AIM:To investigate the effects of adenosine triphosphate(ATP)and melatonin,which have antioxidant and antiinflammatory activities,on potential 5-fluorouracil(5-FU)-induced optic nerve damage in rats.METHODS:Twenty-fou...AIM:To investigate the effects of adenosine triphosphate(ATP)and melatonin,which have antioxidant and antiinflammatory activities,on potential 5-fluorouracil(5-FU)-induced optic nerve damage in rats.METHODS:Twenty-four rats were categorized into four groups of six rats:healthy(HG),5-FU(FUG),ATP+5-FU(AFU),and melatonin+5-FU(MFU).ATP(4 mg/kg)and melatonin(10 mg/kg)were administered intraperitoneally and orally,respectively.One hour after ATP and melatonin administration,rats in the AFU,MFU,and FUG were intraperitoneally injected with 5-FU(100 mg/kg).ATP and melatonin were administered once daily for 10d.5-FU was administered at a single dose on days 1,3,and 5 of the experiment.After 10d,the rats were euthanized and optic nerve tissues were extracted.Optic nerve tissues were biochemically and histopathologically examined.RESULTS:ATP and melatonin treatments inhibited the increase in malondialdehyde(MDA)and interleukin-6(IL-6)levels,which were elevated in the FUG.The treatments also prevented the decrease in total glutathione(tGSH)levels and the superoxide dismutase(SOD)and catalase(CAT)activities(P<0.001).This inhibition was higher in the ATP group than in the melatonin group(P<0.001).ATP prevented histopathological damage better than melatonin(P<0.05).CONCLUSION:ATP and melatonin have the potential to be used in alleviating 5-FU-induced optic nerve damage.In addition,ATP treatment shows better protective effects than melatonin.展开更多
BACKGROUND Colorectal cancer(CRC)is the second most prevalent cause of cancer-related mortality and is increasing in younger individuals.Chemotherapy,a crucial adjuvant systemic therapy for CRC management,often leads ...BACKGROUND Colorectal cancer(CRC)is the second most prevalent cause of cancer-related mortality and is increasing in younger individuals.Chemotherapy,a crucial adjuvant systemic therapy for CRC management,often leads to resistance through poorly characterized underlying molecular mechanisms.The long noncoding RNA SNHG5 is highly expressed in CRC and promotes tumor proliferation and invasion,prompting us to hypothesize that SNHG5 may play a crucial role in the chemotherapeutic agent 5-fluorouracil(5-Fu)resistance in CRC.AIM To identify the function and mechanism of SNHG5 in 5-Fu resistance in CRC.METHODS Quantitative real-time polymerase chain reaction was performed to examine the expression of SNHG5 in CRC tissues from 225-Fu-sensitive patients and 145-Fu-resistant patients and in CRC cells and 5-Fu-resistant CRC cells.Cell viability and apoptosis were assessed in SNHG5-overexpressing CRC cells and SNHG5-knockdown 5-Furesistant CRC cells.SNHG5 function in 5-Fu resistance in CRC was further analyzed using a xenograft mouse model.SNHG5 interactions with microRNAs were predicted by bioinformatics analysis.Luciferase reporter and RNA immunoprecipitation assays were performed to verify the binding between SNHG5 and miR-26b.Rescue experiments were performed to validate the functional interaction between SNHG5 and the miR-26b/p-glycoprotein(Pgp)axis.RESULTS SNHG5 expression was upregulated in 5-Fu-resistant CRC tissues and 5-Fu-resistant CRC cells.In vitro functional experiments demonstrated that SNHG5 overexpression significantly reduced cell apoptosis and enhanced cell viability,whereas SNHG5 knockdown in 5-Fu-resistant CRC cells increased cell apoptosis and decreased cell viability upon 5-Fu treatment.In a xenograft mouse model,we confirmed that SNHG5 overexpression led to a reduction in 5-Fu sensitivity in CRC in vivo.Mechanistically,SNHG5 acted as a molecular sponge for miR-26b.Rescue experiments validated that SNHG5 conferred 5-Fu resistance in CRC by regulating the miR-26b/Pgp axis.CONCLUSION SNHG5/miR-26b/Pgp regulates CRC chemosensitivity,providing potential therapeutic targets for the treatment of 5-Fu-resistant CRC.展开更多
AIM:To develop a 5-fluorouracil(5-FU)mesoporous poly(lactic)acid(PLA)delivery system for glaucoma filtration surgery suitable for a single subconjunctival implantation.METHODS:The 5-FU was infiltration-loaded into mes...AIM:To develop a 5-fluorouracil(5-FU)mesoporous poly(lactic)acid(PLA)delivery system for glaucoma filtration surgery suitable for a single subconjunctival implantation.METHODS:The 5-FU was infiltration-loaded into mesoporous PLA.In vitro and in vivo release experiments and ocular toxicology evaluation of the formulation were performed.The antiproliferative effect of this 5-FU-PLA tablet after glaucoma filtration surgery in rabbits was evaluated.Pathology,immunohistochemistry,and Western blot were used to further validate the inhibitory effect of this sustained release system.RESULTS:Various drug formulations were tested,and two 5-FU-PLA tablets,namely 1.5P15(5-FU 1.5 mg+PLA 15000 Da)and 2.5P15(5-FU 2.5 mg+PLA 15000 Da),had the most suitable release profiles in vitro.Further in vivo studies confirmed the safety and sustained-release profiles of both drugs.Both 5-FU-PLA tablets,relative to the free drugs,significantly inhibited tissue proliferation after glaucoma filtration and improved surgical success.Western blot showed that transforming growth factor-β(TGF-β)and connective tissue growth factor(CTGF)were inhibited by 5-FU after filtration surgery,with the effects of the 5-FU-PLA tablets being more lasting.CONCLUSION:The tested 5-FU-PLA tablets provide a sustained release of 5-FU,which may be used for a single subconjunctival implantation to inhibit proliferation after filtration surgery.展开更多
Background:Chitosan oligosaccharide(COS)is the major degradation product of chitosan by enzymatic processes.COS,with complete water solubility,exerts significant biological effects,including anti-cancer activity.We in...Background:Chitosan oligosaccharide(COS)is the major degradation product of chitosan by enzymatic processes.COS,with complete water solubility,exerts significant biological effects,including anti-cancer activity.We investigated the anti-tumor effects of COS on colorectal cancer as effective therapeutic methods with low side effects are lacking.Methods:COS was obtained from low molecular weight chitosan by an enzymatic method and the anticancer effects were measured by cell viability assay,flow cytometry analysis,Western blotting,and xenograft.Results:COS suppressed the proliferation of SNU-C5 cells compared to other colorectal cancer cells,but higher concentrations were required in the xenograft model.Co-treatment with 5-fluorouracil(5-FU)and COS enhanced the anti-cancer effects of 5-FU in SNU-C5 cells in vitro and in vivo.Flow cytometry revealed that COS induced cell cycle arrest at the G0/G1 phase without 5-FU or at the S and G2/M phases with 5-FU but did not affect cell death pathways.COS increased extracellular signal-regulated protein kinase(ERK)activation with or without 5-FU,whereas 5-FU treatment increased p53 activation.A low-dose of an ERK inhibitor suppressed COS-induced ERK activation and resulted in higher proliferation compared with COS.Conclusions:These results suggest that COS might enhance the anti-cancer effects of 5-FU in SNU-C5 colorectal cancer cells by activating ERK.展开更多
In this study,the hypertrophic scar（HS） model in rats was established.5-fluorouracil（5-FU）patch,-1000 V and-2000 V polypropylene（PP） electret 5-FU patches were prepared and applied onto the wound.The in vitro pe...In this study,the hypertrophic scar（HS） model in rats was established.5-fluorouracil（5-FU）patch,-1000 V and-2000 V polypropylene（PP） electret 5-FU patches were prepared and applied onto the wound.The in vitro permeation experiment was performed using the Franz diffusion cell system to determine the permeation cumulative amount and retention amount of5-FU through/in scar skin.The inhibition effect of negative electret on growth of HS was studied by hematoxylin-eosin（HE） staining,Masson staining and the immunohistologicall methods.The permeation study indicated that a negative electret could enhance the permeation and retention of 5-FU through and in scar skin respectively.HE staining and Masson staining indicated a better effect for-1000 V and-2000 V electret 5-FU patches on HS inhibition after28 d post-wounding compared with 5-FU patch.The immunohistological study showed much more reduced expressions of collegan type I,collegan type III,TGF-β1 and HSP47 in scar tissue after application of negative electret 5-FU patches than those of 5-FU patch.A negative electret5-FU patch may be advantageous for HS treatment.展开更多
Six aminoglucose conjugates were synthesized by the reaction of aminoglucose with 5-fluorou-racil-1-acetic acid or 5-fluorouracil-1-propanoic acid and confirmed by IR, 1H NMR and elemental analyses. Their antitumor ac...Six aminoglucose conjugates were synthesized by the reaction of aminoglucose with 5-fluorou-racil-1-acetic acid or 5-fluorouracil-1-propanoic acid and confirmed by IR, 1H NMR and elemental analyses. Their antitumor activities against A2780 cells and PC-14 cells were also evaluated.展开更多
In the present study,the electret 5-fluorouracil patch was developed,the effective surface potential,piezoelectric coefficient d33,open-circuit thermally stimulated discharge（TSD） current spectra and shear adhesion ...In the present study,the electret 5-fluorouracil patch was developed,the effective surface potential,piezoelectric coefficient d33,open-circuit thermally stimulated discharge（TSD） current spectra and shear adhesion of the patch were measured.The drug release profile of the patch was determined by using high performance liquid chromatography method.A stable potential difference which was positively dependent on the surface potential of the electret was generated on two sides of the patch.The measurements of d33 coefficient,TSD current spectra and adhesion performance showed that the electrostatic field of the electret could cause polarization and cohesive strength decreasing of the matrix molecules,change the distribution and interaction of the drug molecules in patch,therefore to increase the release of drug from the transdermal patch.展开更多
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 bloc...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.展开更多
AIM: To prepare chitosan-polyaspartic acid-5-fluorouracil (CTS-Pasp-5Fu) nanoparticles and investigate its anti-carcinoma effect and toxicity. METHODS: CTS-Pasp-5Fu nanoparticles were synthesized by ionic gelatificati...AIM: To prepare chitosan-polyaspartic acid-5-fluorouracil (CTS-Pasp-5Fu) nanoparticles and investigate its anti-carcinoma effect and toxicity. METHODS: CTS-Pasp-5Fu nanoparticles were synthesized by ionic gelatification. Male BABL/c nude mice were injected with SGC-7901 gastric carcinoma cell line mass to establish a human gastric carcinoma model. They were randomly allocated into 4 groups: CTS-Pasp-5Fu (containing 5-Fu 1.25 mg/kg), 5-Fu (1.25 mg/kg), CTS-Pasp and normal saline groups. Tumor weight was measured and assay of colony forming unit-granulocyte and macrophage (CFU-GM) was performed. The structural change of cells and tissues was observed and the Bax and Bcl-2 genes were detected. RESULTS: Compared with normal saline, the inhibition rates of tumor growth for the CTS-Pasp, 5-Fu and CTS-Pasp-5Fu groups were 5.58%, 58.69% and 70.82%, respectively. The tumor inhibition rates for the CTS-Pasp, 5-Fu and CTS-Pasp-5Fu groups were 5.09%, 65.3% and 72.79%, respectively. There was a significant decrease in the number of CFU-GMformation and increase of total bilirubin, and alanine aminotransferase in the 5-Fu group, but no change in those of the other three groups. There was no change in white blood cell count and creatinine among the four groups. Pathological section of liver and nephridial tissues showed that the damage in the 5-Fu group was more severe than that in the CTS-Pasp-5Fu group. 5-Fu and CTS-Pasp-5Fu groups could both down-regulate the Bcl-2 expression and up-regulate the Bax expression to different extent, and the accommodate effect of CTS-Pasp-5Fu was more obvious than 5-Fu. CONCLUSION: The tumor inhibition rate of CTS-Pasp-5Fu nanoparticles is much higher than that of 5-Fu alone.展开更多
AIM:To investigate the inhibitory effects of sinomenine(SIN)combined with 5-fluorouracil(5-FU)on esophageal carcinoma in vitro and in vivo.METHODS:Esophageal carcinoma(Eca-109)cells were cultured in DMEM.The single or...AIM:To investigate the inhibitory effects of sinomenine(SIN)combined with 5-fluorouracil(5-FU)on esophageal carcinoma in vitro and in vivo.METHODS:Esophageal carcinoma(Eca-109)cells were cultured in DMEM.The single or combined growth inhibition effects of SIN and 5-FU on the Eca-109 cells were examined by measuring the absorbance of CCK-8dye in living cells.Hoechst 33258 staining and an Annexin V/PI apoptosis kit were used to detect the percentage of cells undergoing apoptosis.Western blotting was used to investigate the essential mechanism underlying SIN and 5-FU-induced apoptosis.SIN at 25mg/kg and 5-FU at 12 mg/kg every 3 d,either combined or alone,was injected into nude mice and tumor growth inhibition and side effects of the drug treatment were observed.RESULTS:SIN and 5-FU,both in combination and individually,significantly inhibited the proliferation of Eca-109 cells and induced obvious apoptosis.Furthermore,the combined effects were greater than those of the individual agents(P<0.05).Annexin V/PI staining and Hoechst 33258 staining both indicated that the percentage of apoptotic cells induced by SIN and 5-FU combined or alone were significantly different from the control(P<0.05).The up-regulation of Bax and downregulation of Bcl-2 showed that the essential mechanism of apoptosis induced by SIN and 5-FU occurs via the mitochondrial pathway.SIN and 5-FU alone significantly inhibited the growth of tumor xenografts in vivo,and the combined inhibition rate was even higher(P<0.05).During the course of chemotherapy,no obvious side effects were observed in the liver or kidneys.CONCLUSION:The combined effects of SIN and 5-FU on esophageal carcinoma were superior to those of the individual compounds,and the drug combination did not increase the side effects of chemotherapy.展开更多
AIM:To study the anti-hepatocarcinoma effects of 5-fluorouracil (5-Fu) encapsulated by galactosylceramide liposomes (5-Fu-GCL) in vivo and in vitro. METHODS: Tumor-bearing animal model and HepA cell line were respecti...AIM:To study the anti-hepatocarcinoma effects of 5-fluorouracil (5-Fu) encapsulated by galactosylceramide liposomes (5-Fu-GCL) in vivo and in vitro. METHODS: Tumor-bearing animal model and HepA cell line were respectively adopted to evaluate the anti-tumor effects of 5-Fu-GCL in vivo and in vitro. Tumor cell growth inhibition effects of 5-Fu-GCL in vitro were assessed by cell viability assay and MTT assay. In vivo experiment, the inhibitory effects on tumor growth were evaluated by tumor inhibition rate and animal survival days. High performance liquid chromatography was used to detect the concentration-time course of 5-Fu-GCL in intracellular fluid in vitro and the distribution of 5-Fu-GCL in liver tumor tissues in vivo. Apoptosis and cell cycle of tumor cells were demonstrated by flow cytometry. RESULTS: In vitro experiment, 5-Fu-GCL (6.25-100 μmol/L) and free 5-Fu significantly inhibited HepA cell growth. Furthermore, IC50 of 5-Fu-GCL (34.5 μmol/L) was lower than that of free 5-Fu (51.2 μmol/L). In vivo experiment, 5-Fu-GCL (20, 40, 80 mg/kg) significantly suppressed the tumor growth in HepA bearing mice model. Compared with free 5-Fu, the area under curve of 5-Fu-GCL in intracellular fluid increased 2.6 times. Similarly, the distribution of 5-Fu-GCL in liver tumor tissues was significantly higher than that of free 5-Fu. After being treated with 5-Fu-GCL, the apoptotic rate and the proportion of HepA cells in the S phase increased, while the proportion in the G0/G1 and G2/M phases decreased. CONCLUSION: 5-Fu-GCL appears to have anti-hepatocarcinoma effects and its drug action is better than free 5-Fu. Its mechanism is partly related to increased drug concentrations in intracellular fluid and liver tumor tissues, enhanced tumor cell apoptotic rate and arrest of cell cycle in S phase.展开更多
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 e...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.展开更多
AIM： To evaluate the combination of bevacizumab with infusional 5-fluorouracil （5-FU）, leucovorin （LV） and irinotecan （FOLFIRI） in patients with advanced colorectal cancer （CRC） pretreated with combination re...AIM： To evaluate the combination of bevacizumab with infusional 5-fluorouracil （5-FU）, leucovorin （LV） and irinotecan （FOLFIRI） in patients with advanced colorectal cancer （CRC） pretreated with combination regimens including irinotecan and oxaliplatin. METHODS： Fourteen patients （median age 56 years） with advanced CRC, all having progressed after oxaliplatin- and irinotecan-based combination chemotherapy, were enrolled in this study. Patients were treated with 2 h infusion of irinotecan 150 mg/m2 on d 1, plus bevacizumab 5 mg/kg iv infusion for 90 min on d 2, and iv injection of LV 20 mg/m2 followed by a bolus of 5-FU 400 mg/m2 and then 22 h continuous infusion of 600 mg/m2 given on two consecutive days every 14 d. RESULTS： The median number of cycles of chemotherapy was six （range 3-12）. The response rate was 28.5%, one patient had a complete response, and three patients had a partial response. Eight patients had stable disease. The median time to progression was 3.9 mo （95% CI 2.0-8.7）, and the median overall survival was 10.9 mo （95% CI 9.6-12.1）. Grade 3/4 neutropenia occurred in five patients, and two of these developed neutropenic fever. Grade 3 hematuria and hematochezia occurred in one. Grade 2 proteinuria occurred in two patients. However, hypertension, bowel perforation or thromboembolic events did not occur in a total of 90 cycles. CONCLUSION： Bevacizumab with FOLFIRI is well tolerated and a feasible treatment in patients with heavily treated advanced CRC.展开更多
BACKGROUND Bile duct cancer is characterized by fast metastasis and invasion and has been regarded as one of the most aggressive tumors due to the absence of effective diagnosis at an early stage.Therefore,it is in th...BACKGROUND Bile duct cancer is characterized by fast metastasis and invasion and has been regarded as one of the most aggressive tumors due to the absence of effective diagnosis at an early stage.Therefore,it is in the urgent demand to explore novel diagnostic approaches and therapeutic strategies for bile duct cancer to improve patient survival.Raddeanin A(RA)is extracted from the anemone raddeana regel and has been demonstrated to play antitumor roles in various cancers.AIM To investigate the effects of RA treatment on bile duct cancer cells.METHODS In this study,four cholangiocarcinoma cell lines(RBE,LIPF155C,LIPF178C,and LICCF)treated with RA were used to test the cell viability.The RA-associated cell functional analysis,5-fluorouracil(5-Fu)effectiveness as well as cell cycle-and apoptosis-related protein expression were investigated.RESULTS RA reduced cell viability in a dose-dependent pattern in four cell lines,and the migration and colony formation abilities were also impaired by RA in RBE and LIPF155C cell lines.RA sensitized cell lines to 5-Fu treatment and enhanced the effects of 5-Fu in cholangiocarcinoma.Also,RA decreased protein expression of Wee1,while the combinational effect of RA and 5-Fu decreased protein expressions of cyclooxygenase-2,B cell lymphoma 2,and Wee1 but increased protein levels of Bax,cyclin D1,and cyclin E.CONCLUSION Taken together,the results suggest that RA acts as an anti-cancer agent and enhancer of 5-Fu in bile duct cancer cells via regulating multiple cell cycle and apoptosis-related proteins.This finding provides novel clues to exploring a novel antitumor drug for bile duct cancer.展开更多
A novel tungstosilicic polyoxometalate containing 5-fluorouracil and Nd, K26(C4H4FN2O2)8Nd(SiW11O39)4·5H2O (FNSW) was synthesized and its structure was characterized by using elemental analysis, FT-IR spectra, X-...A novel tungstosilicic polyoxometalate containing 5-fluorouracil and Nd, K26(C4H4FN2O2)8Nd(SiW11O39)4·5H2O (FNSW) was synthesized and its structure was characterized by using elemental analysis, FT-IR spectra, X-ray powder diffraction, UV-vis spectra and TG. The results indicated that the compound FNSW had Keggin structure of heteropolyanion and ring structure of 5-fluorouracil, and it had a good thermal stability. With 5-fluorouracil for the positive control group, the cytotoxicity tests in human renal embryonic cell HEK293 and the antitumor activity tests in hepatocellular carcinoma cell HepG-2 were carried out by the methyl thiazolyl tetrazolium method. The toxicity of the compound FNSW was lower than that of 5-fluorouracil, and compared with 5-fluorouracil the compound FNSW could inhibit HepG-2 cell in vitro with significant difference. The rare earth element Nd increased the biological activity of polyoxometalate significantly.展开更多
AIM: To explore the synergistic effect of docosahexaenoic acid(DHA)/5-fluorouracil(5-FU) on the human gastric cancer cell line AGS and examine the underlying mechanism.METHODS: AGS cells were cultured and treated with...AIM: To explore the synergistic effect of docosahexaenoic acid(DHA)/5-fluorouracil(5-FU) on the human gastric cancer cell line AGS and examine the underlying mechanism.METHODS: AGS cells were cultured and treated with a series of concentrations of DHA and 5-FU alone or in combination for 24 and 48 h. To investigate the synergistic effect of DHA and 5-FU on AGS cells, the inhibition of cell proliferation was determined by MTT assay and cell morphology. Flow cytometric analysis was also used to assess cell cycle distribution, and the expression of mitochondrial electron transfer chain complexes(METCs)?Ⅰ, Ⅱ and Ⅴ in AGS cells was further determined by Western blot analysis. RESULTS: DHA and 5-FU alone or in combination could markedly suppress the proliferation of AGS cells in a significant time and dose-dependent manner. DHA markedly strengthened the antiproliferative effect of 5-FU, decreasing the IC50 by 3.56-2.15-fold in an apparent synergy. The morphological changes of the cells were characterized by shrinkage, cell membrane blebbing and decreased adherence. Cell cycle analysis showed a shift of cells into the G0/G1 phase from the S phase following treatment with DHA or 5-FU(G0/G1 phase: 30.04% ± 1.54% vs 49.05% ± 6.41% and 63.39% ± 6.83%, respectively, P < 0.05; S phase: 56.76% ± 3.14% vs 34.75% ± 2.35% and 25.63% ± 2.21%, respectively, P < 0.05). Combination treatment of DHA and 5-FU resulted in a significantly larger shift toward the G0/G1 phase and subsequent reduction in S phase(G0/G1 phase: 69.06% ± 2.63% vs 49.05% ± 6.41% and 63.39% ± 6.83%, respectively, P < 0.05; S phase: 19.80% ± 4.30% vs 34.75% ± 2.35% and 25.63% ± 2.21%, respectively, P < 0.05). This synergy was also reflected in the significant downregulation of the expression of METCs in AGS cells.CONCLUSION: Synergistic anticancer properties of DHA and 5-FU may involve interference with energy production of AGS cells via downregulation of METCs and cell cycle arrest.展开更多
Currently, chemoresistance seriously attenuates the curative outcome of liver cancer. The purpose of our work was to investigate the influence of 6-shogaol on the inhibition of 5-fluorouracil (5-FU) in liver cancer. T...Currently, chemoresistance seriously attenuates the curative outcome of liver cancer. The purpose of our work was to investigate the influence of 6-shogaol on the inhibition of 5-fluorouracil (5-FU) in liver cancer. The cell viability of cancer cells was determined by MTT assay. Liver cancer cell apoptosis and the cell cycle were examined utilizing flow cytometry. Moreover, qRT–PCR and western blotting was used to analyse the mRNA and protein expression levels, respectively. Immunohistochemistry assays were used to examine multidrug resistance protein 1 (MRP1) expression in tumour tissues. In liver cancer cells, we found that 6-shogaol-5-FU combination treatment inhibited cell viability, facilitated G0/G1 cell cycle arrest, and accelerated apoptosis compared with 6-shogaol or 5-FU treatment alone. In cancer cells cotreated with 6-shogaol and 5-FU, AKT/mTOR pathway- and cell cycle-related protein expression levels were inhibited, and MRP1 expression was downregulated. AKT activation or MRP1 increase reversed the influence of combination treatment on liver cancer cell viability, apoptosis and cell cycle arrest. The inhibition of AKT activation to the anticancer effect of 6-shogaol-5-FU could be reversed by MRP1 silencing. Moreover, our results showed that 6-shogaol-5-FU combination treatment notably inhibited tumour growth in vivo. In summary, our data demonstrated that 6-shogaol contributed to the curative outcome of 5-FU in liver cancer by inhibiting the AKT/mTOR/MRP1 signalling pathway.展开更多
AIM： To determine the effect of chemotherapy on wound healing by giving early preoperative 5-fluorouracil （5-FU） to rats with colonic anastomoses.METHODS： Sixty Albino-Wistar male rats （median weight, 235 g） wer...AIM： To determine the effect of chemotherapy on wound healing by giving early preoperative 5-fluorouracil （5-FU） to rats with colonic anastomoses.METHODS： Sixty Albino-Wistar male rats （median weight, 235 g） were used in this study. The rots were fed with standard laboratory food and given tap water ad libitum. The animals were divided into three groups： Group 1： Control group （chemotherapy was not administered）, Group 2： Intraperitoneally （IP） administered 5-FU group （chemotherapy was administered IP to animals at a dose of 20 mg/kg daily during the 5 d preceeding surgery）, Group 3： Intravenously （IV） administered 5-FU group. Chemotherapy was administered v/a the penil vein, using the same dosing scheme and duration as the second group. After a 3-d rest to minimize the side effects of chemotherapy, both groups underwent surgery. One centimeter of colon was resected 2 cm proximally from the peritoneal reflection, then sutured intermittently and subsequently end-to-end anastomosed. In each group, half the animals were given anaesthesia on the 3rd postoperative （PO） day and the other half on the 7th PO day, for in vivo analytic procedures. The abdominal incisions in the rats were dissected, all the new and old anastomotic segments were clearly seen and bursting pressures of each anastomotic segment, tissue hydroxyproline levels and DNA content were determined to assess the histologic tissue repair process. RESULTS： When the IV group was compared with the IP group, bursting pressures of the anastomotic segments on the 3rd and 7th PO days, were found to be significantly decreased, hydroxyproline levels at the anastomotic segment on the 7th PO day were significantly decreased （P 〈 0.01）. CONCLUSION： In this study, we conclude that early preoperative 5-FU, administered IV, negatively affects wound healing. However, IP administered 5-FU does not negatively affect wound healing.展开更多
In order to improve the cancer-targeting and selective activity of antineoplastic agent [5-fluorouracil （5-FU）], a novel pH-responsive drug delivery system [pullulan acetate/sulfonamide （PA/SDM） conjugate] was syn...In order to improve the cancer-targeting and selective activity of antineoplastic agent [5-fluorouracil （5-FU）], a novel pH-responsive drug delivery system [pullulan acetate/sulfonamide （PA/SDM） conjugate] was synthesized by a diafiltration method. Sulfonamide was grafted to the hydrophobicaUy modified pullulan acetate to enhance the pH sensitivity for better cancer-targeting delivery. 5-FU was loaded into the self-assembled nanoparticles by the same method. The drug-loaded self-assembled nanoparticles were successfully obtained and characterized in terms of particle size, morphology and drug loading and release profile at various pHs. The results showed that the mean diameter of the self-assembled particles was approximately 100nm, with uniform size and good spherical morphology. The nanoparticles showed good stability at pH 7.4, which is equal to that of the normal body fluid, but shrank and aggregated below pH 6.8, which is close to the pH with tumors. The loading efficiency and concentration of released 5-FU was monitored at 269 nm on the UVNis spectrophotometer. The release profile was heavily pH-dependent around phvsiological pH, and the release rate was significantly enhanced under pH of 6.8.展开更多
Drug resistance is a major obstacle in the development of effective colorectal cancer(CRC)therapy.Our study aimed to explore the reversal abilities of Jiedu Sangen decoction(JSD)on the 5-fluorouracil(5-FU)resistance a...Drug resistance is a major obstacle in the development of effective colorectal cancer(CRC)therapy.Our study aimed to explore the reversal abilities of Jiedu Sangen decoction(JSD)on the 5-fluorouracil(5-FU)resistance and its underlying molecular mechanisms.Expression changes in HIF-1 of CRC tissues were firstly revealed by bioinformatics analysis.Afterwards,cell viabilities of JSD and 5-FU treatments on 5-FU resistant human colon cancer cells(HCT-8/5-FU)were determined.Expressions of phosphoinositide 3-kinase(PI3K),protein kinase B(AKT)/p-AKT,hypoxia-inducible factor 1(HIF-1α),as well as glycolysis related proteins such as L-lactate dehydrogenase A(LDHA),Glucose transporter type 1(Glut1),Hexokinase 2(HKII),and cysteinyl aspartate specific proteinase(Caspase)family members in HCT-8/5-FU cells,HIF-1αsilenced HCT-8/5-FU cells and tumor tissues were detected by western blotting.HIF-1αwas found over expressed in CRC tissues according to public available datasets in Oncomine.Growth inhibition rates of HCT-8/5-FU cells were increased along with the increase of JSD concentrations.JSD caused down-regulated HIF-1α,PI3K,AKT/p-AKT,HKII and Glut1,as well as up-regulated Caspase3 and Caspase9 in HCT-8/5-FU cells and tumor tissues.In HIF-1αsilenced HCT-8/5-FU cells,synergistic group showed significantly reduced expression levels of PI3K,AKT,p-AKT.Additionally,up-regulated expressions of Caspase6 and Caspase7 were observed.JSD combined with 5-FU also exhibited obvious inhibitory efficiency on tumor growth in vivo.JSD may reverse 5-FU resistance by suppressing glycolysis via PI3K/AKT/HIF-1αsignaling pathway,thereby inhibiting glycolysis and induce apoptosis to enhance anti-tumor activity.展开更多
文摘AIM:To investigate the effects of adenosine triphosphate(ATP)and melatonin,which have antioxidant and antiinflammatory activities,on potential 5-fluorouracil(5-FU)-induced optic nerve damage in rats.METHODS:Twenty-four rats were categorized into four groups of six rats:healthy(HG),5-FU(FUG),ATP+5-FU(AFU),and melatonin+5-FU(MFU).ATP(4 mg/kg)and melatonin(10 mg/kg)were administered intraperitoneally and orally,respectively.One hour after ATP and melatonin administration,rats in the AFU,MFU,and FUG were intraperitoneally injected with 5-FU(100 mg/kg).ATP and melatonin were administered once daily for 10d.5-FU was administered at a single dose on days 1,3,and 5 of the experiment.After 10d,the rats were euthanized and optic nerve tissues were extracted.Optic nerve tissues were biochemically and histopathologically examined.RESULTS:ATP and melatonin treatments inhibited the increase in malondialdehyde(MDA)and interleukin-6(IL-6)levels,which were elevated in the FUG.The treatments also prevented the decrease in total glutathione(tGSH)levels and the superoxide dismutase(SOD)and catalase(CAT)activities(P<0.001).This inhibition was higher in the ATP group than in the melatonin group(P<0.001).ATP prevented histopathological damage better than melatonin(P<0.05).CONCLUSION:ATP and melatonin have the potential to be used in alleviating 5-FU-induced optic nerve damage.In addition,ATP treatment shows better protective effects than melatonin.
基金Supported by the National Natural Science Foundation of China,No.82404088China Postdoctoral Science Foundation,No.2023M730587Changshu Talent Scientific Project,No.KCH202304.
文摘BACKGROUND Colorectal cancer(CRC)is the second most prevalent cause of cancer-related mortality and is increasing in younger individuals.Chemotherapy,a crucial adjuvant systemic therapy for CRC management,often leads to resistance through poorly characterized underlying molecular mechanisms.The long noncoding RNA SNHG5 is highly expressed in CRC and promotes tumor proliferation and invasion,prompting us to hypothesize that SNHG5 may play a crucial role in the chemotherapeutic agent 5-fluorouracil(5-Fu)resistance in CRC.AIM To identify the function and mechanism of SNHG5 in 5-Fu resistance in CRC.METHODS Quantitative real-time polymerase chain reaction was performed to examine the expression of SNHG5 in CRC tissues from 225-Fu-sensitive patients and 145-Fu-resistant patients and in CRC cells and 5-Fu-resistant CRC cells.Cell viability and apoptosis were assessed in SNHG5-overexpressing CRC cells and SNHG5-knockdown 5-Furesistant CRC cells.SNHG5 function in 5-Fu resistance in CRC was further analyzed using a xenograft mouse model.SNHG5 interactions with microRNAs were predicted by bioinformatics analysis.Luciferase reporter and RNA immunoprecipitation assays were performed to verify the binding between SNHG5 and miR-26b.Rescue experiments were performed to validate the functional interaction between SNHG5 and the miR-26b/p-glycoprotein(Pgp)axis.RESULTS SNHG5 expression was upregulated in 5-Fu-resistant CRC tissues and 5-Fu-resistant CRC cells.In vitro functional experiments demonstrated that SNHG5 overexpression significantly reduced cell apoptosis and enhanced cell viability,whereas SNHG5 knockdown in 5-Fu-resistant CRC cells increased cell apoptosis and decreased cell viability upon 5-Fu treatment.In a xenograft mouse model,we confirmed that SNHG5 overexpression led to a reduction in 5-Fu sensitivity in CRC in vivo.Mechanistically,SNHG5 acted as a molecular sponge for miR-26b.Rescue experiments validated that SNHG5 conferred 5-Fu resistance in CRC by regulating the miR-26b/Pgp axis.CONCLUSION SNHG5/miR-26b/Pgp regulates CRC chemosensitivity,providing potential therapeutic targets for the treatment of 5-Fu-resistant CRC.
基金Supported by the National Natural Science Foundation of China(No.82301211)Beijing Natural Science Foundation(No.J230028).
文摘AIM:To develop a 5-fluorouracil(5-FU)mesoporous poly(lactic)acid(PLA)delivery system for glaucoma filtration surgery suitable for a single subconjunctival implantation.METHODS:The 5-FU was infiltration-loaded into mesoporous PLA.In vitro and in vivo release experiments and ocular toxicology evaluation of the formulation were performed.The antiproliferative effect of this 5-FU-PLA tablet after glaucoma filtration surgery in rabbits was evaluated.Pathology,immunohistochemistry,and Western blot were used to further validate the inhibitory effect of this sustained release system.RESULTS:Various drug formulations were tested,and two 5-FU-PLA tablets,namely 1.5P15(5-FU 1.5 mg+PLA 15000 Da)and 2.5P15(5-FU 2.5 mg+PLA 15000 Da),had the most suitable release profiles in vitro.Further in vivo studies confirmed the safety and sustained-release profiles of both drugs.Both 5-FU-PLA tablets,relative to the free drugs,significantly inhibited tissue proliferation after glaucoma filtration and improved surgical success.Western blot showed that transforming growth factor-β(TGF-β)and connective tissue growth factor(CTGF)were inhibited by 5-FU after filtration surgery,with the effects of the 5-FU-PLA tablets being more lasting.CONCLUSION:The tested 5-FU-PLA tablets provide a sustained release of 5-FU,which may be used for a single subconjunctival implantation to inhibit proliferation after filtration surgery.
基金supported by the Basic Science Research Program through the National Research Foundation of Korea(NRF)funded by the Korea government(2021R1F1A1063023)by the Ministry of Education(RS-2023-00270936).
文摘Background:Chitosan oligosaccharide(COS)is the major degradation product of chitosan by enzymatic processes.COS,with complete water solubility,exerts significant biological effects,including anti-cancer activity.We investigated the anti-tumor effects of COS on colorectal cancer as effective therapeutic methods with low side effects are lacking.Methods:COS was obtained from low molecular weight chitosan by an enzymatic method and the anticancer effects were measured by cell viability assay,flow cytometry analysis,Western blotting,and xenograft.Results:COS suppressed the proliferation of SNU-C5 cells compared to other colorectal cancer cells,but higher concentrations were required in the xenograft model.Co-treatment with 5-fluorouracil(5-FU)and COS enhanced the anti-cancer effects of 5-FU in SNU-C5 cells in vitro and in vivo.Flow cytometry revealed that COS induced cell cycle arrest at the G0/G1 phase without 5-FU or at the S and G2/M phases with 5-FU but did not affect cell death pathways.COS increased extracellular signal-regulated protein kinase(ERK)activation with or without 5-FU,whereas 5-FU treatment increased p53 activation.A low-dose of an ERK inhibitor suppressed COS-induced ERK activation and resulted in higher proliferation compared with COS.Conclusions:These results suggest that COS might enhance the anti-cancer effects of 5-FU in SNU-C5 colorectal cancer cells by activating ERK.
基金National Natural Science Foundation of China(Grant No.51477175) for financial support
文摘In this study,the hypertrophic scar（HS） model in rats was established.5-fluorouracil（5-FU）patch,-1000 V and-2000 V polypropylene（PP） electret 5-FU patches were prepared and applied onto the wound.The in vitro permeation experiment was performed using the Franz diffusion cell system to determine the permeation cumulative amount and retention amount of5-FU through/in scar skin.The inhibition effect of negative electret on growth of HS was studied by hematoxylin-eosin（HE） staining,Masson staining and the immunohistologicall methods.The permeation study indicated that a negative electret could enhance the permeation and retention of 5-FU through and in scar skin respectively.HE staining and Masson staining indicated a better effect for-1000 V and-2000 V electret 5-FU patches on HS inhibition after28 d post-wounding compared with 5-FU patch.The immunohistological study showed much more reduced expressions of collegan type I,collegan type III,TGF-β1 and HSP47 in scar tissue after application of negative electret 5-FU patches than those of 5-FU patch.A negative electret5-FU patch may be advantageous for HS treatment.
文摘Six aminoglucose conjugates were synthesized by the reaction of aminoglucose with 5-fluorou-racil-1-acetic acid or 5-fluorouracil-1-propanoic acid and confirmed by IR, 1H NMR and elemental analyses. Their antitumor activities against A2780 cells and PC-14 cells were also evaluated.
基金National Natural Science Foundation of China(Grant No.51477175) for financial support
文摘In the present study,the electret 5-fluorouracil patch was developed,the effective surface potential,piezoelectric coefficient d33,open-circuit thermally stimulated discharge（TSD） current spectra and shear adhesion of the patch were measured.The drug release profile of the patch was determined by using high performance liquid chromatography method.A stable potential difference which was positively dependent on the surface potential of the electret was generated on two sides of the patch.The measurements of d33 coefficient,TSD current spectra and adhesion performance showed that the electrostatic field of the electret could cause polarization and cohesive strength decreasing of the matrix molecules,change the distribution and interaction of the drug molecules in patch,therefore to increase the release of drug from the transdermal patch.
文摘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.
基金Shanghai Science and Technology Committee, No. 0452nm065
文摘AIM: To prepare chitosan-polyaspartic acid-5-fluorouracil (CTS-Pasp-5Fu) nanoparticles and investigate its anti-carcinoma effect and toxicity. METHODS: CTS-Pasp-5Fu nanoparticles were synthesized by ionic gelatification. Male BABL/c nude mice were injected with SGC-7901 gastric carcinoma cell line mass to establish a human gastric carcinoma model. They were randomly allocated into 4 groups: CTS-Pasp-5Fu (containing 5-Fu 1.25 mg/kg), 5-Fu (1.25 mg/kg), CTS-Pasp and normal saline groups. Tumor weight was measured and assay of colony forming unit-granulocyte and macrophage (CFU-GM) was performed. The structural change of cells and tissues was observed and the Bax and Bcl-2 genes were detected. RESULTS: Compared with normal saline, the inhibition rates of tumor growth for the CTS-Pasp, 5-Fu and CTS-Pasp-5Fu groups were 5.58%, 58.69% and 70.82%, respectively. The tumor inhibition rates for the CTS-Pasp, 5-Fu and CTS-Pasp-5Fu groups were 5.09%, 65.3% and 72.79%, respectively. There was a significant decrease in the number of CFU-GMformation and increase of total bilirubin, and alanine aminotransferase in the 5-Fu group, but no change in those of the other three groups. There was no change in white blood cell count and creatinine among the four groups. Pathological section of liver and nephridial tissues showed that the damage in the 5-Fu group was more severe than that in the CTS-Pasp-5Fu group. 5-Fu and CTS-Pasp-5Fu groups could both down-regulate the Bcl-2 expression and up-regulate the Bax expression to different extent, and the accommodate effect of CTS-Pasp-5Fu was more obvious than 5-Fu. CONCLUSION: The tumor inhibition rate of CTS-Pasp-5Fu nanoparticles is much higher than that of 5-Fu alone.
文摘AIM:To investigate the inhibitory effects of sinomenine(SIN)combined with 5-fluorouracil(5-FU)on esophageal carcinoma in vitro and in vivo.METHODS:Esophageal carcinoma(Eca-109)cells were cultured in DMEM.The single or combined growth inhibition effects of SIN and 5-FU on the Eca-109 cells were examined by measuring the absorbance of CCK-8dye in living cells.Hoechst 33258 staining and an Annexin V/PI apoptosis kit were used to detect the percentage of cells undergoing apoptosis.Western blotting was used to investigate the essential mechanism underlying SIN and 5-FU-induced apoptosis.SIN at 25mg/kg and 5-FU at 12 mg/kg every 3 d,either combined or alone,was injected into nude mice and tumor growth inhibition and side effects of the drug treatment were observed.RESULTS:SIN and 5-FU,both in combination and individually,significantly inhibited the proliferation of Eca-109 cells and induced obvious apoptosis.Furthermore,the combined effects were greater than those of the individual agents(P<0.05).Annexin V/PI staining and Hoechst 33258 staining both indicated that the percentage of apoptotic cells induced by SIN and 5-FU combined or alone were significantly different from the control(P<0.05).The up-regulation of Bax and downregulation of Bcl-2 showed that the essential mechanism of apoptosis induced by SIN and 5-FU occurs via the mitochondrial pathway.SIN and 5-FU alone significantly inhibited the growth of tumor xenografts in vivo,and the combined inhibition rate was even higher(P<0.05).During the course of chemotherapy,no obvious side effects were observed in the liver or kidneys.CONCLUSION:The combined effects of SIN and 5-FU on esophageal carcinoma were superior to those of the individual compounds,and the drug combination did not increase the side effects of chemotherapy.
基金Supported by the Key Teacher Foundation of Ministry of Education of China, No. 1869 Young Teacher Foundation of Department of Education of Anhui Province, No. 2000jp112
文摘AIM:To study the anti-hepatocarcinoma effects of 5-fluorouracil (5-Fu) encapsulated by galactosylceramide liposomes (5-Fu-GCL) in vivo and in vitro. METHODS: Tumor-bearing animal model and HepA cell line were respectively adopted to evaluate the anti-tumor effects of 5-Fu-GCL in vivo and in vitro. Tumor cell growth inhibition effects of 5-Fu-GCL in vitro were assessed by cell viability assay and MTT assay. In vivo experiment, the inhibitory effects on tumor growth were evaluated by tumor inhibition rate and animal survival days. High performance liquid chromatography was used to detect the concentration-time course of 5-Fu-GCL in intracellular fluid in vitro and the distribution of 5-Fu-GCL in liver tumor tissues in vivo. Apoptosis and cell cycle of tumor cells were demonstrated by flow cytometry. RESULTS: In vitro experiment, 5-Fu-GCL (6.25-100 μmol/L) and free 5-Fu significantly inhibited HepA cell growth. Furthermore, IC50 of 5-Fu-GCL (34.5 μmol/L) was lower than that of free 5-Fu (51.2 μmol/L). In vivo experiment, 5-Fu-GCL (20, 40, 80 mg/kg) significantly suppressed the tumor growth in HepA bearing mice model. Compared with free 5-Fu, the area under curve of 5-Fu-GCL in intracellular fluid increased 2.6 times. Similarly, the distribution of 5-Fu-GCL in liver tumor tissues was significantly higher than that of free 5-Fu. After being treated with 5-Fu-GCL, the apoptotic rate and the proportion of HepA cells in the S phase increased, while the proportion in the G0/G1 and G2/M phases decreased. CONCLUSION: 5-Fu-GCL appears to have anti-hepatocarcinoma effects and its drug action is better than free 5-Fu. Its mechanism is partly related to increased drug concentrations in intracellular fluid and liver tumor tissues, enhanced tumor cell apoptotic rate and arrest of cell cycle in S phase.
基金National High Technology Research and Development Program of China('863' Program,Grant No.2004AA2Z3783)National Natural Science Foundation(Grant No.20172006 and 20672009)
文摘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.
文摘AIM： To evaluate the combination of bevacizumab with infusional 5-fluorouracil （5-FU）, leucovorin （LV） and irinotecan （FOLFIRI） in patients with advanced colorectal cancer （CRC） pretreated with combination regimens including irinotecan and oxaliplatin. METHODS： Fourteen patients （median age 56 years） with advanced CRC, all having progressed after oxaliplatin- and irinotecan-based combination chemotherapy, were enrolled in this study. Patients were treated with 2 h infusion of irinotecan 150 mg/m2 on d 1, plus bevacizumab 5 mg/kg iv infusion for 90 min on d 2, and iv injection of LV 20 mg/m2 followed by a bolus of 5-FU 400 mg/m2 and then 22 h continuous infusion of 600 mg/m2 given on two consecutive days every 14 d. RESULTS： The median number of cycles of chemotherapy was six （range 3-12）. The response rate was 28.5%, one patient had a complete response, and three patients had a partial response. Eight patients had stable disease. The median time to progression was 3.9 mo （95% CI 2.0-8.7）, and the median overall survival was 10.9 mo （95% CI 9.6-12.1）. Grade 3/4 neutropenia occurred in five patients, and two of these developed neutropenic fever. Grade 3 hematuria and hematochezia occurred in one. Grade 2 proteinuria occurred in two patients. However, hypertension, bowel perforation or thromboembolic events did not occur in a total of 90 cycles. CONCLUSION： Bevacizumab with FOLFIRI is well tolerated and a feasible treatment in patients with heavily treated advanced CRC.
文摘BACKGROUND Bile duct cancer is characterized by fast metastasis and invasion and has been regarded as one of the most aggressive tumors due to the absence of effective diagnosis at an early stage.Therefore,it is in the urgent demand to explore novel diagnostic approaches and therapeutic strategies for bile duct cancer to improve patient survival.Raddeanin A(RA)is extracted from the anemone raddeana regel and has been demonstrated to play antitumor roles in various cancers.AIM To investigate the effects of RA treatment on bile duct cancer cells.METHODS In this study,four cholangiocarcinoma cell lines(RBE,LIPF155C,LIPF178C,and LICCF)treated with RA were used to test the cell viability.The RA-associated cell functional analysis,5-fluorouracil(5-Fu)effectiveness as well as cell cycle-and apoptosis-related protein expression were investigated.RESULTS RA reduced cell viability in a dose-dependent pattern in four cell lines,and the migration and colony formation abilities were also impaired by RA in RBE and LIPF155C cell lines.RA sensitized cell lines to 5-Fu treatment and enhanced the effects of 5-Fu in cholangiocarcinoma.Also,RA decreased protein expression of Wee1,while the combinational effect of RA and 5-Fu decreased protein expressions of cyclooxygenase-2,B cell lymphoma 2,and Wee1 but increased protein levels of Bax,cyclin D1,and cyclin E.CONCLUSION Taken together,the results suggest that RA acts as an anti-cancer agent and enhancer of 5-Fu in bile duct cancer cells via regulating multiple cell cycle and apoptosis-related proteins.This finding provides novel clues to exploring a novel antitumor drug for bile duct cancer.
基金Project supported by the Chemical Materials Institute, China Academy of Engineering Physicsthe Doctoral Innovation Research Assistance Program of the Science and Technology Review
文摘A novel tungstosilicic polyoxometalate containing 5-fluorouracil and Nd, K26(C4H4FN2O2)8Nd(SiW11O39)4·5H2O (FNSW) was synthesized and its structure was characterized by using elemental analysis, FT-IR spectra, X-ray powder diffraction, UV-vis spectra and TG. The results indicated that the compound FNSW had Keggin structure of heteropolyanion and ring structure of 5-fluorouracil, and it had a good thermal stability. With 5-fluorouracil for the positive control group, the cytotoxicity tests in human renal embryonic cell HEK293 and the antitumor activity tests in hepatocellular carcinoma cell HepG-2 were carried out by the methyl thiazolyl tetrazolium method. The toxicity of the compound FNSW was lower than that of 5-fluorouracil, and compared with 5-fluorouracil the compound FNSW could inhibit HepG-2 cell in vitro with significant difference. The rare earth element Nd increased the biological activity of polyoxometalate significantly.
文摘AIM: To explore the synergistic effect of docosahexaenoic acid(DHA)/5-fluorouracil(5-FU) on the human gastric cancer cell line AGS and examine the underlying mechanism.METHODS: AGS cells were cultured and treated with a series of concentrations of DHA and 5-FU alone or in combination for 24 and 48 h. To investigate the synergistic effect of DHA and 5-FU on AGS cells, the inhibition of cell proliferation was determined by MTT assay and cell morphology. Flow cytometric analysis was also used to assess cell cycle distribution, and the expression of mitochondrial electron transfer chain complexes(METCs)?Ⅰ, Ⅱ and Ⅴ in AGS cells was further determined by Western blot analysis. RESULTS: DHA and 5-FU alone or in combination could markedly suppress the proliferation of AGS cells in a significant time and dose-dependent manner. DHA markedly strengthened the antiproliferative effect of 5-FU, decreasing the IC50 by 3.56-2.15-fold in an apparent synergy. The morphological changes of the cells were characterized by shrinkage, cell membrane blebbing and decreased adherence. Cell cycle analysis showed a shift of cells into the G0/G1 phase from the S phase following treatment with DHA or 5-FU(G0/G1 phase: 30.04% ± 1.54% vs 49.05% ± 6.41% and 63.39% ± 6.83%, respectively, P < 0.05; S phase: 56.76% ± 3.14% vs 34.75% ± 2.35% and 25.63% ± 2.21%, respectively, P < 0.05). Combination treatment of DHA and 5-FU resulted in a significantly larger shift toward the G0/G1 phase and subsequent reduction in S phase(G0/G1 phase: 69.06% ± 2.63% vs 49.05% ± 6.41% and 63.39% ± 6.83%, respectively, P < 0.05; S phase: 19.80% ± 4.30% vs 34.75% ± 2.35% and 25.63% ± 2.21%, respectively, P < 0.05). This synergy was also reflected in the significant downregulation of the expression of METCs in AGS cells.CONCLUSION: Synergistic anticancer properties of DHA and 5-FU may involve interference with energy production of AGS cells via downregulation of METCs and cell cycle arrest.
文摘Currently, chemoresistance seriously attenuates the curative outcome of liver cancer. The purpose of our work was to investigate the influence of 6-shogaol on the inhibition of 5-fluorouracil (5-FU) in liver cancer. The cell viability of cancer cells was determined by MTT assay. Liver cancer cell apoptosis and the cell cycle were examined utilizing flow cytometry. Moreover, qRT–PCR and western blotting was used to analyse the mRNA and protein expression levels, respectively. Immunohistochemistry assays were used to examine multidrug resistance protein 1 (MRP1) expression in tumour tissues. In liver cancer cells, we found that 6-shogaol-5-FU combination treatment inhibited cell viability, facilitated G0/G1 cell cycle arrest, and accelerated apoptosis compared with 6-shogaol or 5-FU treatment alone. In cancer cells cotreated with 6-shogaol and 5-FU, AKT/mTOR pathway- and cell cycle-related protein expression levels were inhibited, and MRP1 expression was downregulated. AKT activation or MRP1 increase reversed the influence of combination treatment on liver cancer cell viability, apoptosis and cell cycle arrest. The inhibition of AKT activation to the anticancer effect of 6-shogaol-5-FU could be reversed by MRP1 silencing. Moreover, our results showed that 6-shogaol-5-FU combination treatment notably inhibited tumour growth in vivo. In summary, our data demonstrated that 6-shogaol contributed to the curative outcome of 5-FU in liver cancer by inhibiting the AKT/mTOR/MRP1 signalling pathway.
基金Supported by Haydarpa■a Numune Education and Research Hospital
文摘AIM： To determine the effect of chemotherapy on wound healing by giving early preoperative 5-fluorouracil （5-FU） to rats with colonic anastomoses.METHODS： Sixty Albino-Wistar male rats （median weight, 235 g） were used in this study. The rots were fed with standard laboratory food and given tap water ad libitum. The animals were divided into three groups： Group 1： Control group （chemotherapy was not administered）, Group 2： Intraperitoneally （IP） administered 5-FU group （chemotherapy was administered IP to animals at a dose of 20 mg/kg daily during the 5 d preceeding surgery）, Group 3： Intravenously （IV） administered 5-FU group. Chemotherapy was administered v/a the penil vein, using the same dosing scheme and duration as the second group. After a 3-d rest to minimize the side effects of chemotherapy, both groups underwent surgery. One centimeter of colon was resected 2 cm proximally from the peritoneal reflection, then sutured intermittently and subsequently end-to-end anastomosed. In each group, half the animals were given anaesthesia on the 3rd postoperative （PO） day and the other half on the 7th PO day, for in vivo analytic procedures. The abdominal incisions in the rats were dissected, all the new and old anastomotic segments were clearly seen and bursting pressures of each anastomotic segment, tissue hydroxyproline levels and DNA content were determined to assess the histologic tissue repair process. RESULTS： When the IV group was compared with the IP group, bursting pressures of the anastomotic segments on the 3rd and 7th PO days, were found to be significantly decreased, hydroxyproline levels at the anastomotic segment on the 7th PO day were significantly decreased （P 〈 0.01）. CONCLUSION： In this study, we conclude that early preoperative 5-FU, administered IV, negatively affects wound healing. However, IP administered 5-FU does not negatively affect wound healing.
文摘In order to improve the cancer-targeting and selective activity of antineoplastic agent [5-fluorouracil （5-FU）], a novel pH-responsive drug delivery system [pullulan acetate/sulfonamide （PA/SDM） conjugate] was synthesized by a diafiltration method. Sulfonamide was grafted to the hydrophobicaUy modified pullulan acetate to enhance the pH sensitivity for better cancer-targeting delivery. 5-FU was loaded into the self-assembled nanoparticles by the same method. The drug-loaded self-assembled nanoparticles were successfully obtained and characterized in terms of particle size, morphology and drug loading and release profile at various pHs. The results showed that the mean diameter of the self-assembled particles was approximately 100nm, with uniform size and good spherical morphology. The nanoparticles showed good stability at pH 7.4, which is equal to that of the normal body fluid, but shrank and aggregated below pH 6.8, which is close to the pH with tumors. The loading efficiency and concentration of released 5-FU was monitored at 269 nm on the UVNis spectrophotometer. The release profile was heavily pH-dependent around phvsiological pH, and the release rate was significantly enhanced under pH of 6.8.
基金General Research Program for Education of Zhejiang Provincial(No.Y202045212)the Seventh Batch of Provincial Famous Traditional Chinese Medicine Studios in Zhejiang Province,Cultivation Program for Innovative Talent Graduate Students(No.721100G00713)+2 种基金Zhejiang Provincial Program for the Cultivation of the Young and Middle-Aged Academic Leaders in Colleges and Universities(No.2017-248)Zhejiang Provincial Project for the Key Discipline of Traditional Chinese Medicine(No.2017-XK-A09)Zhejiang Provincial Project for the Science and Technology Program of Traditional Chinese Medicine(No.2015ZZ013).
文摘Drug resistance is a major obstacle in the development of effective colorectal cancer(CRC)therapy.Our study aimed to explore the reversal abilities of Jiedu Sangen decoction(JSD)on the 5-fluorouracil(5-FU)resistance and its underlying molecular mechanisms.Expression changes in HIF-1 of CRC tissues were firstly revealed by bioinformatics analysis.Afterwards,cell viabilities of JSD and 5-FU treatments on 5-FU resistant human colon cancer cells(HCT-8/5-FU)were determined.Expressions of phosphoinositide 3-kinase(PI3K),protein kinase B(AKT)/p-AKT,hypoxia-inducible factor 1(HIF-1α),as well as glycolysis related proteins such as L-lactate dehydrogenase A(LDHA),Glucose transporter type 1(Glut1),Hexokinase 2(HKII),and cysteinyl aspartate specific proteinase(Caspase)family members in HCT-8/5-FU cells,HIF-1αsilenced HCT-8/5-FU cells and tumor tissues were detected by western blotting.HIF-1αwas found over expressed in CRC tissues according to public available datasets in Oncomine.Growth inhibition rates of HCT-8/5-FU cells were increased along with the increase of JSD concentrations.JSD caused down-regulated HIF-1α,PI3K,AKT/p-AKT,HKII and Glut1,as well as up-regulated Caspase3 and Caspase9 in HCT-8/5-FU cells and tumor tissues.In HIF-1αsilenced HCT-8/5-FU cells,synergistic group showed significantly reduced expression levels of PI3K,AKT,p-AKT.Additionally,up-regulated expressions of Caspase6 and Caspase7 were observed.JSD combined with 5-FU also exhibited obvious inhibitory efficiency on tumor growth in vivo.JSD may reverse 5-FU resistance by suppressing glycolysis via PI3K/AKT/HIF-1αsignaling pathway,thereby inhibiting glycolysis and induce apoptosis to enhance anti-tumor activity.
