA+5-FU/LV联合DDP腹腔灌注辅助化疗对胃癌的疗效.方法:OXA 85mg/㎡ d1+LV 0.2/㎡ d1-2+5-Fu 0.4/㎡ d1-2+5-FU 1.2/㎡ 44h双周方案,共执行6个月化疗,腹腔灌注化疗:DDP60mg每周,共6周后停用.结果:2004年1月-2009年7月共收治96例胃癌术后病人,83例完成12周期化疗,4年生存率55.4%,5年生存率40.9%,13例因为年龄、不良反应和经费等原因未能完成计划,无不良反应致死,总体不良反应耐受良好.结论:OXA+5-FU/LV联合DDP腹腔灌注辅助化疗胃癌疗效确切且不良反应低.     

紫杉醇联合化疗方案治疗晚期胃癌的疗效观察

目的 观察国产紫杉醇(PTX)联合5-氟脲嘧啶(5-Fu)、羟基喜树碱(HCPT)、顺铂(DDP)方案治疗晚期胃癌的疗效和毒副反应.方法 采用PTX 135 mg/m2,加入生理盐水静滴3 h,d1;5-Fu 300 mg/m2,静滴,d1-5;HCPT 8 mg/m2,静滴,d1-5;DDP 20 mg/m2,静滴,d1-5;3～4周为1周期,行2周期治疗后判定疗效.结果 42例中38例可评价疗效,全组完全缓解(CR)1例(2.6%),部分缓解(PR)15例(39.5%),稳定(NC)16例(42.1%),进展(PD)6例(15.8%),有效率(CR PR)42.1%.毒副反应以骨髓抑制、脱发和关节肌肉痛为主,其它毒副反应均较轻微可耐受,无化疗相关死亡.结论 紫杉醇为主方案治疗晚期胃癌疗效肯定,毒副反应能耐受,值得进一步在临床使用.     

同步放化疗治疗中晚期食管癌60例

目的 观察对中晚期食管癌患者同步放化疗,疗效及毒副作用.方法 中晚期食管癌120例,随机分放化疗组60例(简称放化组)和单纯放疗组60例(简称单放组).放疗采用常规分割,DT40 Gy后缩小照射野,避开脊髓斜野照射,加量DT20～30 Gy,6～7周完成.放化组放疗1、4周后应用顺铂(DDP)20 mg/d、亚叶酸钙(CF)0.1 g/d,CF静脉滴注1/2量时5-氟尿嘧啶(5-Fu)500 mg/d静脉滴注,连续5 d为1个周期,化疗当天进行放疗.结果 放化组与单放组1、2、3年生存率分别为67%、46%、34%和52%、38%、24%;放射性肺炎分别为14例和12例;外周血细胞下降分别为26例和17例;胃肠道反应分别为25例和9例;死亡分别为38例和48例.两组治疗效果比较差异有统计学意义(P＜0.05).结论 放疗同步PLF方案化疗治疗中晚期食管癌生存率高,毒副作用及不良反应低.     

ERCC1和TS基因多态性在预测顺铂联合5-氟尿嘧啶治疗晚期食管癌疗效中的意义

目的:探讨切除修复交叉互补基因1(excision repair cross-complementation group 1,ERCC1)、胸苷酸合成酶(thymidylate synthase,TS)、谷胱苷肽-S-转移酶P1(glutathione-S-transferase P1,GSTP1)和亚甲酰四氢叶酸还原酶(methylenetetrahydrofolate reductase,MTHFR)的基因多态性,在预测顺铂联合5-氟尿嘧啶治疗晚期食管癌疗效中的作用. 方法:107例晚期食管癌患者入组并行顺铂联合5-氟尿嘧啶共3个周期的化疗,最终98例患者按要求完成该治疗且有随访资料.通过测序的方法检测98例患者上述基因位点的多态性,分析基因多态性与化疗客观反应率(response rate,RR)和无进展生存 (progression-free survival,PFS) 期的关系. 结果: ERCC1-C8092A位点A/A或A/C型患者的RR和PFS期优于C/C型患者(P=0.010和P=0.008).TS基因5'端非翻译区(five prime untranslated region,UTR)为2R2R、2R3C或3C3C型患者的RR和PFS期优于2R3G、3C3G或3G3G型患者(P=0.007和P=0.018).GSTP1和MTHFR基因位点的多态性与RR和PFS期无显著相关性.结论:ERCC1-C8092A位点为A/A或A/C型,TS-5'UTR位点为2R2R、2R3C或3C3C型的晚期食管癌患者对顺铂联合5-氟尿嘧啶治疗方案更为敏感.     

TS mRNA表达与食管鳞癌患者5-FU化疗临床预后的相关研究

目的：探讨食管鳞癌石蜡包埋组织中胸腺嘧啶核苷酸合成酶基因（thymidylate synthase,TS）mRNA表达水平与接受氟尿嘧啶（Fluorouracil,5-FU）化疗的患者临床病理的关系及其预后意义。方法：采用实时荧光定量RT-PCR检测22例福尔马林固定-石蜡包埋食管鳞癌组织TS mRNA的表达水平,并比较其表达水平与接受5-FU化疗的患者的临床病理及生存期之间的关系。结果：TS mRNA的表达水平与患者年龄、性别、肿瘤分化程度、TNM分期、是否吸烟饮酒、浸润深度、淋巴结转移、远处转移、血管侵犯以及神经累及均无显著性相关（P〉0.05）。TS mRNA的表达水平与食管鳞癌肿瘤组织COX2（P=0.419）、p53（P=0.804）、PCNA（P=0.555）、VEGF（P=0.184）、MDR（P=0.593）、EGFR（P=0.482）、SSTR2（P=0.377）的蛋白表达情况均无显著相关性。以5-FU为基础化疗的食管鳞癌患者,TS mRNA低表达者的总生存时间较TS mRNA高表达者明显延长（P=0.017）。经COX多因素回归分析显示,食管鳞癌肿瘤组织中TS mRNA表达水平可以成为以5-FU为基础化疗的食管鳞癌患者独立的预测指标（P=0.029,95%CI：1.161-16.278）。结论：TS mRNA表达可能与食管鳞癌患者5-FU化疗后总生存时间（OS）呈负相关。食管鳞癌肿瘤组织中TS mR-NA表达水平可以作为预测以5-FU为基础化疗患者预后的独立指标。TS mRNA表达水平与食管鳞癌的恶性生物学行为无相关性。     

Experimental chemotherapy against human esophageal carcinoma xenografts with TS-1, cisplatin and docetaxel

Three strains of human esophageal carcinoma xenografts established in our institution were tested against combination chemotherapy in vivo and in vitro. TS-1 plus cisplatin (CDDP) was shown to be an effective combination against two carcinoma strains of moderately-differentiated type. Determination of the thymidylate synthase (TS) demonstrated a higher inhibition of the enzyme by adding CDDP to 5-FU, suggesting biochemical modulation. The remaining strain of poorly-differentiated type was resistant to the combination and an attempt was made to add docetaxel (DTX) to show that the three-drug combination was effective against the strain. Combination chemotherapy including TS-1 and CDDP thus appears to be useful treatment choice for esophageal carcinoma.     

Chemoradiotherapy with low-dose cisplatin and 5-FU for advanced esophageal cancer

We evaluated the efficacy of chemoradiotherapy (CRT) for advanced esophageal cancer, from the view point of response. The relationship between chemo-radiosensitivity and dihydropyridine dehydrogenase (DPD), thymidylate synthase (TS), and p53 was investigated immunohistochemically. Thirteen patients with inoperable advanced esophageal cancer were involved in this study. CDDP of 10 mg/m2/day and 5-FU of 335 mg/m2/day were infused intravenously (day 1-5, day 15-19). Radiation was delivered concomitantly at a total dose of 30 Gy. Expressions of p53, DPD and TS were detected using immunohistology in the biopsy samples taken before CRT from 8 patients. Partial response was observed in 8 cases, no change in 4 cases, and progressive disease in one case. The overall response rate was 62%. The reduction rate was higher in tumors positive for p53 expression than in negative ones. The same was true for DPD and TS. The Treatment effect was more precisely predicted by combination of p53, DPD and TS. CRT with low-dose CDDP + 5-FU chemotherapy was effective and combination with p53, DPD, and TS might be a predictive marker for CRT in patients with advanced esophageal cancer.     

胃癌组织中胸苷酸合成酶、胸苷磷酸化酶mRNA表达及其临床意义

背景与目的:化学治疗在胃癌治疗中扮演了重要的作用。通过肿瘤组织中某些基因表达的水平来选择化疗药物已成为今后化疗的方向。胸苷酸合成酶(TS)、胸苷磷酸化酶(TP)是氟尿嘧啶(5-FU)体内的关键代谢酶,其表达水平影响恶性肿瘤患者接受5-FU化疗后的预后。本研究探讨胃癌组织中TS、TP mRNA表达水平与预后的关系。方法:采用实时定量RT-PCR技术检测51例胃腺癌组织TS、TP mRNA表达水平。结果:胃癌组织TS、TP mRNA表达水平的中位数分别为0.94和21.20,TS高表达组和低表达组之间无瘤生存期和总生存期差异有显著性(P<0.05),TP高表达组和低表达组之间总生存期差异有显著性(P<0.05),但无瘤生存期之间差异无显著性(P>0.05)。TS、TP mRNA表达与年龄、性别、淋巴结转移、组织学分级及临床分期均无相关性(P>0.05)。结论:检测TS、TP mRNA表达水平对接受5-FU为基础治疗方案的胃癌患者的预后有很好的预测价值。     

Immunostaining of thymidylate synthase and p53 for predicting chemoresistance to S-1/cisplatin in gastric cancer

High expression of thymidylate synthase (TS) and inactivation of p53 are allegedly associated with chemoresistance. The authors evaluated TS and p53 expression in gastric cancer treated with neoadjuvant S-1/cisplatin chemotherapy. Paraffin sections of pretreatment biopsy and surgical specimens from 41 gastric cancers were immunostained for TS and p53 protein after appropriate antigen retrieval. Fifty-one cases without neoadjuvant chemotherapy were also studied. In the pretreatment biopsies, high expression of TS was seen in 8% of the histologic responders, in 28% of the nonresponders and in 31% of the controls. High expression of p53 was observed in 56% of the nonresponders, but in 8% of the responders and in 29% of the controls (P<0.01 and P<0.05, respectively). The TS- and/or p53-high phenotype was seen in 76% of the nonresponders and in 54% of the controls, but in 8% of the responders (P<0.0001 and P<0.005, respectively). The data of the surgical specimens were consistent with those of the pretreatment biopsies. These results suggest that immunostaining for TS and p53 protein is useful for pretreatment selection of gastric cancer patients unresponsive to S-1/cisplatin chemotherapy.     

Prognostic value of p53, glutathione S-transferase pi, and thymidylate synthase for neoadjuvant cisplatin-based chemotherapy in head and neck cancer.

Neoadjuvant cisplatin-based chemotherapy has been widely used in the last decade for organ preservation or unresectable disease in advanced stage head and neck cancer. We examined the expression of a series of tumor markers that have been associated with chemotherapy resistance in pretreatment biopsies from 68 patients who received cisplatin-based neoadjuvant chemotherapy at either of two institutions. Patients received either cisplatin/5-fluorouracil (n = 49) or cisplatin/paclitaxel (n = 19). Expression of p53, glutathione S-transferase pi (GSTpi), thymidylate synthase (TS), c-erbB2, and multidrug resistance-associated protein was examined by immunohistochemistry. Expression of glutathione synthetase mRNA was measured by in situ hybridization. The overall response rate for cisplatin-based neoadjuvant treatment was 79%. The expression of several of the tumor markers was associated with resistance to neoadjuvant treatment, but none reached statistical significance. Overall survival (OS) was strongly correlated with the absence of p53 expression. The OS at 3 years was 81% in the p53-negative group, whereas it was 30% in the p53-positive group for patients treated with neoadjuvant chemotherapy (P < 0.0001). Expression of GST pi and TS was also significantly correlated with decreased OS after neoadjuvant treatment. At 3 years, the OS rate was 82% in the low GSTpi score group, compared to 46% in the high GSTpi score group (P = 0.0018). In the TS-negative group, the 3-year OS rate was 71% compared with 40% in the TS-positive group (P = 0.0071). We conclude that p53, GSTpi, and TS may be clinically important predictors of survival in patients receiving neoadjuvant chemotherapy for head and neck cancer.