拓扑替康作为二线化疗药物在卵巢癌化疗中的药物敏感性实验

背景与目的：晚期卵巢癌的治疗通常采用肿瘤细胞减灭术辅以化学治疗,常用的一线化疗方案为含顺铂的联合化疗,但绝大多数晚期卵巢癌容易复发,并产生耐药,本研究通过药物敏感性实验评价拓扑替康在复发性和对顺铂耐药的卵巢癌患者中应用的临床价值。方法：采用三磷酸腺苷生物发光法对41例新鲜卵巢癌组织标本(其中9例为复发癌组织标本)进行药敏实验,药物采用顺铂和拓扑替康,分别配制成1倍血浆峰值浓度。结果：41例卵巢癌组织标本中,对拓扑替康敏感的比率(80．5％)高于顺铂(51．2％),在21例对顺铂耐药的卵巢癌组织标本中有18例对拓扑替康敏感。结论：拓扑替康可以作为一种较好的二线化疗药物用于卵巢癌患者的化疗,特别是在对顺铂耐药的情况下。     

卵巢上皮癌组织中hMSH2的表达及其与化疗耐药的关系

目的 检测不同化疗敏感程度的卵巢上皮癌组织中hMSH2基因的表达,分析其与化疗耐药及预后的关系。方法 80例新鲜卵巢上皮癌组织均由手术中取得,采用ATP-TCA技术检测卵巢癌组织对八种药物：紫杉醇、卡铂、拓泊替康、多西他赛、吉西他滨、环磷酰胺体内代谢产物、依托泊苷及博来霉素的体外敏感性。采用Real-time PCR及Western blot法分别检测80例卵巢上皮癌组织中hMSH2 基因mRNA和蛋白水平的表达情况。结果 对紫杉醇耐药的卵巢上皮癌组中,hMSH2基因在mRNA及蛋白水平的表达均明显高于敏感组（P<0.01）,在对卡铂、拓泊替康、多西他赛耐药组中hMSH2表达水平也明显高于敏感组（P<0.05）;hMSH2基因的相对表达值与卡铂、拓泊替康、多西他赛的敏感度系数有显著相关性（P≤0.05）。早期卵巢癌患者组织的hMSH2表达水平明显低于晚期卵巢癌组织（P<0.05）。高、中分化卵巢癌组织hMSH2蛋白表达水平明显低于低分化卵巢癌组织（P=0.000）。原发卵巢癌患者组织的hMSH2表达水平明显低于复发卵巢癌患者组织（P<0.01）。结论 hMSH2基因的高表达与卵巢癌化疗耐药及预后相关,化疗可能诱导hMSH2基因的高表达;下调hMSH2基因的表达或许是逆转肿瘤耐药的新途径。     

复发或难治性小细胞肺癌的化疗进展

复发或难治的SCLC预后差,化疗对其缓解率低,中位生存时间为4个月[1].广泛期的.所有患者或局限期的大多数患者,肿瘤进展后需要二线化疗.对于复发的SCLC,仍有多种药物具有抗肿瘤活性,如紫杉类的紫杉醇(PTX)、泰索帝,拓扑异构酶Ⅰ的抑制剂拓扑替康(TPT)、伊立替康(CPT-11),异环磷酰胺、足叶乙苷(VP-16)、顺铂及卡铂等.复发或转移后的二线化疗尚无公认的统一标准治疗.目前应用较多的化疗方案包括:TPT单药化疗,TPT PDD,TPT IFO,TPT PTX等的联合化疗;CPT-11 IFO、CPT-11 PDD、CPT-11 CBP、CPT-11 PDD VP-16的联合化疗;PTX CBP、PTX IFO的联合化疗;国内应用HCPT代替TPT及CPT-11联合化疗等.含阿霉素的联合化疗,在铂类及VP-16失败后几乎无效.     

三维培养药敏实验测定的结直肠癌化疗敏感性与多药耐药基因蛋白表达的关系

背景与目的：目前肿瘤化疗疗效尚不理想,通过预测个体肿瘤对化疗药物的敏感性来指导临床治疗,有可能提高化疗疗效。本研究通过三维培养药敏实验测定结直肠癌的药物敏感性,并分析与肿瘤组织多药耐药基因表达产物水平的关系。方法：应用三维培养体外药敏实验技术,检测表阿霉素、顺铂、草酸铂、氟尿嘧啶（5-fluorouracil,5-FU）、泰素帝、伊立替康6种单药和5-FU＋表阿霉素＋顺铂、5-FU＋伊立替康、5-FU＋草酸铂、5-FU＋泰素帝＋顺铂4组联合用药对22例结直肠癌组织的抑制率,抑制率大于30％定义为敏感,计算敏感率。应用逆转录聚合酶链反应和免疫组化法测定结直肠癌组织中MDR1、MRP1、ABCG2基因蛋白表达水平;用Spearman相关分析法分析肿瘤药物敏感性和多药耐药蛋白表达的相关性。结果：单药组抑制率最高为草酸铂（17．5％）,敏感率最高为5-FU（36．4％）;联合用药组抑制率最高为5-FU＋草酸铂（54．1％）,敏感率最高为5-FU＋表阿霉素＋顺铂（71．4％）和5-FU＋泰素帝＋JJRSt3（71．4％）;联合用药组抑制率和敏感率均高于单药组（P〈0．05）。MDR1、MRP1、ABCG2mRNA的阳性率分别为88．9％、55．6％、55．6％：MDR1、MRP1、ABCG2蛋白的阳性率分别为55．6％、33.3％、50．0％;多药耐药基因MDR1、MRP1、ABCG2mRNA和蛋白的表达无相关性（P〉0．05）。ABCG2蛋白高表达与结直肠癌对表阿霉素的耐药有相关性（P〈0．05）。结论：结直肠癌多药耐药蛋白表达与肿瘤药物敏感性有一定相关性;结合三维培养药敏实验和多药耐药基因表达产物水平检测,有可能对个体肿瘤的化疗敏感性进行预测,筛选化疗敏感药物。     

耐药基因检测及体外药敏试验在卵巢癌个体化治疗中的价值

目的 探讨卵巢癌耐药基因表达与体外药敏试验及临床生物学行为的关系.方法 采用流式细胞术和MTT法对60例卵巢癌患者分别检测组织中的COX-2、CX43、P-gp基因表达和对常用化疗药物的敏感性,并对其临床近期疗效关系进行分析.结果 COX-2表达在顺铂(DDP)耐药组高于DDP敏感组,差异有统计学意义(P=0.01).CX43表达在DDP耐药组低于DDP敏感组,差异有统计学意义(P=0.005).P-gp表达在对依托泊苷(VP16)耐药组高于VP16敏感组,差异有统计学意义(P=0.009).CX43表达在对紫杉醇(Taxol)耐药组低于Taxol敏感组.差异有统计学意义(P=0.001).COX-2高表达、CX43低表达、P-gp高表达的癌组织对化疗药物的敏感性低于COX-2低表达、CX43高表达、P-gP低表达者.5-Fu、CBP、VCR、PYM、EPI、GEM的敏感性与COX-2、CX43、P-gp表达高低无显著相关性.结论 卵巢癌组织中COX-2与P-gp高表达、CX43低表达与部分化疗药物的体外药敏试验敏感性有关.耐药基因相关蛋白COX-2、P-gp、CX43的检测,结合肿瘤药敏试验结果选择敏感化疗方案能提高化疗疗效.从而使卵巢癌治疗个体化.     

食管癌细胞体外培养药敏试验与P-gp、LRP表达的相关性研究

目的 研究不同食管癌患者对药物的敏感性及其与P-糖蛋白(P-gp)、肺耐药相关蛋白(LRP)的关系,为食管癌的临床化疗提供个体化用药的实验室依据.方法 选取手术切除的新鲜食管癌组织标本,选用食管癌化疗常用的药物及化疗方案进行食管癌原代培养细胞MTT药物敏感试验,同时应用免疫组织化学方法检测食管癌细胞P-gp及LRP的表达情况.结果 单一用药对食管癌细胞的敏感性不同或不完全相同(P＜0.05).联合用药以紫杉醇联合顺铂效果最好,其次为顺铂联合长春瑞滨、顺铂联合5-氟尿嘧啶.顺铂的敏感性与P-gp表达程度无关(P＞0.05),与LRP表达的强弱有关(P＜0.05),长春瑞滨、紫杉醇的敏感性均与P-gp和LRP表达的程度有关(P＜0.05),5-氟尿嘧啶与P-gp、LRP的表达程度无关(P＞0.05).结论 采用食管癌体外药敏试验能筛选出对每个患者的敏感药物,指导肿瘤患者的个体化用药,P-gp和LRP表达与部分化疗药物的耐药存在相关性,可为指导临床个体化用药的选择提供依据.     

非小细胞肺癌组织BCRP和GST-π表达及其与化疗敏感性关系的研究

目的:观察乳腺癌耐药蛋白(breast cancer resistance protein.BCRP)、谷胱甘肽-S-转移酶-π(GST-π)在非小细胞肺癌(non-small cell lung cancer, NSCLC)中的表达,探讨其与化疗药物敏感性的关系.方法:应用MTT法对60例未经化疗的NSCLC患者行体外化疗药物多柔比星、拓扑替康、紫杉醇、长春新碱和顺铂的敏感性检测,并用免疫组织化学方法对BCRP、GST-π在NSCLC中的表达进行检测.将其表达情况与对应的化疗耐药性进行相关分析.结果:60例NSCLC患者中,31例(51.7%)对多柔比星耐药,32例(53.3%)对拓扑替康耐药,12例(20.0%)对紫杉醇耐药,15例(25.0%)对长春新碱耐药,32例(53.3%)对顺铂耐药.腺癌耐药例数多于鳞癌,但两者差异无统计学意义,P>0.05.BCRP、GST-π在60例NSCLC患者中阳性率分别为43.3%(26/60)和60.0%(36/60),BCRP、GST-π在腺癌中的阳性率高于鳞癌,但两者差异无统计学意义,P>0.05.BCRP和GST-π在NSCLC中的表达呈明显相关,P<0.05.BCRP和GST-π的表达与化疗药物敏感性之间均存在明显相关,P<0.05.结论:BCRP、GST-π可能共同参与介导NSCLC的多药耐药,两者在NSCLC中的阳性表达及共表达可作为预测NSCLC患者多药耐药的指标之一.     

消化道肿瘤组织中P-gp、凋亡抑制蛋白表达与体外化疗药敏性的关系及其意义

背景与目的:p-糖蛋白(P-gp)介导的经典耐药途径和细胞凋亡抑制是肿瘤多药耐药(MDR)研究最多的两种机制,肿瘤细胞多种MDR相关基因/蛋白共同表达、相互作用而出现多态性耐药.本研究通过分析肿瘤P-gP和凋亡抑制蛋白p53、Survivin、bcl-2表达与化疗药敏性的关系,探讨消化道肿瘤组织MDR相关因子表达能否反映肿瘤的化疗耐药性.方法:84例胃癌、大肠癌标本进行MTT法体外化疗药物敏感性实验,免疫组化染色检测组织中P-gp、p53、Survivin、bcl-2的表达,分析4种多药耐药相关因子表达与9种药物对肿瘤细胞抑制率的关系.结果:肿瘤组织中P-gp、p53、Survivin、bcl-2表达率分别为96.4%、64.3%、89.3%、60.7%;P-gp与bcl-2表达、Survivin与bcl-2表达具有正相关性(r=0.5072,r=0.3027,P<0.05).在肿瘤组织耐药因子表达程度与药物对肿瘤细胞抑制率的关系中,P-gp强表达组PIN、OXA、DDP对肿瘤细胞的抑制率明显低于弱表达组(P<0.05);p53强表达与PTX、DDP对肿瘤细胞的抑制率明显降低有关(P<0.05);Survivin强表达时,VCR、DDP对肿瘤细胞的抑制率明显降低(P<0.05).但OXA对肿瘤细胞的抑制率明显增加(P<0.01);bcl-2强表达时,5-FU、VCR、EADM、OXA对肿瘤细胞的抑制率明显低于弱表达组(P<0.05).结论:消化道肿瘤P-gp、p53、Survivin、bcl-2表达程度仅与其对部分化疗药物的耐药性有关.评价消化道肿瘤组织某种耐药因子表达与化疗药物耐药性的关系必须考虑多种因素调节的影响.     

晚期胃癌化疗进展

随着细胞毒药物和分子靶点药物的研发,晚期胃癌患者姑息化疗取得一定进展。患者中位生存期可接近1年。本文主要介绍新药多西紫杉醇、紫杉醇、奥沙利铂、伊立替康、卡培他滨、S1及靶向药物在晚期胃癌治疗中的作用以及局部晚期胃癌的化疗策略,尤其重点介绍Ⅲ期临床试验研究结果。提出一些新联合方案,如含多西他赛的DCF方案、含奥沙利铂的EOX和FLO方案、含卡培他滨的EOX和顺铂＋希罗达方案、含伊立替康的ILF方案、含S1的S1＋DDP方案,可以作为一线治疗晚期胃癌的新的参考方案。而靶向药物在晚期胃癌治疗中结论尚不明确,其有效性、安全性和最终收益有待进一步的研究;新辅助化疗可作为局部晚期胃癌治疗的选择。     

三药联合化疗和单药拓扑替康二线治疗小细胞肺癌的疗效和安全性比较

  目的  比较顺铂、依托泊苷、伊立替康联合化疗方案和单药拓扑替康二线治疗敏感复发型小细胞肺癌(smalll cell lung cancer, SCLC)的疗效和安全性。  方法  收集2014年9月至2017年9月吉林省肿瘤医院就诊78例患者资料, 筛选敏感复发型小细胞肺癌患者, 其中36例患者给予顺铂、依托泊苷、伊立替康联合化疗方案, 42例患者给予单药拓扑替康化疗。联合化疗组药物用法:顺铂25 mg/m2, 第1天、第8天静脉滴注; 依托泊苷60 mg/m2, 第1、2、3天静脉滴注; 伊立替康90 mg/m2, 第8天静脉滴注, 连续给予5个2周方案的化疗。单药拓扑替康组药物用法:拓扑替康1.5 mg/m2, 第1~5天静脉滴注, 每3周1个周期。评价两组治疗方案的无进展生存时间(progressionfree survival, PFS)、总生存时间(overall survival, OS)及安全性。  结果  联合化疗组中位无进展生存时间(mPFS)5.3个月(95% CI:4.3~ 5.8), 拓扑替康组mPFS 3.2个月(95% CI:2.7~4.0), 差异具有统计学意义(P=0.003 0);联合化疗组中位总生存时间(mOS)16.3个月(95% CI:13.8~19.1), 拓扑替康组mOS 13.1个月, 差异具有统计学意义(P=0.009 7)。联合化疗组和单药拓扑替康组常见的3/4级不良事件主要有中性粒细胞下降[31例(86.1%) vs.28例(66.7%)]、白细胞下降[29例(80.6%) vs.21例(50.0%)]、贫血[26例(72.2%) vs.10例(23.8%)]、血小板下降[13(36.1%) vs.11(26.2%)]。联合化疗组发生1例治疗相关死亡(发热性中性粒细胞下降合并肺部感染), 拓扑替康组无治疗相关的死亡发生。  结论  顺铂、依托泊苷、伊立替康联合化疗方案比单药拓扑替康疗效更好, 可考虑作为敏感复发型SCLC患者二线化疗的备选方案之一。两种化疗方案毒性均可耐受, 但联合化疗组不良事件发生率更高, 应进一步探索更为合适的化疗剂量。      

PKD2 mediates multi-drug resistance in breast cancer cells through modulation of P-glycoprotein expression

Multi-drug resistance (MDR) represents a major obstacle for chemotherapeutic treatment of a wide variety of human cancers. Increased expression of drug efflux pumps, such as the P-glycoprotein (P-gp) have been linked to development of MDR. Herein, we have identified protein kinase D isoform 2 (PKD2) as an important regulator of MDR and P-gp expression in paclitaxel-treated breast cancer cell lines. PKD2 was expressed with the highest phosphorylated activation status in the MDA-MB-231 cell line. MDA-MB-231 cells were also found to exhibit the highest level of resistance to an array of chemotherapeutic drugs. To further characterize the relationship between PKD2 activation and MDR, we next focused on the effects of the chemotherapeutic agent paclitaxel in MDA-MB-231 cells. Treatment with paclitaxel was shown to induce both PKD2 phosphorylation and P-gp expression in a time-dependent manner. Importantly, shRNA-mediated knockdown of PKD2 in MDA-MB-231 cells resulted in a significant decrease in resistance to paclitaxel, evident as significant decreases in both the IC₅₀ value and the resistance index (RI). Concurrent with the decrease in drug resistance, paclitaxel-induced expression of P-gp was also significantly reduced in PKD knockdown cells. These results indicate that PKD2 is required for paclitaxel-induced MDR and expression of P-gp. Therefore, modulation of PKD2 activity represents an attractive therapeutic strategy for improvement of the clinical effectiveness of chemotherapy.     

Prediction of chemotherapeutic response by collagen gel droplet embedded culture-drug sensitivity test in human breast cancers

Collagen gel droplet embedded culture-drug sensitivity test (CD-DST) is the newly developed in vitro chemosensitivity test that has several advantages over the conventional ones. The aim of the present study is to examine the clinical usefulness of this test in the prediction of response to chemotherapy in breast cancer patients. Seventy patients with primary (n = 45) or locally recurrent (n = 25) breast cancers were recruited, and each patient underwent tumor biopsy before chemotherapy. The biopsy specimens were used for CD-DST and immunohistological examination of 6 biological markers (P-gp, erbB2, p53, BCL2, MIB1 and ER-alpha). As chemotherapy, cyclophosphamide 600 mg/m(2) plus epirubicin 60 mg/m(2) q3w (CE, n = 28) or docetaxel 60 mg/m(2) q3w (DOC, n = 42) was given. Interpretable results using the CD-DST assay were obtained from 84.3% (59/70) of tumor specimens studied. Of the 18 tumors diagnosed as CE sensitive by CD-DST, 15 (83.3%) exhibited a response to CE therapy and none of the 5 tumors diagnosed as CE resistant by CD-DST exhibited a response to CE therapy. Of the 14 tumors diagnosed as DOC sensitive by CD-DST, 13 (92.9%) exhibited a response to DOC therapy and only one of the 22 tumors diagnosed as DOC resistant by CD-DST exhibited a response to DOC therapy. P-gp expression was found to exhibit a significant (p < 0.05) association with the resistance to CE therapy but not to DOC therapy. Diagnostic accuracy (72.7%) achieved by P-gp was lower than that (87.0%) achieved by CD-DST in CE therapy. Expressions of other biological markers (erbB2, p53, BCL2, MIB1 and ER-alpha) were not significantly associated with response to CE or DOC therapy. These results demonstrate that CD-DST can predict the response to CE and DOC therapy with a high accuracy in breast cancer patients and seems to be superior to the conventional predictors.     

The Hippo pathway in chemotherapeutic drug resistance

Chemotherapy is one of the major treatments for cancer patients. Although chemotherapeutic drugs can sometimes effectively suppress tumor growth in cancer patients, a significant proportion of patients are either intrinsically resistant or later develop resistance to primary chemotherapy, leading to disease relapse and patient mortality. The best way to conquer the resistance is the better understanding of the molecular network in cancer cells in response to drugs. Therefore, identification of signaling pathways and molecules involved in drug resistance is essential for successful treatment of cancers. The Hippo pathway is an emerging signaling pathway that plays important roles in tumorigenesis, stem cell self‐renewal and differentiation, organ size control as well as many other biological processes. Therefore, exploring novel roles of the Hippo pathway in various biological functions has become one of the cutting‐edge research areas in cancer and other biomedical research. Recently, we and others have provided new evidence that the Hippo pathway is involved in the resistance of different types of cancer cells to various chemotherapeutic drugs. In this review, we will discuss the specific roles of the Hippo pathway in chemotherapy, potential applications for studying this network in response to drugs as well as the future direction in identification of therapeutic targets.     

紫杉类药物治疗晚期乳腺癌疗效及其分子指标的相关性研究

目的探讨晚期乳腺癌患者应用含紫杉醇联合化疗方案的疗效评价及与分子指标的相关性。方法经病理确诊的170例患者入组,经紫杉醇单药或含紫杉醇联合方案化疗,至少治疗2个周期后,评价疗效和不良反应及与分子指标的相关性研究。结果ER阳性有效率为33.3%,ER阴性为48.5%,两者差异有显著性(P=0.018);当HER-2过表达定义为≥++时,有效率为55.7%,低表达者和阴性患者为33.3%,两者比较差异有显著性(P=0.004)。而PR、p53、MDR-1、BCL-2的阳性、阴性表达组间没有明显差别。对ER及HER-2的共表达进一步分层分析显示,在ER阴性同时HER-2过表达患者的有效率高达65.7%,其他各组均在35%左右,两者比较差异有显著性(P= 0.001);而其他三组差异无显著性。结论ER阴性患者有效率显著高于ER阳性患者,HER-2过表达的患者紫杉类药物敏感性较高。     

Benzquinamide inhibits P-glycoprotein mediated drug efflux and potentiates anticancer agent cytotoxicity in multidrug resistant cells.

We have previously shown that efflux of cytotoxic drugs from multidrug resistant (MDR) cell lines can be quantitated at the single cell level using a sensitive fluorescence microscopy technique. Based on the structure of compounds which inhibited the efflux of Rhodamine-123 (Rho-123) using this methodology, we hypothesized that the antiemetic, antihistaminic agent benzquinamide (BZQ) would interfere with P-glycoprotein (P-gp) mediated drug transport and potentiate the effects of anticancer agents in MDR cell lines. We show that BZQ interferes with P-gp mediated drug efflux and increases drug accumulation in MDR cells using Rho-123 as a fluorescent probe. BZQ increases the cytotoxicity of chemotherapeutic agents to both human and hamster MDR cell lines in vitro. A slight increase in cytotoxicity to chemotherapeutic agents is also observed in the parental cell lines with BZQ. BZQ increases [3H]daunorubicin accumulation and inhibits the binding of [125I]iodoaryl azidoprazosin to the P-gp in MDR cells. BZQ is a new agent to increase the cytotoxic effects of anticancer agents in MDR cells and may ultimately prove useful as an adjunct in cancer chemotherapy.     

Extensive contribution of the multidrug transporters P-glycoprotein and Mrp1 to basal drug resistance

Despite accumulating evidence that multidrug resistance transporter proteins play a part in drug resistance in some clinical cancers, it remains unclear whether the relatively low levels of multidrug resistance transporter expression found in most untreated tumors could substantially affect their basal sensitivity to antineoplastic drugs. To shed light on this problem, the drug sensitivities of wild-type mouse cell lines were compared with those of lines in which the Mdr1a and Mdr1b genes encoding P-glycoprotein (P-gp) were inactivated and lines in which the Mrp1 gene was inactivated in addition to Mdr1a and Mdr1b. These models permit a clean dissection of the contribution of each transporter to drug resistance at expression levels similar to those in normal tissues and avoid complications that might arise from previous exposure of cell lines to drug selection. For substrate drugs, we found that these contributions can indeed be very substantial. Lines lacking functional P-gp were, on average, markedly more sensitive to paclitaxel (16-fold), anthracyclines (4-fold) and Vinca alkaloids (3-fold). Lines lacking both P-gp and Mrp1 were (compared with wild-type lines) hypersensitive to an even broader array of drugs, including epipodophyllotoxins (4-7-fold), anthracyclines (6-7-fold), camptothecins (3-fold), arsenite (4-fold) and Vinca alkaloids, especially vincristine (28-fold). Thus, even very low levels of P-gp and Mrp1 expression that may be difficult to detect in tumors could significantly affect their innate sensitivity to a wide range of clinically important substrate drugs. An implication is that the use of resistance reversal agents to sensitize drug-naive tumors may be appropriate in more cases than is presently appreciated.     

Prediction of chemotherapeutic response by Technetium 99m--MIBI scintigraphy in breast carcinoma patients

BACKGROUND: Significance of Technetium 99m ((99m)Tc)-MIBI scintigraphy in the prediction of response to anthracylines and taxanes (both are substrates for P-glycoprotein [P-gp]) as well as relation between (99m)Tc-MIBI uptake and P-gp or MDR1 mRNA expression in tumors were studied in patients with breast carcinoma. METHODS: Forty-six female patients with locally advanced (n = 15) or metastatic (n = 31) breast carcinoma were recruited in this study. Before chemotherapy (epirubicin and cyclophosphamide [n = 20] or decetaxel [n = 26]), (99m)Tc-MIBI scintigraphy was performed to obtain the T/N (tumor to normal tissue) ratios of (99m)Tc-MIBI uptake at 10 minutes (T/N[e]) and at 180 minutes (T/N[d]) after the (99m)Tc-MIBI injection. Expression of MDR1 mRNA and P-gp in tumors (n = 32) were determined by a quantitative real-time polymerase chain reaction and immunohistochemistry, respectively. RESULTS: Clinical significance of T/N(e) and T/N(d) ratios in the prediction of chemotherapeutic response was evaluated using the arbitrary cutoff values of 3.0 for T/N(e) ratios and 2.0 for T/N(d) ratios. Positive predictive value, negative predictive value, and diagnostic accuracy of T/N(d) ratios (81.0%, 96.0%, and 89.1%, respectively) were higher, although statistically not significant, than those of T/N(e) ratios (73.3%, 77.4%, and 76.1%, respectively), and these values were not affected by type of chemotherapy. MDR1 mRNA levels were not significantly different between the lesions with high (> or = 2.0) and low (< 2.0) T/N(d) ratios, but P-gp expression was significantly (P < 0.01) higher in the lesions with low T/N(d) ratios than in those with high T/N(d) ratios. CONCLUSIONS: T/N(d) ratios determined by (99m)Tc-MIBI scintigraphy are useful in the prediction of response to chemotherapy with epirubicin and cyclophosphamide or docetaxel as well as in the in vivo evaluation of P-gp expression status in tumors in patients with locally advanced or recurrent breast carcinoma.     

Hypoxia suppresses chemotherapeutic drug-induced p53 Serine 46 phosphorylation by triggering HIPK2 degradation

The molecular mechanisms by which hypoxic tumor cells escape radio- and chemotherapy are largely unclear. Homeodomain-interacting protein kinase 2 (HIPK2) drives the apoptotic program in response to DNA-damaging chemotherapeutic drug treatment by phosphorylating the tumor suppressor protein p53 at Ser46. HIPK2 is kept inactive in unstressed cells through ubiquitination and degradation facilitated by the ubiquitin ligases WSB1 and Siah1. Here, we demonstrate that HIPK2 is degraded during hypoxia in a proteasome-dependent and partially Siah1-dependent fashion. Concordantly, hypoxic tumor cells show an impaired p53 Ser46 phosphorylation in response to treatment with the chemotherapeutic Adriamycin. Remarkably, proteasome-inhibition rescues HIPK2 expression in hypoxic hepatoma cells and restores p53 Ser46 phosphorylation and caspase activity after Adriamycin treatment. Our findings suggest a molecular mechanism by which hypoxic cancer cells can escape chemotherapeutic drug treatment and suggest proteasome-inhibition as a promising approach to sensitise hypoxic cancer cells to therapy.     

肺癌患者外周血中PTOV1的表达与肿瘤对化疗药物顺铂和多西紫杉醇的敏感性的关系

目的 探究肺癌患者外周血中PTOV1的表达情况与肿瘤对化疗药物顺铂和紫杉醇的敏感性的关系.方法 选取56例肺癌患者作为研究对象.采用ECIA法检测化疗药物顺铂和紫杉醇的敏感性,采用RT-PCR法检测患者PTOV1表达水平,分析其与药物敏感性之间的关系.结果 根据药敏结果可知,肺癌对多西紫杉醇的体外敏感率为46.43％,...     

Cell crowding induces interferon regulatory factor 9, which confers resistance to chemotherapeutic drugs

The mechanism of multicellular drug resistance, defined as the reduced efficacy of chemotherapeutic drugs in solid tumors is incompletely understood. Here we report that colon carcinoma cells cultured as 3D microtissues (spheroids) display dramatic increases in the expression of a subset of type I interferon‐(IFN)‐stimulated genes (ISGs). A similar gene signature was associated previously with resistance to radiation and chemotherapy, prompting us to examine the underlying biological mechanisms. Analysis of spheroids formed by different tumor cell lines and studies using knock‐down of gene expression showed that cell crowding leads to the induction of IFN regulatory factor‐9 (IRF9) which together with STAT2 and independently of IFNs, is necessary for ISG upregulation. Increased expression of IRF9 alone was sufficient to induce the ISG subset in monolayer cells and to confer increased resistance to clinically used cytotoxic drugs. Our data reveal a novel mechanism of regulation of a subset of ISGs, leading to drug resistance in solid tumors.