Synergism between 5-fluorouracil and N-methylformamide in HT29 human colon cancer line

In HT29 cells 5-fluorouracil (5FU) cytotoxicity is enhanced by subsequent incubation of cells in medium containing 1% N-methylformamide (NMF). This enhancement does not appear to be related to differences in the repair of 5FU-induced DNA damage. It is proposed that the inhibition of DNA synthesis by NMF (that is reversible and does not result in any detectable toxicity) becomes a lethal event in a cell in which DNA synthesis has already been altered by 5FU exposure. The synergism is sequence dependent (i.e. it does not occur when NMF is given before 5FU) and specific for some cell types as shown by the fact that no synergism was found in L1210 mouse leukaemia cells. In nude mice transplanted s.c. with HT29 cells daily 5FU treatment (for 5 days) followed by daily NMF treatment (for 10 days) caused much greater inhibition of tumour growth than either drug alone or the same combination given in the opposite order (NMF then 5FU). These results, if confirmed on other human colon tumours, could be of clinical interest as a means of increasing the therapeutic efficacy of 5FU in patients with colon cancer.     

虎杖苷逆转人结肠癌细胞株HT-29奥沙利铂耐药性及机制

目的:探讨虎杖苷对结肠癌耐药细胞株HT-29奥沙利铂(oxaliplatin,OXA)耐药性的逆转作用并探讨其可能的作用机制。方法:采用逐步增加药物浓度的方法建立奥沙利铂耐药结肠癌细胞株HT-29/OXA。MTT和CCK-8法测定虎杖苷对HT-29/OXA细胞的耐药性逆转作用,流式细胞术检测细胞凋亡、周期变化,qRT-PCR 检测各组细胞LRP(lung resistance protein)和P-gp(P-glycoprotein)mRNA表达水平,Western blot 检测各组细胞LRP和P-gp蛋白的表达水平。结果:虎杖苷使HT-29/OXA细胞对奥沙利铂的敏感性增加,耐药性得到部分逆转(P＜0.05)。联合应用对结肠癌耐药细胞株HT-29/OXA生长增殖具有明显抑制作用并且能够通过改变细胞周期引起凋亡(P＜0.05)。作用后LRP mRNA和P-gp mRNA表达水平降低,同时下调了LRP和P-gp 蛋白表达(P＜0.05)。结论:虎杖苷部分逆转HT-29/OXA细胞对奥沙利铂的耐药性,其机制与降低细胞内LRP基因从而导致P-gp 的表达降低有关。     

The action of 5-fluorouracil on human HT29 colon cancer cells grown in SCID mice: mitosis, apoptosis and cell differentiation.

This study investigates the effects of the anti-metabolite 5-fluorouracil (5-FU) on the human colon cancer line HT29 (10(7) cells per dose) grown subcutaneously in severe combined immunodeficient (SCID) mice. The efficacy of 5-FU was quantitatively evaluated by comparing the tumour weight, mitotic and apoptotic tumour cell indices and the expression of the Ki-67 nuclear antigen in drug-treated animals and control animals. The tumour cell carbohydrates were assessed using a lectin panel. A significant reduction in the tumour weight was found 4 days after initial 5-FU treatment. 5-FU treatment reduced the percentages of mitoses but increased the apoptotic index in the tumour cells. In addition, 5-FU induced an increase in the signet ring cell population and an increased binding for lectins specific for N-acetylgalactosamine and galactose. However, the vast majority of signet ring cells were negative for Ki-67. The results of this study indicate that continuous treatment with 5-FU for 4 days targets metabolic processes relevant for both cell division and apoptosis. The relative increase in the signet ring population can be explained by the fact that the more proliferation-active stem cell population of the tumour is the primary target of the therapy. The lectin-binding patterns reflect these changes and are therefore differentiation linked.     

Effects of the HDAC inhibitor CG2 in combination with irinotecan, 5-fluorouracil, or oxaliplatin on HCT116 colon cancer cells and xenografts

Chemotherapies for colon cancer have recently advanced. However, there is still a need to develop agents and identify effective regimens for better treatments of colon cancer. Histone deacetylase inhibitors (HDACIs) have shown potential as anti-cancer agents. We investigated the anti-tumor effects of CG2 (an HDACI) in combination with irinotecan, 5-FU, or oxaliplatin. Combinations of CG2 with SN38 (the active form of irinotecan), 5FU, or oxaliplatin were more effective than the agents alone when used to inhibit the growth of HCT116 cells. The protein expressions of acetyl-H3, p21, caspase-3, -8, and -9, PARP, and XIAP were affected in a time- and dose-dependent manner in HCT116 cells treated with the CG2 alone or combined CG2 and SN-38. In HCT116 xenografts, the HDACI CG2 in combination with irinotecan dramatically inhibited tumor growth without showing additive toxicity. These data indicate that CG2 together with irinotecan is a promising combination novel treatment for colon cancer.     

Expression analysis of genes involved in oxaliplatin response and development of oxaliplatin-resistant HT29 colon cancer cells

The interrelationship between platinum resistance and clinical response is not well established. The purpose of this study is to evaluate the expression of 14 genes involved in platinum resistance in a colon cancer cell line (HT29) and its oxaliplatin (OXA)-resistant sublines. Resistant cells exhibited lower expression of many of these genes suggesting that several pathways may be implicated in OXA resistance. Particularly, OXA resistance is accompanied by defects in drug uptake (downregulation of the hCTR1 transporter) and enhanced DNA repair (upregulation of the XPD gene). Our data also confirmed that copper transporters and chaperones are involved in OXA resistance in colorectal cancer cells as evidenced by the overexpression of ATP7A and CCS in response to OXA exposure. Moreover, increased CCS expression suggests a role for SOD1 in OXA detoxification. Whereas exposure to OXA in HT29 induced significant changes in expression of many of the genes analyzed, only ATP7A, XPD and SRPK1 gene expression was increased in OXA-treated HTOXAR3 resistant cells. To our knowledge, this is the first report of implicating SRPK1 in OXA resistance. This study provides the basis for further evaluation of these putative markers of OXA response and resistance in colorectal cancer patients who are candidates for treatment with OXA.     

Inhibition of the p38 MAPK pathway sensitises human colon cancer cells to 5-fluorouracil treatment

Colorectal cancer is the third most common cause of cancer-related deaths in the Western world. 5-Fluorouracil (5-FU) based chemotherapeutic regimes have been the mainstay of systemic treatment for disseminated colorectal cancer for many years. However, it only produces a 25% response rate due to the drug-resistance. The mitogen-activated protein kinase (MAPK) pathway is involved in the anti-apoptotic process; its activation provides cancer cells with a survival advantage to escape the apoptotic challenge. This study assessed whether the p38 MAPK pathway is involved in 5-FU resistance in colorectal cancer cells. 5-FU only or 5-FU combined with a p38 MAPK pathway inhibitor (SB203580) was used to treat 5-FU-resistant colorectal cancer cells. The effect of the treatment on cell viability, death and caspase activities was assessed. Western blotting was used to investigate the responses of apoptosis-related proteins following the treatment. Results showed that p38 MAPK inhibitor significantly increased colorectal cancer cell sensitivity to 5-FU. SB203580 in combination with 5-FU significantly reduced cell viability (P<0.01), and increased cell death and cellular caspase activity (P<0.01). Western blotting data revealed that SB203580 sensitises cancer cells to 5-FU due to an increase in Bax expression. These findings suggest that p38 MAPK is involved in cancer cell survival, and that the inhibition of p38 MAPK can enhance 5-FU to kill colorectal cancer cells.     

Involvement of Nrf2 activation in resistance to 5-fluorouracil in human colon cancer HT-29 cells

Acquisition of drug resistance by cancer cells is attributed to various factors including alterations in apoptotic pathways, enhanced expression of multidrug resistance-associated proteins, altered drug metabolism or uptake and/or overexpression of cytoprotective genes. Thus, potential induction of defence pathways by anticancer drugs might have a marked incidence on cancer cell resistance. 5-Fluorouracil (5-FU) remains the most commonly used anticancer drug for the treatment of colorectal cancer, although objective response rates are as low as 20%. The aim of our study was to investigate the effects of 5-FU on cytoprotective systems in human colon HT-29 cells. Our results demonstrate that 5-FU induced the expression of mRNAs encoding glutathione transferases and antioxidant enzymes. To further determine the mechanisms involved in 5-FU effects, we investigated whether it activates the Nrf2/antioxidant response element pathway which is implicated in the regulation of several genes involved in cytoprotection. Translocation of Nrf2 into the nucleus after 5-FU exposure was demonstrated by immunocytochemistry and western blotting. Using an ARE-driven reporter gene assay, activation of the luciferase activity by 5-FU was also evidenced. Moreover, transfection of HT-29 cells with siRNA directed against Nrf2 inhibited induction of Nrf2 target genes and increased 5-FU cytotoxicity. In conclusion, we demonstrate for the first time that 5-FU activates the Nrf2/ARE pathway which in turn induces cytoprotective genes and modulates chemosensitivity of HT-29 colon cancer cells. Therefore, we postulate that Nrf2 might represent a potential therapeutic target in 5-FU treatment of colon cancer.     

吉西他滨联合奥沙利铂或5氟尿嘧啶治疗晚期胰腺癌的临床应用

目的比较吉西他滨联合奥沙利铂或5氟尿嘧啶(5-Fu)治疗晚期胰腺癌的临床效果。方法选取2013年1月至2015年1月间在黄石市中心医院治疗的86例晚期胰腺癌患者,按随机数字表法分为奥沙利铂组和氟尿嘧啶组,每组43例。比较两组患者短期疗效、无进展生存时间、总生存时间和不良反应发生率。结果两组患者的近期疗效差异均无统计学意义(均P>0.05)。两组患者无进展生存时间和总生存时间差异均无统计学意义(均P>0.05)。氟尿嘧啶组患者并发症发生率显著高于奥沙利铂组,差异有统计学意义(P<0.05)。结论两种治疗方案均具有较好的临床治疗效果,但吉西他滨联合奥沙利铂的治疗方案不良反应更轻微,具有临床应用价值。     

伊立替康或奥沙利铂联合氟尿嘧啶及亚叶酸钙治疗晚期大肠癌

 目的　观察并比较伊立替康联合5-氟尿嘧啶（5-Fu）及亚叶酸钙（CF）与奥沙利铂（L-OHP）联合5-Fu+CF治疗晚期大肠癌的疗效及患者不良反应。方法　随机将晚期大肠癌患者分为两组：伊立替康联合5-Fu+CF组（A组）24例，L-OHP联合5-Fu+CF（B组）25例。每例患者至少完成2个周期以上的化疗。结果　A组：有效（CR+PR）率33.3 %，中位缓解期5.0个月，中位生存期12.4个月。B组：有效率40.0 %，中位缓解期5.3个月，中位生存期14.4个月。A组的延迟性腹泻的发生率为32.0 %， B组周围神经毒性发生率为64.0 %；其他不良反应为骨髓抑制和恶心、呕吐等，两组发生率相近。 结论　伊立替康联合5-Fu+CF与L-OHP联合5-Fu+CF两方案治疗晚期大肠癌疗效相当，患者不良反应均可耐受。     

In vitro radiosensitization by oxaliplatin and 5-fluorouracil in a human colon cancer cell line

The current study was designed to compare the radiosensitizing effects of oxaliplatin and 5-fluorouracil (5FU) in a human colon cancer cell line. A human colon cancer cell line (S1) was treated with various doses of oxaliplatin, 5FU, radiation, and combinations thereof. Various clinically used schedules were mimicked. 5FU was either incubated during 1 h ("bolus") or 24 h ("continuous infusion"). When combining oxaliplatin and 5FU, an isobologram analysis revealed synergistic effects, regardless of 5FU schedule. The IC(10) and IC(50)-doses for the drugs where then combined with radiotherapy. With equitoxic drug doses (IC(50)), radiosensitization was observed in the following order: oxaliplatin > 5FU 24 h > 5FU 1 h exposure. The degree of potentiation corresponded to approximately 0.8 Gy, 0.7 Gy, and 0.2 Gy, respectively. In this experimental setting, oxaliplatin seemed to be a better radiosensitizer than 5FU, and longer incubation time with 5FU was better than short exposure.     

Chemotherapy enhances TNF-related apoptosis-inducing ligand DISC assembly in HT29 human colon cancer cells

Cytokines such as Fas-ligand (Fas-L) and Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) can induce human colon cancer cell apoptosis through engagement of their death domain receptors. All the cancer cells are not sensitive to these cytokines. We have shown recently that low doses of cytotoxic drugs could restore TRAIL-induced cell death in resistant colon cancer cell lines. The present work further explores the death pathway triggered by the cytotoxic drug/TRAIL combination in HT-29 colon cancer cells (www.alexis-corp.com). Clinically relevant concentrations of cisplatin, doxorubicin and 5-fluorouracil synergize with TRAIL to trigger HT-29 cell death. Activation of this pathway leads to apoptosis that involves both caspases and the mitochondria. An increased recruitment of Fas-associated death domain (FADD) and procaspase-8 to the TRAIL-induced death-inducing signaling complex (DISC) was shown in cells exposed to anticancer drugs. Following caspase-8 activation at the DISC level, the mitochondria-dependent death pathway is activated, as demonstrated by the cleavage of Bid, the dissipation of DeltaPsi(m), the release of mitochondrial proteins in the cytosol and the inhibitory effect of Bcl-2 expression. Importantly, besides mitochondrial potentiation, we show here that cytotoxic drugs sensitize HT-29 colon cancer cells to TRAIL-induced cell death by enhancing FADD and procaspase-8 recruitment to the DISC, a novel mechanism whose efficacy could depend partly on Bcl-2 expression level.     

Enhanced antitumor activity of 6-hydroxymethylacylfulvene in combination with irinotecan and 5-fluorouracil in the HT29 human colon tumor xenograft model

6-Hydroxymethylacylfulvene (MGI-114) is a semisynthetic analogue of the toxin illudin S, a product of the Omphalotus mushroom. MGI-114 induces cytotoxicity in a variety of solid tumors in vivo, including the refractory HT29 human colon cancer xenograft. In this study, the potential application of MGI-114 in the treatment of colon cancer was further explored by evaluating the activity of MGI-114 in combination with irinotecan (CPT-11) and 5-fluorouracil (5FU). Groups of 9 nude mice bearing HT29 xenografts were treated with either single agent MGI-114, CPT-11, or 5FU, or MGI-114 in combination with CPT-11 or 5FU. MGI-114 was administered at doses of 3.5 and 7 mg/kg i.p. daily on days 1 through 5, and CPT-11 and 5FU were administered at doses of 50 and 100 mg/kg i.p. on days 1, 12, and 19. In the single agent studies, MGI-114, CPT-11, and 5FU all resulted in decreased final tumor weights compared with vehicle-treated controls (P<0.05), but only MGI-114 at 7 mg/kg produced partial responses. When MGI-114 at 3.5 mg/kg was combined with CPT-11, significant decrements in final tumor weights occurred compared with monotherapy with the same doses of MGI-114 and CPT-11 (P< or =0.001). Also, administration of the low-dose combination (MGI-114 at 35 mg/kg and CPT-11 at 50 mg/kg) resulted in final tumor weights similar to those achieved after administration of high-dose MGI-114 as a single agent. Moreover, the combination of MGI-114 and CPT-11 produced partial responses in nearly all of the animals, with some animals achieving complete responses. The outcome with the combination of MGI-114 and 5FU was less striking, with fewer partial responses and no complete responses. These results suggest enhanced activity when MGI-114 is combined with CPT-11, and clinical trials to further evaluate this combination regimen are planned.     

Apoptosis in cultured human colon cancer cells induced by combined treatments with 5-fluorouracil, tumor necrosis factor-alpha and interferon-alpha

Biochemical analysis using nick end-labeling was performed to investigate the effect of various combinations of 5-fluorouracil, natural human tumor necrosis factor-alpha and natural human interferon-alpha on the induction of apoptosis in RPMI 4788 human colon cancer cells. After treatment with 5-fluorouracil (1 mM) for 48 h, the number of nick end-positive cells was significantly increased in comparison to the situation without treatment. When tumor cells were treated with 1 mM 5-fluorouracil, 2.86 Japan Reference Units (JRU)/ml natural human tumor necrosis factor-alpha and 1 x 10(3) IU/ml natural human interferon-alpha in combination for 48 h, the number of nick end-positive cells was significantly higher than that after treatment with 5-fluorouracil alone. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay revealed a significant decrease of relative viability, as compared to treatment with 5-fluorouracil (1 mM), 5-fluorouracil + natural human tumor necrosis factor-alpha, or 5-fluorouracil + natural human interferon-alpha for 48 h. Pretreatment with 5-fluorouracil (1 mM) for 24 h prior to treatment with natural human tumor necrosis factor-alpha (2.86 JRU/ml) and natural human interferon-alpha (10(3) IU/ml) for 24 h resulted in a significant increase of nick end-positive cells compared to pretreatment with natural human tumor necrosis factor-alpha and natural human interferon-alpha prior to treatment with 5-fluorouracil for 24 h (p < 0.05). These results suggest that 5-fluorouracil alone can induce apoptosis in RPMI 4788 tumor cells and that this effect can be enhanced by combination with natural human tumor necrosis factor-alpha and natural human interferon-alpha.      

Demethylation restores SN38 sensitivity in cells with acquired resistance to SN38 derived from human cervical squamous cancer cells

Using seven monoclonal SN38-resistant subclones established from ME180 human cervical squamous cell carcinoma cells, we examined the demethylation effects of 5-aza-2'-deoxycytidine (5-aza-CdR) on the SN38-sensitivity of the cells as well as the expression of death-associated protein kinase (DAPK) in the SN38-resistant cells. The DAPK expression levels were evaluated among parent ME180 cells, SN38-resistant ME180 cells and cisplatin-resistant ME180 cells by methylation-specific DAPK-PCR, quantitative RT-PCR and western blot analysis. The SN38-resistant cells co-treated with SN38 and 5-aza-CdR strongly exhibited enhanced SN38-sensitivities resembling those found in the parent cells. In the SN38-resistant subclones, no relationships were found between the restored SN38 sensitivity and hypermethylation of the DAPK promoter, DAPK mRNA expression, DAPK protein expression and induction of DAPK protein after 5-aza-CdR treatment, unlike the strong suppression of 5-aza-CdR-induced DAPK protein expression in the cisplatin-resistant subclones. These findings indicate that reversibly methylated molecules, but not DAPK, may regulate SN38 resistance, and that demethylating agents can be strong sensitizing anticancer chemotherapeutic drugs for SN38-resistant cancers.     

Comparison between triple therapy with octreotide, galanin and serotonin vs. irinotecan or oxaliplatin in combination with 5-fluorouracil/leukovorin in human colon cancer

Human colon cancer cells were injected sub-cutaneously into 30 nude mice. After 8 days, the animals were divided into 3 equal groups. The first and second groups received an i.p. injection with 5-fluorouracil/leukovorin (5-FU/LV) for 5 days (20 mg and 10 mg/kg body weight respectively). On the first day of 5-FU/LV treatment, the first group received an i.p. injection of irinotecan (2.5 mg/kg body weight), and the second group received an i.p. injection with oxaliplatin (1 mg/kg body weight). The third group were injected i.p. with 100 microl saline solution containing octreotide, galanin and serotonin. Injections were given 3 times daily for 5 days with a total dose of 150 microg/kg body weight/day. Three days after the treatment, the animals were sacrificed. Whereas the animals treated with triple therapy held a stable body weight, animals treated with 5-FU/LV-irinotecan and 5-FU/LV-oxaliplatin had gradual weight loss, which amounted to approximately 25% of their body weight at the end of the experiment. Moreover, 2 mice in the group treated with 5-FU/LV-irinotecan died, most probably due to side effects. There was no statistically significant difference between the 3 groups regarding tumour proliferation, apoptosis, blood vessel density, EGF- and VEGF-expression. Treatment with triple therapy using octreotide, galanin and serotonin appear to be comparable to 5-FU/LV in combination with irinotecan and oxaliplatin. However, triple therapy seems to have a better safety profile.     

Augmentation of 5-fluorouracil cytotoxicity in human colon cancer cells by dipyridamole

The effect of dipyridamole (DP), an inhibitor of nucleoside transport, on the uptake and toxicity of 5-fluorouracil (FUra) was examined in a human colon cancer cell line (HCT 116). DP substantially increased the cytotoxicity of FUra in cell growth experiments and in viability assays measuring colony formation. The augmentation by DP was dose and time dependent. Several possible mechanisms by which DP enhanced FUra toxicity were investigated. DP did not alter the uptake of FUra into the acid-soluble and -insoluble fractions of HCT 116 cells. While DP did not affect the uptake of FUra, it did inhibit the transport of the nucleoside analogues, fluorouridine and fluorodeoxyuridine, of FUra. Although DP effectively inhibited the uptake of thymidine and uridine in a dose-dependent manner, several lines of evidence suggested that inhibition of nucleoside salvage was not the critical effect. (a) The toxicity of FUra was not prevented by thymidine, uridine, or the combination of thymidine and uridine. Thymidine triphosphate pools, decreased by 50% during the initial 8 h of exposure to FUra, were not further depleted by the addition of DP. The shrinkage in deoxythymidine triphosphate pools produced by FUra was prevented by concomitant exposure to thymidine; however, this did not translate into protection from FUra lethality. The use of dialyzed serum, which greatly diminished the availability of nucleic acid precursors, did not increase the toxicity of FUra. DP increased the cytotoxicity of FUra as effectively in experiments utilizing dialyzed serum as when nondialyzed serum was used. Surprisingly, however, the addition of sufficient thymidine to overcome the DP block did prevent the augmentation of FUra toxicity produced by DP. DP may provide a novel means of enhancing the cytotoxicity of FUra.     

奥沙利铂联合5-FU和吡柔比星治疗晚期胃癌临床疗效分析

目的:观察奥沙利铂联合5-FU和吡柔比星治疗晚期胃癌的疗效及不良反应.方法:36例晚期胃癌患者,初治20例,复治16例.吡柔比星40mg/m2静脉注射d1,奥沙利铂130mg/m2静脉滴注2小时d1,5-FU 375mg/m2·d1-5静脉滴注,每3周重复,每化疗2个周期评价1次疗效. 结果: 36例患者中,总缓解率 44.37%,完全缓解1例,部分缓解41.6%(15例).初治病例缓解率45%(9/20),复治病例缓解率31.25%(5/16).KPS评分提高10分以上者15例(15/36).主要的Ⅲ-Ⅳ度不良反应为:中性粒细胞减少27.7%(10/36),血小板减少13.8%(5/36),贫血16.6%(6/36),恶心呕吐22.2%(8/36).结论:奥沙利铂联合5-FU及吡柔比星治疗晚期胃癌疗效较好,不良反应可以耐受,值得临床进一步应用.     

Cisplatin-induced CD95 redistribution into membrane lipid rafts of HT29 human colon cancer cells

We have shown previously that the death receptor CD95 could contribute to anticancer drug-induced apoptosis of colon cancer cells. In addition, anticancer drugs cooperate with CD95 cognate ligand or agonistic antibodies to trigger cancer cell apoptosis. In the present study, we show that the anticancer drug cisplatin induces clustering of CD95 at the surface of the human colon cancer cell line HT29, an event inhibited by the inhibitor of acid sphingomyelinase (aSMase) imipramine. The cholesterol sequestering agent nystatin also prevents cisplatin-induced CD95 clustering and decreases HT29 cell sensitivity to cisplatin-induced apoptosis and the synergy between cisplatin and anti-CD95 agonistic antibodies. CD95, together with the adaptor molecule Fas-associated death domain and procaspase-8, is redistributed into cholesterol- and sphingolipid-enriched cell fractions after cisplatin treatment, suggesting plasma membrane raft involvement. Interestingly, nystatin prevents the translocation of the aSMase to the extracellular surface of plasma membrane and the production of ceramide, suggesting that these early events require raft integrity. In addition, nystatin prevents cisplatin-induced transient increase in plasma membrane fluidity that could be required for CD95 translocation. Together, these results demonstrate that cisplatin activates aSMase and induces ceramide production, which triggers the redistribution of CD95 into the plasma membrane rafts. Such redistribution contributes to cell death and sensitizes tumor cells to CD95-mediated apoptosis.     

替加氟和氟尿嘧啶分别与草酸铂联合持续静脉滴入治疗晚期胃癌的比较研究

目的：探讨持续静脉滴入替加氟、氟尿嘧（5-FU）分别与草酸铂（L-OHP）联合对晚期胃癌的效果。方法：67例晚期胃癌患者分别接受方案A（32例）和方案B（35例）治疗。方案A：替加氟800mg／m^2,持续静脉滴入（24h）,d1～d5;甲酰四氢叶酸（LV）200mg／m^2,静脉滴入（2h）,d1～d5;L-OHP135mg／m^2,静脉滴入（2h）,d1。方案B：5-FU750mg／m^2,持续静脉滴入（24h）,d1～d5;LV与L—OHP应用方法同方案A。均21d为1个周期。结果：67例患者中CR9例,PR34例,有效率64．0％。TTP和MST分别为7．2个月和11．3个月。方案A有效率高于方案B,分别为68．8％和60．0％,但差异无统计学意义（Χ^2=0．557,P=0．456）。初次化疗患者有效率高于既往接受化疗者,分别为73．7％和60．4％。对复治患者方案A有效率为69．6％,方案B为52．0％,尽管方案A组有效率呈现增高的趋势,但差异无统计学意义（Χ^2=1．545,P=0．214）。两种治疗方案的不良反应均易于耐受。结论：持续静脉滴入替加氟、氟尿嘧啶分别与草酸铂联合可以作为晚期胃癌安全有效的治疗方案。