两性霉素B和5-氟胞嘧啶的体外联合药敏试验

参照美国国家临床试验标准化委员会(NCCLS)提出的标准,采用棋盘微量稀释法对28株隐球菌和念珠菌进行两性霉素B和5-氟胞嘧啶的体外联合药敏试验。结果显示联合用药时各药物的最低抑菌浓度(minimal inhibitory concentration,MIC)几何均值比单独用药显著降低(P<0.01);两性霉素B和5-氟胞嘧啶的协同相加作用较为明显,而且未发现有拮抗作用,部分抑菌浓度指数(fractional inhibitory concentration index,FICI)的平均值为0.8。提示两性霉素B和5-氟胞嘧啶对致病酵母主要表现为协同相加作用。

Antineoplastic Effect of Calcium Channel Blocker-Verapamil and 5-Fluorouracil Intraperitoneal Chemotherapy on Hepatocarcinoma-Bearing Rats

Objective To study the antineoplastic effect of the calcium channel blocker verapamil and 5-fluorouracil intraperitoneal chemotherapy onhepatocarcinoma-bearing rats, and examine the action between calcium channel blockers and cytotoxic drugs.Methods We adopted the method of subcapsular implantation of carcinoma tissues of walker-256 in the left liver lobe as a model of livercarcinoma-bearing rats. All experimental animals were divided into four groups. On the sixth day post implantation, in group A (controlgroup) 6 ml of saline was injected intraperitoneally once a day for 3 days. In group B (single chemotherapy group) 6 ml of 5-Fu 75 mg/kg was injected intraperitoneally once a day for 3 days. In group C (combination of treatment group) both 5-Fu (75 mg/kg) and verapamil(25 mg/kg) were administered simultaneously as in A and B. In group D (simple verapamil group) only 6 ml of verapamil (25 mg/kg)was administered as above.Results Compared with groups A, B and D, The volume of cancer and the contents of liver cancer DNA and protein were significantlyreduced. The rates of inhibiting cancer (89.9% in group C and 35.4% in group B) were significantly increased in group C. Group C hadsignificantly long survival time compared to groups A, B and D ( P < 0.05) . By light microscopy, a number of focal necroses were foundin cancer tissue in group C.Conclusion Calcium channel blockers can enhance the antineoplastic effect of 5-Fu intraperitoneal chemotherapy to liver cancer ; Theuse of verapamil can not increase the toxicity of 5-Fu.

Systemic gemcitabine combined with intra-arterial low-dose cisplatin and 5-fluorouracil for advanced hepatocellular carcinoma: Seven cases

The combination of intra-arterial low-dose cisplatin and 5-fluorouracil (5-FU) is effective against advanced hepatocellular carcinoma (HCC). Systemic gemcitabine chemotherapy seems effective in many cancers. We report the results of combination therapy with systemic gemcitabine, intra-arterial low-dose cisplatin and 5-FU (GEMFP). Seven patients with non-resectable advanced HCC were treated with GEMFP. One course of chemotherapy consisted of daily intra-arterial cisplatin (20 mg/body weight/hour on d 1, 10 mg/body weight per 0.5 h on d 2-5 and 8-12), followed by 5-FU (250 mg/body weight per 5 h on d 1-5 and 8-12) via an injection port. Gemcitabine at 1000 mg/m2 was administered intravenously at 0.5 h on d 1 and 8. The objective response was 57%. The response to GEMFP was as follows: complete response (no patients), partial response (four patients), stable disease (three patients), and progressive disease (no patients). The median survival period was 8 mo (range, 5-55). With regard to the National Cancer Institute Common Toxicity Criteria (NCI-CTC) grade 3 or 4 adverse reactions, seven (100%), seven, six (86%) and one (14%) patients developed leukopenia, neutropenia, thrombocytopenia and anemia, respectively. GEMFP may potentially be effective for non- resectable advanced HCC, but it has severe hematologic toxicity.

Re-evaluation of antitumor effects of combination chemotherapy with interferon-α and 5-fluorouracil for advanced hepatocellular carcinoma

AIM： To evaluate the efficacy of combination chemotherapy with interferon-α （IFNα） and 5-fluorouracil （5-FU） in patients with advanced hepatocellular carcinoma （HCC）. METHODS： Twenty-eight HCC patients in advanced stage were enrolled in the study. They were treated with IFNα/ 5-FU combination chemotherapy. One cycle of therapy lasted for 4 wk. IFNα （3×10^6 units） was subcutaneously injected thrice weekly on days 1, 3, and 5 for 3 wk, and 5-FU （500 mg/d） was administered via the proper hepatic artery for 5 consecutive days per week for 3 wk. No drugs were administered during the 4th wk. The effect of combination chemotherapy was evaluated in each patient alter every cycle based on the reduction of tumor volume. RESULTS： Alter the 1^st cycle of therapy, 16 patients showed a partial response （PR, 57.1%） but none showed a complete response （CR, 0%）. At the end of therapy, the number of patients who showed a CR, PR, or no response （NR） was 1, 10, and 17, respectively. The response rate for therapy （CR＋PR） was 21.5%. Biochemical tests before therapy were compared between responsive （CR＋PR） and non-responsive （NR） patients, but no significant differences were found for any of the parameters examined, indicating that no reasonable predictors could be identified in our analysis. CONCLUSION： Attempts should be made to discriminate between responders and non-responders by evaluating tumor size alter the first cycle of IFNα/5-FU combination chemotherapy. For non-responders, therapy should not proceed to the next cycle, and instead, different combination of anticancer drugs should be explored. 2005 The WJG Press and Elsevier Inc. All rights reserved

Successful treatment of advanced hepatocellular carcinoma by combined administration of 5-fluorouracil and pegylated interferon-a

We report a case of hepatocellular carcinoma （HCC） treated successfully by transarterial chemoembolization （TACE） followed by combination therapy of 5-fluorouracil （5-FU） and pegylated interferon-α （PEG-IFN-α）. In the present case, the patient had massive and advanced HCC with a diameter of over 8 cm located in segment 7 （S7） of the liver. Furthermore, the tumor invaded into the major branch of the portal vein （Vp3）. After TACE, combined administration of 5-FU and PEG-IFN-α was performed for 5 too. HCC was totally eradicated and the serum levels of tumor markers were markedly decreased by the treatment. Although it has been reported that the combined use of conventional IFN-α and 5-FU showed striking effects on HCC in some cases, this case may suggest the more promising effect of PEG-IFN-α with a long-lasting effect, in the combined use with 5-FU for the treatment of massive advanced HCC.

Activity and safety of pegylated liposomal doxorubicin,5-fluorouracil and folinic acid in inoperable hepatocellular carcinoma:A phase Ⅱ study

AIM: To improve the results of New therapeutic strategies in hepatocellular carcinoma (HCC). We have conducted a phase Ⅱ study with pegylated liposomal doxorubicin (PLD), 5-fluorouracil (5FU) and folinic acid (FA). METHODS: Thirty-one patients with hystologically- confirmed, inoperable HCC, received combination chemotherapy with PLD 25 mg/mq on d 1, 5FU 1200 mg/mq in 48 h continuous infusion, and oral FA 30 mg on d 1 and 2 every 3 wk until disease progression or intolerable toxicity. RESULTS: The median age was 65 years (range 41-82) and 28 patients were hepatitis C virus seropositive (90%). The majority of patients were Child-Pugh Class B (55%). Two patients showed a partial response (PR), and 16 had stable disease (SD). With a median follow-up of 14 mo, the median time to progression of all evaluable patients was 4 mo (95% CI 1.7-7). Median overall survival was 9 mo (95% CI 3-24 mo). After 1 year, 9 of 18 PR/SD patients were alive. Chemotherapy was well tolerated. CONCLUSION: PLD/FU/FA combination seems capable of achieving durable stabilization of HCC. The manageable toxicity supports a role for combination with other anticancer agents.

NEUTROPHIL INFILTRATION IS INVOLVED IN 5-FLUOROURACIL INDUCED LIPID PEROXIDATIVE DAMAGE OF THE SMALL INTESTINE

This study evaluated the mechanisms of 5-fluorouracil (5-FU) induced intestinal damage by investi-gating the lipid peroxide (LPO) level, myeloperoxidase (MPO) activity and disaccharidase activity in rats.Group Ⅰ animals (n=6) were sacrificed and served as a normal control group. Group Ⅱ animaIes (n= 24 )were given a single intraperitoneal injection of 5-FU (150 mg/kg) and every 8 rats were sacrificed on day1,3 and 5 after injection respectively. Results: LPO concentration in blood and intestinal mucosa was sig-nificantly higher in the group Ⅱ than in the group Ⅰ on day 1 and 3 (P<0. 05) MPO activity was signif-icantly higher in the group I than in the group Ⅰ at different times (P<0. 01 ). Lactase activity on day 5(P<0. 01); sucrase activity (P<0. 01 and P<0. 05 respectiviely) and maltase activity (P<0. 01 ) on day3 and 5, were significantly lower in the group than in the group l. Conclusion: The results indicatethat neutrophil infiltration may be involved in 5-FU-induced lipid peroxidative damage of the small intes-tine which was reflected by the decreased disaccharidases activities.

Spindle cell carcinoma of the breast as complex cystic lesion: a case report

Spindle cell carcinoma of the breast is a rare tumor. This tumor can proliferate rapidly and cause cystic changes because of internal tissue necrosis. We evaluated a 54-year-old woman with right breast lump. Mammography showed a category four mass with a diameter of 2.5 cm. Ultrasonography(US) revealed a complex cystic lesion, and fine-needle aspiration(FNA) cytology demonstrated bloody fluid and malignant cells. Partial breast resection and sentinel lymph node biopsy were performed. Immunohistology revealed spindle cells with positive results for cytokeratin(AE1/AE3) and vimentin, partially positive results for s-100, and negative results for desmin and α-actin. The pathological stage was IIA, and biochemical characterization showed that the tumor was triple negative. Six courses of FEC-100 chemotherapy(5-fluorouracil 500 mg/m2, epirubicin 100 mg/m2, and cyclophosphamide 500 mg/m2) were administered. Radiotherapy was performed. This case is discussed with reference to the literature.

Mechanism of apoptotic effects induced by 5 fluorouracil on human liver carcinoma Bel7402 cell line

Objective To evaluate the effect of endogenous nitric oxide (NO) on the ability of 5 fluourouracil (5 FU) to induce apoptosis in the liver carcinoma Bel7402 cell line, and to observe the anti tumor mechanism and effective adjuvant of 5 FU Methods Cells were cultured under routine conditions with Dulbecco's modified Eagle's medium (DMEM) without L arginine (L Arg) We observed the expression of inducible nitric oxide synthase (iNOS) and apoptosis of cells induced by 5 FU with L Arg added to the medium The production of nitric oxide was determined by the cell expression of iNOS detected by immunohistochemical staining, and by the concentrations of nitrite and nitrate in the supernatant Results 5 fluourouracil significantly increased the iNOS expression to 0 1687±0 01968 ( P <0 05, vs control group), and the concentration of nitric oxide to 213±30 2 μmol/L ( P <0 05, vs control group) The apoptotic cell rate increased significantly to 17 85±0 78%, while the necrotic cell rate decreased to 32 99±0 83% ( P <0 05, compared with the 5 FU group) N ω nitro L Arginine methyl ester (L NAME), the antagonist of L Arg, can block the apoptotic effects of endogenous nitric oxide Conclusions 5 FU had a synergistic effects with L Arg by increasing the production of endogenous nitric oxide Endogenous nitric oxide plays an important role in the process where 5 FU induces apoptosis in liver carcinoma cells L Arg may be a good adjuvant for chemotherapy with 5 FU

Sensitization of prostate cancer cell lines to 5-fluorocytosine induced by adenoviral vector carrying a CD transcription unit

Objective To investigate the efficiency of the cytosine deaminase adenoviral/5-fluorocytosine system on prostate cancer cell lines.Methods We used cell culture, infectivity and sensitivity tests, to observe bystander effect by animal tests.Results Established prostate cancer cell lines are eventually infectible by adenoviral vector. The ratio of vector/cell at which infection occurs depends on the specific cell line. The peak of expression of the transferred cytosine deaminase gene occurred in cells at different time, but persisted beyond 11 days. These prostate cell lines are sensitized to 5-fluorocytosine by infection with adenoviral vector carrying the cytosine deaminase gene. Only 5% of the LNCap and 10% of the RM-1 cells were infected and produced 100% cell death. In the animal test, there was significant inhibition of tumor growth at a ratio of 400 vector particles/cell with the systematic treatment of 5-fluorocytosine.Conclusions Adenoviral vector carrying a cytosine deaminase transcription unit can sensitize prostate cancer cell lines to 5-fluorocytosine. The system can significantly inhibit the growth of prostatic tumors in mice.

Enhanced antitumor effect of TM208 in combination with 5-fluorouracil in H_(22) transplanted mice

4-Methylpiperazine-l-carbodithioc-acid-3-cyano-3,3-diphenylpropyl ester hydrochloride（TM208）,a newly synthesized dithiocarbamate derivative,exhibits antitumor effect in vivo with low toxicity.However,the antitumor effect of TM208 in combination with drugs in clinical use for cytotoxic chemotherapy has not been identified.In our study,the antitumor effects and toxicities of TM208 in combination with cisplatin（DDP）,cyclophosphamide（CTX） and 5-fluorouracil（5-Fu）,respectively,were evaluated in vivo using a transplanted solid-type hepatocarcinoma H_（22） mice model.The results suggested that 5-Fu（5 mg/kg/2d） potentiated the antitumor effect of TM208（100 mg/kg/d） with significantly higher tumor inhibition rates（P0.01） and a slight elevation of toxicity;however,DDP and CTX in combination with TM208 did not exhibit similar enhanced antitumor effect.For further investigation,we found that the TM208 and 5-Fu combination therapy led to G_2/M cell cycle arrest of tumor cells in vivo by downregulating the protein expression of cyclin Bl,cdc2,cdk7,and upregulating the expression of p21 and p53.The protein expression levels of cyclin Dl and cyclin E were also downregulated in tumor cells treated with TM208 and 5-Fu,while those of cdk4 and cdk2 remained unchanged.The change of mRNA expression level of cdc2 was consistent with that of its protein in each group,while the mRNA expression of cyclin B1 remained unchanged among each group.These results demonstrated the dosage regimen of TM208 for combination therapy and could serve as evidence for clinical use of TM208 as an antineoplastic drug.

Polysaccharides from Tricholoma matsutake and Lentinus edodes enhance 5-fluorouracil-mediated H22 cell growth inhibition

OBJECTIVE： Few studies have investigated the ef- fects produced by combinations of polysaccharides and chemotherapeutic drugs in cancer treatment. We hypothesized that a combination of polysaccha- rides （COP） from Lentinus edodes and Tricholoma matsutake would improve the efficacy of 5-fluoro- uracil （5-FU）-mediated inhibition of H22 cell growth. METHODS： Mice were injected H22 cells and then treated with either 5-FU, polysaccharides from Tri- choloma matsutake （PTM）, polysaccharides from Lentinus edodes （PL）, PTM ＋ PL, 5-FU ＋ PTM, 5-FU ＋ PL, or 5-FU ＋ COR The tumor weight and volume, and splenic CD4 ＋ and CD8 ＋ T cell frequencies, were determined. Additionally, splenic natural killer （NK） cell and cytotoxic T lymphocyte （CTL） activities were assessed and the serum levels of tumor necro- sis factor-a （TNF-a）, Interleukin-2 （IL-2）, and Interfer- on-y （IFN-y） were measured. RESULTS： Compared with mice from the control,5-FU, PL, PTM, PTM ＋ PL, 5-FU ＋ PL, and 5-FU ＋ PTM groups, mice treated with 5-FU ＋ COP showed： （a） significantly reduced tumor weight and volume （P〈 0.05）, （b） significantly higher serum levels of TNF-α, IL-2, and IFN-y （P〈0.05）, （c） significantly increased CD4＋ and CD8＋ 1 cell frequencies in the spleen （P〈 0.05）, and （d） significantly increased splenic NK cell and CTL activities （P〈0.05）. The tumor weight and volume in mice treated with 5-FU＋PL or 5-FU＋PTM were significantly reduced compared with mice treated with 5-FU alone （P〈0.05）. Serum levels of TNF-α, 11.-2, and IFN-y, frequencies of CD4 ＋ and CD8＋ T cells in the spleen, and splenic NK and CTL activities were also significantly increased in mice treated with 5-FU＋PL or 5-FU＋PTM compared with mice treated with 5-FU alone （P〈0.05）. CONCLUSION： Polysaccharides from Lentinus edodes and Tricholoma matsutake could enhance the efficacy of 5-FU-mediated H22 cell growth inhi- bition.