P-gp、GST-π、TS蛋白在宫颈癌中的表达及临床意义

目的探讨宫颈癌组织中P-糖蛋白(P-gp)、谷胱甘肽S-转移酶-π(GST-π)和胸苷酸合成酶(TS)的表达及临床意义。方法采用免疫组化方法检测51例宫颈癌组织及9例正常宫颈组织中P-gp、GST-π和TS蛋白的表达情况。结果9例正常宫颈组织中,P-gp、TS蛋白均不表达,GST-π蛋白高表达4例(44.44%)。51例宫颈癌组织中,P-gp、GST-π和TS蛋白表达率分别为45.10%、62.75%和43.14%。宫颈癌组织中P-gp、TS蛋白的表达率高于正常组织(P<0.05)。宫颈癌中P-gp和GST-π蛋白共表达率为29.41%,GST-π和TS蛋白共表达率为29.41%,P-gp和TS蛋白共表达率为19.61%,3种耐药蛋白共表达率为13.73%。P-gp、GST-π和TS蛋白表达与宫颈癌组织分化和临床分期均不相关(P>0.05)。结论P-gp、GST-π和TS蛋白表达可能在宫颈癌的原发性多药耐药起重要作用。     

胃癌组织中P-gp、GST-π和TopoⅡ的表达及临床意义

目的 探讨胃癌组织中P-糖蛋白（P-gp)，谷胱甘肽S-转移酶（GST-π）和DNA拓扑异构酶（TopoⅡ）表达的临床意义。方法 应用免疫组织化学S-P法检测125例胃癌组织中P-gp,GST-π和TopoⅡ的表达情况，并结合临床病理因素进行分析。结果 125例胃癌组织中，P-gp阳性表达71例（56.8%),GST-π阳性表达78例（62.4%),TopoⅡ阳性表达108例。结论 联合检测P-gp,GST-π和TopoⅡ对制定胃癌化疗方案有一定的指导意义。     

乳腺癌组织细胞体外对化疗药物敏感性检测结果与GST-πTopoⅡ表达的关系

目的:探讨乳腺癌组织细胞体外对化疗药物敏感性检测结果(ATP-TCA法)与GST-π、TopoⅡ表达的关系.方法:用ATP-TCA法检测45例乳腺癌标本对4种常用化疗单药表阿霉素(EPI)、紫杉醇(PTX)、多西紫杉醇(TXT)、吉西他滨(GEM)及2种联合用药表阿霉素+多西紫杉醇(EPI+TXT)和环磷酰胺+表阿霉素+5-氟尿嘧啶(CEF)的敏感性,并用免疫组化方法检测乳腺癌组织GST-π、TopoⅡ的表达.结果:ATP-TCA检测结果显示,表阿霉素、紫杉醇、多西紫杉醇、吉西他滨体外对乳腺癌细胞增殖抑制率分别为62.2%、35.6%、8.9%、15.6%;联合用药EPI+TXT、CEF的抑制率分别是77.8%、73.3%,高于单药紫杉醇、多西紫杉醇、吉西他滨,有显著性差异,P<0.01.45例乳腺癌标本中GST-π阳性表达率为44.4%(20/45),TopoⅡ阳性表达率为62.2%(28/45).在GST-π表达阴性或TopoⅡ表达阳性时,表阿霉素、EPI+TXT及CEF方案对乳腺癌组织细胞增殖抑制率较高,有显著性差异,P<0.01.结论:ATP-TCA法结合GST-π、TopoⅡ的表达可用于乳腺癌化疗药物的选择.     

胸苷酸合成酶基因多态性及其蛋白表达与食管鳞状细胞癌淋巴结转移的关系

背景与目的:胸苷酸合成酶(thymidylatesynthase,TS)是DNA合成的关键酶。TS基因5′非编码区(untranslatedregion,UTR)串联重复序列和G/C单核苷酸多态性(singlenucleotidepolymorphism,SNP)可能导致酶表达或活性的改变,从而改变个体对肿瘤的易感性及预后。本实验的目的是探讨TS5′-UTR多态性与食管鳞状细胞癌(esophagealsquamouscellcarcinoma,ESCC)淋巴结转移的关系,并探讨此多态性对TS蛋白表达的影响。方法:从232例ESCC患者和348例健康对照的外周血中提取白细胞DNA,分别用PCR和PCR-RFLP方法检测TS5′UTR28bp串联重复序列和G/CSNP的基因型。51例患者的术后切除组织采用免疫组织化学染色的方法(S-P法)检测肿瘤组织中的TS蛋白的表达情况。结果:5′UTR的3G/3G,3G/3C,3C/3C,2R/3G,2R/3C,2R/2R和其它基因型频率在健康对照组分别为17.5%,17.3%,29.3%,12.9%,17.8%,3.7%,1.5%和在病例组中分别为16.0%,16.0%,29.3%,13.8%,17.6%,4.3%,3.0%;3G,3C,2R和其它等位基因型频率在健康对照组中分别为32.8%,47.0%,19.5%,0.7%和在病例组中分别为31.2%,46.8%,20.5%,1.5%。与3G/3G基因型相比,2R/3G基因型显著增加淋巴结转移的危险性(年龄和性别校正OR=11.53,95%CI=2.67～49.74)。TS表达水平与患者的性别、年龄、淋巴结转移和临床病理分期无关,而与TS5'UTR基因型密切相关(P<0.05)。结论:TS5′UTR重复序列及SNP多态性与ESCC淋巴结转移有关,而TS蛋白表达水平与淋巴结转移无关。     

卵巢癌中TopoⅡα、GST-π、P-gp表达与化疗反应性及预后的关系

目的:研究卵巢癌中拓扑异构酶Ⅱα(topoisomeraseα,TopoⅡα)、谷胱甘肽S转移酶π(glutathioneStranserasesπ,GSTπ)、P糖蛋白(Pglycoproein,Pgp)的表达与化疗反应性及预后的关系。方法:采用免疫组化SP法,计算机图象分析技术对80例卵巢癌、20例良性上皮性卵巢肿瘤、20例正常卵巢组织中TopoⅡα、GSTπ、Pgp的表达进行检测。结果:GSTπ、Pgp阳性组患者的化疗反应率显著低于阴性组(分别为51.60%vs88.90%;43.80%vs70.80%,P<0.05)。GSTπ、Pgp阳性对耐药的预测值为48.40%、56.20%;GSTπ、Pgp阴性对化疗反应的预测值为88.90%、70.80%。TopoⅡα阴性而GSTπ、Pgp阳性组以及TopoⅡα阳性而GSTπ、Pgp阴性组患者的化疗反应率分别为33.30%、100.00%,前者显著低于后者(P<0.05)。GSTπ、Pgp阳性组患者术后生存时间均显著短于阴性组(P<0.05,P<0.01)。TopoⅡα阴性而GSTπ、Pgp阳性组患者的术后生存时间显著短于TopoⅡα阳性而GSTπ、Pgp阴性组(P<0.01),Cox多因素分析表明Pgp的表达是影响术后生存的独立因素。结论:TopoⅡα、GSTπ、Pgp的联合检测对合理制定化疗方案、预测化疗反应性及估计预后具有积极的指导意义。     

胃癌组织TSER多态性与5-Fu体外药敏的关系

目的 探讨胃癌组织胸苷酸合成酶增强子区(TSER)多态性与5-Fu体外药敏的关系。方法 对45例胃癌患者新鲜标本进行体外肿瘤细胞原代培养,用ATP-TCA法检测肿瘤细胞对5-Fu的敏感性并用PCR法检测肿瘤的TSER多态性,分析TSER多态性分布频率与体外药敏有效率的关系。结果 TSER多态性三种基因型频率分布： 2R／2R、2R／3R、3R／3R基因组分别为6.7%(3/45)、31.1%(14/45)和62.2%(28/45)。5-Fu总有效率为33.3%(14/42)。3R／3R基因组26例,有效5例,无效21例,有效率19.2%;（2R／2R、2R／3R）基因组16例,有效 9例,无效7例,有效率56.3%。TSER基因型组之间对5-Fu敏感性存在显著差异性（P<0.05）。结论 TSER多态性对5-Fu化疗敏感性可能有关,基因型检测可能有助于预测胃癌组织对5-Fu化疗敏感性。     

多药耐药基因产物表达和细胞凋亡对胃癌影响的研究

目的　探讨多药耐药 (MDR)基因产物和细胞凋亡指数 (AI)表达与胃癌分型、分期、预后的关系。方法　应用免疫组化及原位末端标记法 (TUNEL) ,对 80例胃癌标本进行MDR指标 (P gp、GST π、TOPOⅡ )及AI检测。结果　P gp表达与临床分期有关 (P <0 .0 5 ) ,正常组织P gp表达高者生存期长 (P <0 .0 5 ) ;GST π表达强度与预后有关 ,高表达者生存期短 (P <0 .0 5 ) ;TOPOⅡ表达与分型有关 (P <0 .0 5 ) ,低分化癌表达高于高中分化癌 ;凋亡指数表达与临床分期有关 (P <0 .0 5 ) ,高表达者其临床分期越晚。结论　MDR与细胞凋亡都属细胞正常基因组表达的一部分 ,在正常组织及癌组织均可有表达。正常组织P gp、GST π的表达与预后有关 ,不同生存期的MDR与细胞凋亡表达差异无显著性 (P >0 .0 5 ) ,但MDR与AI的表达与胃癌的生物学行为有关     

化疗药物杀伤原代胃癌细胞效应与P-糖蛋白和GST-π表达的关系

背景与目的:化疗耐药是影响进展期胃癌疗效的主要原因之一。本研究旨在评价不同化疗药物对原代胃癌细胞的体外杀伤效应及其诱导凋亡能力,同时研究上述效应与胃癌组织P鄄糖蛋白(P鄄gp)和谷胱甘肽S转移酶π(GST鄄π)表达的关系。方法:39例分离纯化后的人新鲜胃癌细胞,分别暴露于血浆峰浓度的5鄄氟尿嘧啶(5鄄FU)、顺铂(DDP)、丝裂霉素(MMC)、阿霉素(ADM)及羟基喜树碱(HCPT)。用台盼蓝染色法和MTT法检测经上述药物作用后肿瘤细胞活力及代谢活性的变化;用原位末端转移酶标记法(TdT法)检测胃癌细胞凋亡率;并用免疫组化染色检测胃癌组织中GST鄄π和P鄄gp的表达。结果:经化疗药物作用后,体外培养的胃癌细胞出现不同程度的形态学改变、代谢活性下降及细胞凋亡。不同个体肿瘤细胞对不同化疗药物的敏感性不同。MTT结果提示,所测药物对胃癌细胞的平均抑制率由高到低依次为MMC[(38.6±7.7)%],DDP[(38.1±8.8)%],5鄄FU[(37.8±10.3)%],ADM[(31.9±10.4)%],HCPT[(29.9±10.2)%]。MMC、DDP及5鄄FU的平均抑制率明显高于HCPT及ADM(P<0.01)。TdT结果提示,诱导胃癌细胞凋亡率由高到低的药物依次为DDP[(32.1±7.7)%],5鄄FU[(31.1±8.8)%],MMC[(29.8±6.3)%],HCPT[(21.9±7.4)%],ADM[(19.9±7.4)%]。本组病例GST鄄π和P鄄gp的     

P-糖蛋白、谷胱甘肽-s转移酶的表达与胃癌细胞耐药的关系研究

目的初步探索胃癌多药耐药细胞系SGC7901／VCR的耐药机制。方法间歇诱导法,胃癌细胞系SGC7901经长春新碱（VCR）短时间诱导后,对长春新碱产生耐药。MTT法检测对VCR、5-氟尿嘧啶、表阿霉索的耐药性。Western blot检测P-糖蛋白（P—glucoprotein,P—gp）、谷胱甘肽-s转移酶（ghtathione—s transferring enzyme,GST—s）的表达。结果耐药细胞SGC7901／VCR对长春新碱耐药提高16．56倍,此耐药株同时对5-氟尿嘧啶、表阿霉素呈交叉耐药,耐药指数分别达6．9、13．05。SGC7901／VCR的P—gP、GST—s出现表达增强。结论长春新碱短时间诱导后,SGC7901产生多药耐药性（multi—drug resistance,MDR）,且P—gp、GST—s表达增强。反之,抑制P—gP、GsT—s蛋白的表达,则有可能降低细胞耐药从而逆转胃癌MDR。     

胸苷酸合成酶和拓扑异构酶-1及Ki-67对伊立替康联合5-氟脲嘧啶治疗晚期大肠癌的预测价值

目的探讨胸苷酸合成酶(TS)、拓扑异构酶1(Topo1)和肿瘤增殖指标Ki67对伊立替康(CPT11)联合5氟脲嘧啶(5Fu)治疗晚期大肠癌患者的临床疗效和预后的预测价值。方法采用免疫组化方法检测了CPT11+5Fu一线治疗78例大肠癌患者的TS、Topo1和Ki67的表达,并与化疗疗效和患者的临床预后进行了分析。结果各检测指标的表达水平与临床疗效之间无关,但是临床预后不同。其中,TS低表达患者表现明显长的肿瘤进展时间(TTP,P<0.05)和存活期(OS,P<0.05);Ki67低表达也预示长的OS(P<0.05)。与单个指标相比较,两个指标的联合也不能预测临床疗效,但是对预后的判断作用明显提高。TS低表达、Ki67低表达以及TS和Ki67均低表达患者的中位TTP分别为9,8和17个月(P=0.02);TS低表达、Topo1低表达以及TS和Topo1均低表达患者的中位TTP分别为9,9和13个月(P=0.03);而Topo1低表达、Ki67低表达、Ki67和Topo1均低表达患者的中位TTP分别为8,9和11个月(P=0.05)。其中任何两个指标均低表达肿瘤的TTP和OS均明显长于高表达者(P<0.05)。结论TS、Topo1和Ki67不能预测大肠癌患者CPT11+5Fu的疗效,但对其临床预后有一定的预测作用。其中任何两个指标的联合,比单一指标对患者预后的预测价值明显提高。     

In vitro platinum drug chemosensitivity of human cervical squamous cell carcinoma cell lines with intrinsic and acquired resistance to cisplatin.

The platinum drug chemosensitivity of five human cervical squamous cell carcinoma cell lines (HX/151, HX/155, HX/156, HX/160 and HX/171) derived from previously untreated patients has been determined. Compared to our data obtained previously using human ovarian carcinoma cell lines, all five lines were relatively resistant to cisplatin, carboplatin, iproplatin and tetraplatin. One of the lines (HX/156) was exceptionally sensitive to the novel platinum (IV) ammine/amine dicarboxylates JM216 [bis-acetatoammine dichloro (cyclohexylamine) platinum (IV)] and JM221 [ammine dibutyrato dichloro (cyclohexylamine) platinum (IV)]. The range in IC50 values across the five lines was approximately 2.5-fold for cisplatin, carboplatin and iproplatin, 13-fold for tetraplatin and JM216, and 25-fold for JM221. No significant correlation (P > 0.05) was observed between platinum drug chemosensitivity and either glutathione levels or cadmium chloride sensitivity, an indicator of metallothionein levels. In addition, there was no significant correlation (P > 0.05) between cisplatin cytotoxicity and intracellular cisplatin accumulation or JM216 cytotoxicity and intracellular JM216 accumulation over the dose range 5-100 microM (2 h exposure). The exceptional sensitivity of HX/156 to JM216 appears, at least partially, to be a result of enhanced accumulation of JM216. An 8.6-fold acquired cisplatin resistant stable variant of HX/155 has been generated in vitro. Intracellular cisplatin accumulation was reduced by 2.4 +/- 0.3-fold (mean +/- s.d.) in HX/155cisR across the dose range 1-100 microM (2 h exposure). Glutathione levels in HX/155cisR were elevated by 1.3-fold in terms of protein content and by 1.6-fold in terms of cell number. HX/155cisR was 1.9-fold resistant to cadmium chloride. Total platinum bound to DNA after cisplatin exposure (10, 25, 50 or 100 microM for 2 h) was 3.6 +/- 0.6-fold (mean +/- s.d.) lower in HX/155cisR. Hence the mechanism of acquired cisplatin resistance in HX/155cisR appears to be multifocal, with reduced intracellular drug accumulation and elevated glutathione and metallothionein levels combining to reduce DNA platination levels. While HX/155cisR was cross-resistant to tetraplatin and carboplatin, novel platinum (II) and (IV) ammine/amine complexes, including JM216 and JM221, partially circumvented resistance (resistance factors of 1.5-2). Non cross-resistance was observed to iproplatin and nine non-platinum anticancer agents. Intracellular tetraplatin accumulation was reduced by 1.8 +/- 0.1-fold (mean +/- s.d.) in HX/155cisR across the dose range 1-100 microM (2 h exposure). In contrast, after JM216 exposure (1-100 microM for 2 h), no significant difference in intracellular platinum levels between HX/155 and HX/155cisR was observed.(ABSTRACT TRUNCATED AT 400 WORDS)     

Combined modalities of resistance in an oxaliplatin-resistant human gastric cancer cell line with enhanced sensitivity to 5-fluorouracil

To identify mechanisms underlying oxaliplatin resistance, a subline of the human gastric adenocarcinoma TSGH cell line, S3, was made resistant to oxaliplatin by continuous selection against increasing drug concentrations. Compared with the parental TSGH cells, the S3 subline showed 58-fold resistance to oxaliplatin; it also displayed 11-, 2-, and 4.7-fold resistance to cis-diammine-dichloroplatinum (II) (CDDP), copper sulphate, and arsenic trioxide, respectively. Interestingly, S3 cells were fourfold more susceptible to 5-fluorouracil-induced cytotoxicity due to downregulation of thymidylate synthase. Despite elevated glutathione levels in S3 cells, there was no alteration of resistant phenotype to oxaliplatin or CDDP when cells were co-treated with glutathione-depleting agent, l-buthionine-(S,R)-sulphoximine. Cellular CDDP and oxaliplatin accumulation was decreased in S3 cells. In addition, amounts of oxaliplatin- and CDDP-DNA adducts in S3 cells were about 15 and 40% of those seen with TSGH cells, respectively. Western blot analysis showed increased the expression level of copper transporter ATP7A in S3 cells compared with TSGH cells. Partial reversal of the resistance of S3 cells to oxaliplatin and CDDP was observed by treating cell with ATP7A-targeted siRNA oligonucleotides or P-type ATPase-inhibitor sodium orthovanadate. Besides, host reactivation assay revealed enhanced repair of oxaliplatin- or CDDP-damaged DNA in S3 cells compared with TSGH cells. Together, our results show that the mechanism responsible for oxaliplatin and CDDP resistance in S3 cells is the combination of increased DNA repair and overexpression of ATP7A. Downregulation of thymidylate synthase in S3 cells renders them more susceptible to 5-fluorouracil-induced cytotoxicity. These findings could pave ways for future efforts to overcome oxaliplatin resistance.     

环氧化酶-2在肝细胞肝癌中的表达及与多药耐药的相关性研究

目的观察环氧化酶-2（COX-2）、P糖蛋白（P-gp）在肝细胞肝癌（HCC）中的表达并分析两者的相关性。方法应用免疫组化S-P法、逆转录多聚酶链反应法（RT-PCR）检测重庆医科大学附属第二医院2005年10月～2007年6月手术切除经病理证实的52例HCC标本、癌旁组织及10例正常肝组织中COX-2和P-gp及其基因的表达情况。结果COX-2/COX-2 mRNA、P-gp/MDR1 mRNA在肝细胞肝癌组织中的表达明显上调,与其在正常肝组织、癌旁组织中的表达比较差异有统计学意义（P〈0.01）。且COX-2、P-gp在肝细胞肝癌中的阳性表达具有明显相关性,相关系数r=0.563（P〈0.01）。结论（1）COX-2高表达参与了肝癌的发生、发展。（2）COX-2与P-gp在肝细胞肝癌中的表达密切相关,COX-2可能干预P-gp的表达从而参与肝癌的多药耐药过程。     

Overexpression of cIAP2 contributes to 5-FU resistance and a poor prognosis in oral squamous cell carcinoma

Background:

Resistance to 5-fluorouracil (5-FU) is a major obstacle in treating oral squamous cell carcinoma (OSCC). However, little is known about apoptosis resistance, which contributes to 5-FU resistance in OSCC.

Methods:

We focussed on the cellular inhibitor of apoptosis protein 2 (cIAP2) on the basis of a DNA microarray data using parental and 5-FU-resistant OSCC cell lines. The effects of cIAP2 downregulation on 5-FU sensitivity and apoptosis were evaluated. An immunohistochemical analysis of cIAP2 and related proteins, cIAP1 and X-linked IAP, was performed in 54 OSCC patients who were treated with 5-FU-based chemoradiotherapy and surgery.

Results:

The downregulation of cIAP2 significantly enhanced the sensitivity of the 5-FU-resistant cells to 5-FU, with a significant increase in apoptosis. The immunohistochemical analysis demonstrated a high cIAP2 tumour expression to significantly correlate with the pathological response to chemoradiotherapy. Furthermore, a Cox regression analysis revealed the cIAP2 expression status (hazard ratio, 4.91; P=0.037) and the pathological response to chemoradiotherapy (hazard ratio, 0.418; P=0.016) to be significant prognostic factors for OSCC patients.

Conclusion:

These novel findings demonstrate that cIAP2 may represent a potentially useful therapeutic target for improving the treatment and survival of OSCC patients, particularly in the setting of 5-FU resistance.     

胃癌组织中环氧合酶-2表达及其与P-gp表达相关性的研究

目的 :探讨环氧合酶 2 (COX 2 )蛋白在胃癌组织中的表达 ,并探讨COX 2对P糖蛋白 (P gp)表达的影响。方法 :应用免疫组织化学方法检测 4 8例胃癌及 10例正常胃组织中COX 2蛋白与P gp蛋白的表达。结果 :正常胃组织中未见COX 2表达 ,胃癌组织中COX 2阳性率为 6 0 .4 % (2 9/ 4 8) ,其阳性表达与肿瘤的TNM分期及淋巴结转移相关 (P <0 .0 5 )。COX 2阳性组中P gp表达阳性率为 82 .8% (2 4 / 2 9) ,而COX 2阴性组P gp同时阴性率 6 3.2 %(12 / 19) ,两者有高度正相关性 ,相关系数r=0 .4 70 (P <0 .0 1)。结论 :COX 2蛋白的表达参与胃癌的发生及恶性进展 ,并可能干预P gp表达 ,参与对肿瘤的多药耐药 (MDR)的调节作用     

食管鳞癌组织MTSS1表达及其与转移潜能相关性研究

目的:探讨食管鳞癌组织中转移抑制基因1(MTSS1)表达与临床病理因素的关系,以及与食管鳞癌细胞迁移和侵袭的关系。方法:蛋白质印迹法和免疫组化检测106例食管鳞癌及癌旁正常组织以及食管鳞癌细胞系中MTSS1的表达;Transwell法检测MTSS1高表达细胞系的迁移和侵袭,观察用小分子干扰RNA(siRNA)敲降MTSS1后对迁移和侵袭的影响。结果:MTSS1在食管组织中表达为0.756±0.101,明显高于食管鳞癌组织的表达(0.596±0.110),差异有统计学意义,t=3.011,P=0.009。MTSS1在食管癌组织中表达与有无淋巴结转移相关,χ2=10.9,P<0.01;MTSS1高表达食管鳞细胞系KYSE180转染MTSS1-siRNA后48h,在mRNA水平的抑制率为(91.96±1.72)%,在蛋白水平的抑制率为(90.40±0.70)%,均能显著降低MTSS1的表达。体外实验发现,MTSS1能够抑制食管鳞癌细胞的迁移和侵袭,降低MTSS1表达后,KYSE180细胞的迁移数从(1 521±122)个升高至(2 122±111)个,P=0.003;侵袭细胞数从(1 297±137)个升高至(1 983±81)个,P=0.002。结论:MTSS1与食管癌的淋巴结转移呈负相关,并且能抑制食管鳞癌细胞的迁移和侵袭。MTSS1可能是食管鳞癌的转移抑制基因。     

Ki-67抗原与子宫颈鳞癌新辅助化疗和放疗的敏感性研究

目的探讨Ki-67抗原与子宫颈鳞癌新辅助化疗（NACT）和放射治疗（RT）的敏感相关性。方法在新辅助化疗前后用免疫组化检测32例宫颈鳞癌组织Ki-67的表达。结果化疗前患者Ki-67的表达水平在不同年龄段组（〈45岁和≥45岁）、不同临床期别组（Ⅰb～Ⅱa和Ⅱb～Ⅲb）和不同病理分级组（高中分化和低分化）之间相互比较差异有统计学意义（P=0.008、0.009、0.000）。化疗后患者Ki-67表达水平与化疗前比较明显下降,差异有统计学意义（P=0.000）。化疗前Ki-67表达程度不同,化疗和化放疗的疗效明显不同,化疗疗效高表达组与低表达组比较差异有统计学意义（P=0.033）;化放疗疗效高表达组与低表达组比较差异无统计学意义（P=0.375）;高表达组、低表达组对化疗和化放疗的疗效比较差异均有统计学意义（P=0.001、0.000）。结论子宫颈鳞癌治疗前Ki-67表达强度与化疗敏感性呈正相关;虽然存在Ki-67阳性表达强度愈强、NACT＋RT的完全缓解率愈高的趋势,但未显示明显的放射敏感相关性;治疗前检测Ki-67表达可以为预测化疗和放疗敏感性提供客观依据,但Ki-67能否确定为预测子宫颈鳞癌新辅助化疗和放疗敏感性的可靠指标还需增加样本作进一步研究。     

Gene expression changes in cervical squamous cell carcinoma after initiation of chemoradiation and correlation with clinical outcome

PURPOSE: The purpose of this study was to investigate early gene expression changes after chemoradiation in a human solid tumor, allowing identification of chemoradiation-induced gene expression changes in the tumor as well as the tumor microenvironment. In addition we aimed to identify a gene expression profile that was associated with clinical outcome. METHODS AND MATERIALS: Microarray experiments were performed on cervical cancer specimens obtained before and 48 h after chemoradiation from 12 patients with Stage IB2 to IIIB squamous cell carcinoma of the cervix treated between April 2001 and August 2002. RESULTS: A total of 262 genes were identified that were significantly changed after chemoradiation. Genes involved in DNA repair were identified including DDB2, ERCC4, GADD45A, and XPC. In addition, significantly regulated cell-to-cell signaling pathways included insulin-like growth factor-1 (IGF-1), interferon, and vascular endothelial growth factor signaling. At a median follow-up of 41 months, 5 of 12 patients had experienced either local or distant failure. Supervised clustering analysis identified a 58-gene set from the pretreatment samples that were differentially expressed between patients with and without recurrence. Genes involved in integrin signaling and apoptosis pathways were identified in this gene set. Immortalization-upregulated protein (IMUP), IGF-2, and ARHD had particularly marked differences in expression between patients with and without recurrence. CONCLUSIONS: Genetic profiling identified genes regulated by chemoradiation including DNA damage and cell-to-cell signaling pathways. Genes associated with recurrence were identified that will require validation in an independent patient data set to determine whether the 58-gene set associated with clinical outcome could be useful as a prognostic assay.     

食管鳞癌组织中V-ATPase的表达及其与化疗药物耐药相关性探讨

目的:探讨V-ATPase在食管鳞癌中的表达及其病理分级、TNM分期中的差异性;检测相应癌组织对化疗药物的敏感性,分析其与V-ATPase表达的相关性,为进一步研究V-ATPase耐药性及其机制提供依据.方法:采用免疫组化EnVinsion法检测V-ATPase在66例食管鳞癌中的表达,MTT法检测相应癌组织对化疗药物的敏感性,分析其与V-ATPase表达的相关性.结果:V-ATPase阳性表达主要定位于胞膜上和胞质中,总阳性率68.18%,病理分级和TNM分期三组间的表达差异性非常显著,P值各为0.003、0.000,分级各两组间的检验除Ⅱ与Ⅲ组间差异性不显著(P=0.06)外,其余组间的P值均小于0.05;TNM分期中除Ⅱb与Ⅲ间的差异性不显著外(P=0.368),其余组间P值均为0.000.转移组与非转移组相比差异性非常显著(P=0.000);环磷酰胺、5-氟尿嘧啶、吉西他滨、阿霉素、丝裂霉素、长春瑞滨、紫杉醇、羟喜树碱、顺铂、卡铂化疗药在食管鳞癌组织中药物敏感性试验结果与其相应组织V-ATPase表达相关检验,除丝裂霉素、紫杉醇外,其余P值均<0.05,相关系数rs除紫杉醇外均小于-0.30,即除丝裂霉素、紫杉醇外都有较好的相关性.结论:V-ATPase在食管鳞癌中高表达,表达的高低与病理分级、TNM分期、淋巴转移相关联,很可能与食管鳞癌化疗药物耐药有关.