癌细胞原代培养对化疗药物敏感性的探讨

目的通过对不同抗癌药物敏感性做比较,以期寻找各自的合理化疗用药方案,从而指导不同癌症病人的化疗。方法通过肿瘤细胞体外药敏试验（即四甲基偶氮唑盐着色法,MTT）,对161例肿瘤（胃癌28例,肠癌38例,膀胱癌8例,乳腺癌33例,其他肿瘤54例）新鲜瘤组织进行表阿霉素（EADM）、氨甲蝶呤（MTX）、丝裂霉素（MMC）、长春新碱（VCR）、5-氟脲嘧啶（5-FU）、羟基喜树碱（OPT）、顺铂（DDP）、卡铂（CBP）、环磷酰胺（CTX）、足叶乙甙（VP-16）、β-揽香烯（β-elemene）11种化疗药物敏感性检测,并对其结果进行比较。结果11种抗癌药对不同的肿瘤类型耐药率不同。结论各种类型肿瘤细胞对化疗药物的选择虽有一定共性,但同种肿瘤的不同个体对同种化疗药物的抑制率差异却存有显著性。肿瘤细胞体外药物敏感性测定对肿瘤病人个体的化疗具有一定价值。     

体外胶质瘤细胞原代培养对不同化疗药物敏感性初步研究

目的:现察7种抗肿瘤药物对体外原代培养的胶质瘤细胞的作用,为临床化疗方案的设计提供参考.方法:32例术后病理证实为胶质瘤的新鲜标本取材,制备肿瘤单细胞悬液进行体外原代培养,与肿瘤药DDP,VM-26,VP-16,BCNU,VCR,PCB,Taxol的临床血浆峰值浓度(PPC)作用72小时,MTT法检测不同肿瘤个体对不同化疗药物的敏感和耐药情况.结果:成功进行了32例临床标本的原代培养及药敏试验,其PPC下的抑制率(IR%)＞50%者,DDP有14例;VCR有5例;VM-26有7例;VP-16有9例;PCB有3例;BCNU有2例;Taxoi有1例;其敏感性依次为:DDP＞VP-16＞VM-26＞VCR＞PBZ＞BCNU＞Taxol.结论:7种常用的抗肿瘤药物均有耐药的情况,进行化疗药物的敏感测定可以避免耐药药物的使用,为提高临床化疗效果提供指导.     

胃癌细胞对化疗药物的敏感性及其与Pgp、GST-π和Topo Ⅱ表达的关系

目的探讨胃癌在体外对化疗药物的敏感性和与P-糖蛋白(P-glycoprotein Pgp)、谷胱甘肽S转移酶π(glutathione-S-transferase GST-π)和拓扑异构酶Ⅱ(topoisomeraseⅡ TopoⅡ)表达的关系。方法收集81例手术切除胃癌标本,制备单细胞悬液,分别加入HCPT、CDDP、ADM、5-Fu和MMC培养48h,用MTT比色法检测胃癌细胞对化疗药物的敏感性;免疫组化技术检测Pgp、GST-π和TopoⅡ蛋白在胃癌组织中的表达。结果胃癌细胞对不同化疗药物敏感性不同:5-Fu(43.4±9.2)、CDDP(41.9±8.7)和HCPT(40.6±8.3)对胃癌细胞的抑制率与ADM(31.6±7.8)和MMC(28.7±7.3)比较有统计学意义(P0.05)。胃癌组织中Pgp、GST-π和TopoⅡ蛋白的阳性率分别为61.33%、65.33%和68.00%。Pgp阳性者显示对ADM、HCPT有明显的体外耐药性(P0.05),GST-π在5-Fu、CDDP和MMC耐药组阳性率显著高于敏感组(P0.05),而TopoⅡ在HCPT、ADM和MMC耐药组中的表达显著低于敏感组(P0.05)。结论 Pgp、GST-π和TopoⅡ可以作为胃癌对化疗药物原发性耐药的标志,结合MTT药敏检测,有助于筛选有效化疗药物。     

高温逆转人胃癌细胞SGC7901多药耐药性的初步研究

目的:观察高温对人胃癌耐药细胞多药耐药性的逆转作用.方法:对人胃癌耐药细胞株SGC7901/ADM予高温43℃处理,用MTT试验检测高温对ADM、5-FU、DDP、TAX作用下细胞生存率和IC50,并以人胃癌敏感细胞株SG-C7901为对照.结果:实验发现人胃癌耐药株sGc7901/ADM细胞除了对诱导耐药的ADM耐受,对CDDP、5-FU、TAX也有交叉耐药.加温至43℃,耐药株SGC7901/ADM细胞的耐药指数明显下降,而且对ADM组、CDDP组、TAX组人胃癌耐药株SGC7901/ADM细胞耐药逆转倍数分别为3.77、2.24、6.25,但对5-FU组SGC7901/ADM细胞的耐药逆转指数较低,为1.11.结论:高温可以增加耐药株SGC7901/ADM细胞对化疗药物ADM、DDP、TAX的敏感性,一定程度逆转细胞的多药耐药性.     

2010年CLSI头孢菌素折点改变对产ESBLs奇异变形杆菌药物敏感性结果评估和分析

目的评估2009年CLSI M100-S19及2010年CLSI M100-S20文件中头孢他啶（CAZ）、头孢噻肟（CTX）和头孢唑啉（CFZ）最低抑菌浓度新旧折点变化对产ESBLs奇异变形杆菌药物敏感性试验结果的影响。方法对临床分离33株奇异变形杆菌进行产ESBLs菌株的确证试验,琼脂稀释法检测最低抑菌浓度（MIC）,根据药物敏感性结果分别对产ESBLs奇异变形杆菌和非产ESBLs奇异变形杆菌在S19和S20新旧折点下CAZ、CTX和CFZ三种药物的敏感性以及ESBLs阳性菌株分布率进行界定。结果 33株奇异变形杆菌中,产ESBLs菌株6株（18.2%）,由旧折点下耐药率50%（CAZ）、50%（CTX）和66.7%（CFZ）分别上升为新折点下66.7%（CAZ）、100%（CTX）和100%（CFZ）,敏感率由旧折点下33.3%（CAZ）和50%（CTX）分别下降为新折点下16.7%（CAZ）和0%（CTX）,CFZ在新旧折点下均为0,新旧折点标准下药敏结果分布率的差异均有统计学意义。结论对CTX、CFZ,按照CLSI S20新折点琼脂稀释法MICs折点标准判读药敏结果与ESBLs表型检测结果具有高度一致性,临床可以根据药敏结果选择用药,无需进行产ESBLs检测。但对于CAZ,尚需要进一步深入研究和评价。     

体外药物敏感实验为依据的恶性脑胶质瘤个体化化疗初步研究

目的:建立胶质瘤细胞体外原代培养模型,利用MTT法进行体外药物敏感实验,为临床化疗方案的设计提供理论指导,实施个体化化疗。方法:32例术后病理证实为胶质瘤(WHOⅢ级)的新鲜标本,制备肿瘤单细胞悬液进行体外原代培养,与7种抗肿瘤药物在临床血浆峰值浓度(PPC)条件下作用72小时,MTT法标记存活的肿瘤细胞,用酶标仪检测光密度值(OD),计算出抑制率(IR),检测不同肿瘤个体对化疗药物的敏感和耐药情况,从而指导临床个体化化疗方案的制定。另选取同期符合上述入选标准的20例间变型星形细胞瘤患者作为对照组,按照VM-26加DDP方案经验化疗,化疗4个疗程结束后,复查影像学,按照WHO肿瘤疗效评价标准评价治疗效果,分为稳定(SD),进展(PD),缓解(PR)。结果:32例临床标本的原代培养及药敏试验,其PPC下的抑制率(IR%)>50%者,DDP有20例;VCR有9例;VM-26有12例;VP-16有17例;Procarbazine有7例;BCNU有6例;Taxol有3例;其敏感性依次为:DDP>VP-16>VM-26>VCR>Procarbazine>BCNU>Taxol。根据体外药物敏感实验结果制定个体化化疗方案治疗29例,肿瘤缓解率为47.2%,对照组为29.4%,2组x2检验统计P<0.05。结论:7种常用的抗肿瘤药物均有耐药的情况,进行化疗药物的敏感测定可以避免耐药药物的使用。根据体外药物敏感实验结果制定个体化化疗方案化疗与对照组相比近期疗效较满意。     

甘氨鹅脱氧胆酸钠通过MAPK/ERK1/2介导Bcl-2在Ser70位点的磷酸化引起人肝细胞癌的抗药

B细胞淋巴瘤-2（Bcl-2）是一种重要的抗凋亡蛋白质,在多种人类肿瘤中普遍过表达。甘氨鹅脱氧胆酸钠（GCDA）与消化道肿瘤的发生发展密切相关,并能介导肝癌细胞对化疗药物的抵抗。本文旨在探讨在GCDA介导的人肝细胞癌（HCC）耐药性中Bcl-2的作用及其机制。本研究以肝癌细胞系为研究对象,Western印迹结果显示,Bcl-2在多种肝癌细胞系中均有表达。设计靶向Bcl-2的siRNA沉默HCC细胞系内源性Bcl-2的表达,发现Bcl-2沉默之后促进了化疗药物5-FU介导的HCC细胞凋亡。机制上,GCDA可介导Bcl-2在Ser70位点的磷酸化,而Ser70位点的磷酸化能够被PD98059（MAPK/ERK1/2抑制剂）所抑制。构建huBcl2-WT和huBcl2-S70A真核表达载体,脂质体转染HCC细胞系。用Annexin V-FITC/PI流式细胞术检测凋亡细胞。结果显示,huBcl2-WT过表达能抑制5 FU介导的凋亡,S70位点失活突变成A后,Bcl-2的过表达不能抑制5-FU介导的凋亡。本研究提示,GCDA通过MAPK/ERK1/2通路介导的Bcl-2 Ser70位点的磷酸化,在肝癌细胞的存活和抗药中发挥重要作用。抑制Bcl-2能够促进化疗药物5-FU介导的HCC细胞凋亡,该结果为治疗GCDA介导的耐药性肝癌提供新的思路。     

甘氨鹅脱氧胆酸钠通过MAPK/ERK1/2介导Bcl-2在Ser70位点的磷酸化引起人肝细胞癌的抗药

B细胞淋巴瘤-2（Bcl-2）是一种重要的抗凋亡蛋白质,在多种人类肿瘤中普遍过表达。甘氨鹅脱氧胆酸钠（GCDA）与消化道肿瘤的发生发展密切相关,并能介导肝癌细胞对化疗药物的抵抗。本文旨在探讨在GCDA介导的人肝细胞癌（HCC）耐药性中Bcl-2的作用及其机制。本研究以肝癌细胞系为研究对象,Western印迹结果显示,Bcl-2在多种肝癌细胞系中均有表达。设计靶向Bcl-2的siRNA沉默HCC细胞系内源性Bcl-2的表达,发现Bcl-2沉默之后促进了化疗药物5-FU介导的HCC细胞凋亡。机制上,GCDA可介导Bcl-2在Ser70位点的磷酸化,而Ser70位点的磷酸化能够被PD98059（MAPK/ERK1/2抑制剂）所抑制。构建huBcl2-WT和huBcl2-S70A真核表达载体,脂质体转染HCC细胞系。用Annexin V-FITC/PI流式细胞术检测凋亡细胞。结果显示,huBcl2-WT过表达能抑制5 FU介导的凋亡,S70位点失活突变成A后,Bcl-2的过表达不能抑制5-FU介导的凋亡。本研究提示,GCDA通过MAPK/ERK1/2通路介导的Bcl-2 Ser70位点的磷酸化,在肝癌细胞的存活和抗药中发挥重要作用。抑制Bcl-2能够促进化疗药物5-FU介导的HCC细胞凋亡,该结果为治疗GCDA介导的耐药性肝癌提供新的思路。     

不同序贯的索拉非尼与化疗药物联用对人肝癌细胞Bel一7402的增殖抑制作用

应用MTT法检测了靶向性药物索拉非尼（Sorafenib）分别与阿霉素（ADM）、氟尿嘧啶（5一FU）、顺铂（DDP）和紫杉醇（PTX）等4种化疗药物按照不同给药序贯联合作用对肝癌细胞Bel-7402增殖的影响。结果表明,索拉非尼与4种化疗药物联用对Bel-7402细胞增殖的抑制作用效果均要好于单独用药,对细胞的Ic,。明显低于单独用药。联合用药效果受到给药序贯的影响,索拉非尼先于化疗药物给药,cI值（除与紫杉醇联用）均大于1,表现为拮抗效应;索拉非尼后于化疗药物给药,cI值均小于1,表现为明显的协同效应。研究结果可供肝癌f临床治疗参考,有助于lI缶床降低用药剂量,减轻药物毒副作用。     

人参多糖对环磷酰胺的增效减毒作用

目的探讨人参多糖（ginseng polysaccharide,GPS）对化疗药物环磷酰胺（cyclophosphamide,CTX）抗肿瘤的增效减毒作用。方法建立小鼠肝癌H22实体瘤模型,随机分组,设模型对照组（生理盐水）、环磷酰胺组（30 mg/kg）、人参多糖给药组（7.5、15、30 mg/kg剂量组）和联合给药组（GPS 7.5、15、30 mg/kg,CTX 30 mg/kg）;人参多糖尾静脉注射,CTX腹腔给药,连续给药10 d;测定抑瘤率、血液学指标、脾脏系数和胸腺系数,评价人参多糖对环磷酰胺的增效减毒作用。结果 GPS、GPS＋CTX各组肿瘤生长明显低于模型对照组（P〈0.01）,GPS中、高剂量＋CTX联合给药组肿瘤生长明显低于CTX组（P〈0.05,P〈0.01）。GPS高剂量＋CTX组与CTX组相比,体重、脾脏指数和胸腺指数明显升高（P〈0.05）。结论人参多糖对化疗药物环磷酰胺抗小鼠肝癌H22肿瘤具有增效减毒作用。     

Effect of estrogen on induction of micronuclei by mutagens in male mice

The effect of estrogen on the induction of micronucleated polychromatic erythrocytes (MPCE) by mutagens was examined in male mice. In the dose-response study, a dose-related inhibition of the mitomycin C (MMC)-induced MPCE frequency by estradiol (E2) treatment was observed. In the time study, inhibitory effects of E2 on MPCE frequency by MMC were observed when MMC was administered at 0 or 1 day after injection of E2. The most effective protocol for inhibition was when E2 and MMC were used on the same day. Of mutagens other than MMC, only vincristine (VCR) showed a significant decrease in MPCE frequency when used together with E2. Benzo[a]pyrene (BaP) and 5-fluorouracil (5-FU) showed no significant decrease in MPCE frequency. The data suggest that the induction of micronuclei by mutagens is inhibited by treatment with estrogen, and this could result in a sex difference in the sensitivity of mice employed in the micronucleus test. Mechanisms of the inhibitory effects of estrogen are discussed; these might include a suppression of erythropoiesis and a possible effect on the cell membrane permeability of erythroblasts.     

Ten model mutagens evaluated by the micronucleus test.

The following ten mutagenic compounds were subjected to the micronucleus bone marrow test (MNT) in the mouse: cyclophosphamide (CTX), thiotepa (TT), vincristin (VCR), colcemid (COLC), adriamycin (AM), bleomycin (BM), cytosin arabinoside (ARA C), 6-mercaptopurine (6-MP), methotrexate (MTX) and 5-fluorouracil (5-FU). Dose-effect curves were established for all compounds. With the exception of CTX, COLC and AM, the drugs also were subjected to chromosome analyses on Chinese hamster fibroblasts in vitro. The MNT revealed loss of chromatin due to chromosome breakage and rearrangements by CTX, TT and AM, to breakage by ARA C, 6-MP, MTX and 5-FU, as well as loss of entire chromosomes caused by impairment of the spindle by VCR and COLC. With the exception of BM, the effects were demonstrable in the therapeutic dose range. The MNT, provided it is carried out by the methodology of the authors, not only reveals chromatin loss but permits important conclusions in regard to the proliferative state of the bone marrow and the specific time of action of the mutagens in the cell cycle. If arrest of the cell cycle occurs, as in the case of anti-metabolites MTX and 5-FU particularly, the routine scheme of investigation needs to be modified since micronucleated cells appear only after release of the metabolic block, i.e. after a delay of 24 h. The negative bone marrow results obtained with BM emphasize the importance of combining in vivo and in vitro tests.     

Sensitivity of human pancreatic adenocarcinoma tumor lines to chemotherapy, radiotherapy, and hyperthermia

BACKGROUND: Surgical treatment of pancreatic adenocarcinoma has failed to produce many cures secondary to high rates of intraperitoneal relapses and liver metastases. The aim of this ex vivo study was to evaluate the inherent chemosensitivity, radiosensitivity and hyperthermic sensitivity of pancreatic adenocarcinoma and to investigate the usefulness of a 3-(4,5-dimetylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay utilized in each sensitivity test. METHODS: Nine human pancreatic adenocarcinomas were tested ex vivo after growth in nude mice. After 72 hr of chemotherapy, radiotherapy and hyperthermia, efficacy was assessed using MTT assay to determine the ratio of surviving fraction of treated cells-to-that of untreated control cells (TIC ratio). RESULTS: Tumor sensitivities as measured by the IC50 (drug concentration producing 50% growth inhibition) varied largely between drugs, ranging larger than 3 x 10(5) ng/mL for 5-FU, larger than 1.5 x 10(2) ng/mL for MMC, 20 ng/mL to 1.4 x 10(3) ng/mL for ADM, and 80 ng/mL to 2.4 x 10(3) ng/mL for CDDP. D0 (dose of radiation reducing the surviving fraction to 37%) ranged from 3.2 to 8.3 Gy (mean +/- standard deviation; 5.8 +/- 1.6 Gy). For hyperthermia, the mean T50 (duration of hyperthermia reducing the surviving fraction to 50%) at 43 degrees C was 9.4 +/- 3.3 min 4.8 to 14.2 min). The T/C ratio at 43 degrees C for 12 min was less than that at 41 degrees C for 30 min (p = .01; the Wilcoxon signed-ranks test). No clear relationship among chemosensitivity, radiosensitivity, hyperthermic sensitivity and pathologic features could be established. CONCLUSIONS: Nine human pancreatic adenocarcinomas varied widely in their sensitivity to chemotherapies, especially for 5-FU. These results suggested that MTT assay may be useful in excluding some less sensitive cases of pancreatic cancer. For hyperthermia, sufficient therapeutic time and temperature may realize enough effect against pancreatic adenocarcinoma.     

K562耐药细胞的建立及相关蛋白表达改变的研究

为研究肿瘤细胞发生多药耐药后蛋白整体水平表达的改变,将K562细胞与阿霉素(ADR)共同培养,逐渐增加药物浓度,最后建立耐阿霉素的细胞K562/ADR株。MTT法检测阿霉素(ADR)、顺铂(DDP)、5-氟尿嘧啶(5-FU)和长春新碱(VCR)对K562和K562/ADR细胞的半数抑制率(IC_(50))。利用蛋白质组学技术,通过双向凝胶电泳分离K562和K562/ADR细胞的总蛋白,银染显色,分析差异蛋白,对部分蛋白点进行胶内酶解,用基质辅助激光解析飞行时间质谱法得肽质量指纹图谱,用AutoMS-Fit软件查询NCBInr数据库鉴定蛋白质。结果表明K562细胞经ADR诱导后出现多药耐药现象,ADR、DDP、5-FU和VCR对K562/ADR细胞的IC_(50)明显高于K562。将K562和K562/ADR的双向电泳图谱进行差异比较,初步鉴定仅在K562/ADR图谱上出现的蛋白是一些与细胞分裂、基因转录有关的蛋白质。这些蛋白的变化与耐药细胞的特性相关,可能与临床化疗的多药耐药现象有联系。     

K562耐药细胞的建立及相关蛋白表达改变的研究

为研究肿瘤细胞发生多药耐药后蛋白整体水平表达的改变,将K562细胞与阿霉素(ADR)共同培养,逐渐增加药物浓度,最后建立耐阿霉素的细胞K562／ADR株。MTT法检测阿霉素(ADR)、顺铂(DDP)、5-氟尿嘧啶(5-FU)和长春新碱(VCR)对K562和K562／ADR细胞的半数抑制率(IC50)。利用蛋白质组学技术,通过双向凝胶电泳分离K562和K562／ADR细胞的总蛋白,银染显色,分析差异蛋白,对部分蛋白点进行胶内酶解,用基质辅助激光解析飞行时间质谱法得肽质量指纹图谱,用AutoMS-Fit软件查询NCBInr数据库鉴定蛋白质。结果表明K562细胞经ADR诱导后出现多药耐药现象,ADR、DDP、5-FU和VCR对K562／ADR细胞的IC50明显高于K562。将K562和K562／ADR的双向电泳图谱进行差异比较,初步鉴定仅在K562／ADR图谱上出现的蛋白是一些与细胞分裂、基因转录有关的蛋白质。这些蛋白的变化与耐药细胞的特性相关,可能与临床化疗的多药耐药现象有联系。     

A morphometric tool applied to angiogenesis research based on vessel segmentation

To investigate the relationship between P-glycoprotein (Pgp), glutathione S-transferase π (GST-π) and topoisomerase II (Topo II) expression and human gastric cancer chemoresistance in vitro. Primary single-cell suspensions were prepared from fresh specimens of primary gastric cancer and exposed to hydroxycamptothecin (HCPT), cisplatin (CDDP), 5-fluorouracil (5-FU), adriamycin (ADM) and mitomycin (MMC) for 48 h. Cell metabolic activity and rate of inhibition were evaluated using tetrazolium (MTT) assay. Pgp, GST-π and Topo II expression was determined in gastric carcinoma tissue samples using immunohistochemistry. Chemosensitivity of the gastric cancer cells varied; the rates of inhibition of cells exposed to HCPT, CDDP and 5-FU were significantly higher than that of cells exposed to ADM and MMC (p?相似文献   

Interactions of drugs and radiation in haemopoietic tissue assessed by lethality of mice after whole-body irradiation

Drug-radiation interactions in haemopoietic tissue were assessed as the lethality of mice within 7-28 days after whole-body irradiation. The investigated drugs were adriamycin (ADM), bleomycin (BLM), cyclophosphamide (CTX), 5-fluorouracil (5-FU), methotrexate (MTX), mitomycin C (MM-C) and cis-diamminedichloroplatinum II (cis-DDP). The drugs were administered as single doses 15 min before graded doses of whole-body irradiation or at different intervals from 7 days before to 7 days after fixed radiation doses. ADM, CTX, 5-FU, MM-C and cis-DDP enhanced the radiation response when administered 15 min before irradiation. The dose effect factor (DEF) was 9.11 for 5-FU and in the range 1.25-1.59 for the other drugs. MTX administration 15 min before irradiation had no effect (DEF 1.00). However, MTX increased lethality if given 1-3 days after irradiation (DEF 1.21-1.76) and protected against lethality if given 1-3 days before irradiation (DEF 0.83). A similar time dependence was observed for ADM, CTX, 5-FU, MM-C and cis-DDP. Protection against lethality was not observed but in all these cases the lethality was significantly lower at administration 1-3 days before than 1-3 days after irradiation. A proper investigation of the effect of BLM was not possible as the combination of this drug and whole-body irradiation caused a high rate of gastrointestinal deaths.     

Antitumor effect of levamisole in combination with anaerobic corynebacterium,OK-432 (streptococcal preparation), and chemotherapy in mice

Summary The antitumor activity of levamisole (LMS) used in combination with anaerobic Corynebacterium liquefaciens (CL), OK-432 (OK), or anticancer chemotherapy was investigated in ascitic tumor-bearing mice. With the combination of CL and LMS or OK and LMS, the best result was observed when LMS was given after CL or OK. In the combination of CL and LMS with mitomycin-C (MMC) or 5-fluorouracil (5-FU), a significant increase in mean survival time and number of 50-day survivors was seen when LMS was given after CL. Finally, with combinations of MMC and two of these three immunostimulants, the best inhibitory effect on tumor growth was observed with the combination of CL and LMS or that of CL and OK. It was also clearly demonstrated that LMS should be administered after CL, and CL after OK. The reverse order of administration significantly depressed the antitumor activity.     

Application of non-steroidal anti-inflammatory drugs to enhance 5-fluorouracil efficacy in experimental systems

The elevated cyclooxygenase-2 (COX-2) expression has been shown to affect the carcinogenesis and tumor progression processes, including cell proliferation, motility and angiogenesis. COX-2 is overexpressed in approximately 80% of sporadic colorectal carcinomas and COX-2 enzyme is the best defined target of non-steroidal anti-inflammatory drugs (NSAIDs). In the chemotherapy of colorectal carcinomas 5-fluorouracil (5-FU) has been the most important of the basic drugs for more than 40 years. In order to improve the effectiveness of 5-FU therapy different biological modifiers i.e. inhibitors of its catabolism or activators of anabolism have been studied recently. The rate-limiting enzyme of 5-FU catabolism is dihydropyrimidine dehydrogenase (DPD) since more than 80% of the administered 5-FU is catabolized by DPD. Tumoral DPD has become of clinical interest because elevated intratumoral DPD can decrease the tumor response to 5-FU therapy. The main purpose of our experiments was to investigate the effect of COX inhibitors on the efficacy of 5-FU on high and low COX-2 expressing HCA-7 and HT-29 human colon adenocarcinoma cell lines, respectively, and also on xenografts derived from HT-29 cells. The cytotoxic and antitumor effects of 5-FU in the presence of low doses of indomethacin (non-selective COX-2 inhibitor) and that of NS-398 (highly selective COX-2 inhibitor) on HT-29 and HCA-7 cells and also on the HT-29 xenograft were investigated. In addition, our intention was to understand the mechanism(s) by which NSAIDs could enhance the cytotoxic effect of 5-FU. Our data indicated that the elevated COX-2 expression of HCA-7, the collagen-induced HT-29-C cells and of the HT-29 xenograft were associated with reduced 5-FU sensitivity. Based on the fact that at the same time DPD activity was also increased it might be conceivable that a possible explanation for the decrease of 5-FU sensitivity is the co-existence of high COX-2 and DPD activity. Indomethacin or NS-398 enhanced in a simultaneous and significant manner the sensitivity and cytotoxic effect of 5-FU on high COX-2 expressing cells and xenografts through the modulation of DPD - decrease of its mRNA expression and/or enzyme activity. Based on our results it could be presumable that 5-FU efficacy is limited by the COX-2 associated high DPD expression and activity in patients with colorectal cancer as well, therefore further clinical studies are warranted to decide if NSAIDs in the therapeutic protocol might improve the antitumor potency of 5-FU. Réti A. Application of non-steroidal anti-inflammatory drugs to enhance 5-fluorouracil efficacy in experimental systems.