Cardiac Manifestations with Chemotherapeutic Agents: 5 Fluorouracil-Induced Coronary Artery Vasospasm

5-fluorouracil (5-FU) is a fluorinated, pyrimidine analog, antineoplastic agent that is used in the treatment of several solid organ cancers. Cardiotoxicity is uncommon but life-threatening manifestations such as myocardial infarction may manifest owing to 5-FU-induced coronary artery spasm. Administering smaller doses of the drug, more frequently than not, decreases the risk of cardiotoxicity compared to large doses or with continuous infusions. We present a case of ST-segment elevation in a patient without known coronary artery disease who had presented following continuous 5-FU infusion. Coronary angiogram confirmed absence of coronary artery disease and intravenous calcium channel blockers administration was commensurate with the patient’s improvement in symptoms. We discuss the literature on 5-FU and its association with coronary artery spasm, and also briefly review chemotherapy-induced cardiotoxicities to help better prepare internists and other primary health care providers to face similar challenges, particularly of the uncommon but potentially life-threatening manifestations.

Holistic Approach in the Treatment of Actinic Keratosis: Benefits and Disadvantages of 5-Fluorouracil, Imiquimod, Diclofenac and Curaderm

Background Actinic keratosis is the most prevalent premalignant skin disorder in the white population. Current guidelines provide no clear recommendations about preferred treatments. Methods The parameters;effectiveness, treatment duration, recurrence, side effects and cost of treatment were investigated for three frequently used topical therapies which were then compared with a most recent developed topical therapy. Published clinical data obtained from the literature was used to compare these parameters for 5-fluorouracil, imiquimod and diclofenac and relate them with the newly developed Curaderm. Results A wide variation in the concentrations of the active anti-keratotic ingredients, application frequency, duration of treatment, recurrence rates and cost of treatment exist between the different topical therapies. The efficacy rates and side effects were less variable. Overall, Curaderm is the most suitable treatment for actinic keratosis. Clinical evidence is presented illustrating the effects of Curaderm on field-directed treatments and solitary treatments of actinic keratoses. Conclusions Current medical guidelines do not provide clear recommendations on which treatment approach for actinic keratosis is preferred. Direct head-to-head comparison between treatments with emphasis on efficacy, safety, treatment duration, compliance, convenience, cosmetic outcome, patient acceptance and cost should be available to the patient, the practising physician, healthcare system and should assist in therapeutic treatment guidelines and policymaking. Given the very favourable profiles of these parameters with Curaderm when compared with other home-based treatments, it should be considered that Curaderm is first-in-line.

肿瘤阳性显像剂5-^(18)F-fluorouracil的标记与动物实验

目的 探讨18F fluorouracil(FU)作为肿瘤阳性显像剂的可能性。方法 标记与合成了18F FU ,研究其在正常与荷瘤裸鼠中的生物分布 ,进行正常与荷瘤兔的PET显像。结果 HPLC及其他质控分析结果均证实18F FU动物实验与临床应用的可行性 ,生物分布及显像研究表明它在肿瘤组织中有较多的摄取。结论 18F FU是一种有潜力的肿瘤阳性显像剂。

Induction chemotherapy with docetaxel,cisplatin and fluorouracil followed by concurrent chemoradiotherapy for unresectable sinonasal undifferentiated carcinoma: Two cases of report

BACKGROUND Sinonasal undifferentiated carcinoma(SNUC) is a rare aggressive tumor that is often unresectable. Optimal treatment for patients with unresectable,locally advanced SNUC(LA-SNUC) has not been established,and the patient outcome remains poor. We report two cases of unresectable LA-SNUC in which induction chemotherapy with docetaxel,cisplatin and fluorouracil(TPF) followed by radiotherapy with concurrent cisplatin(CCRT),a standard treatment option for locally advanced head and neck cancer,demonstrated promising outcomes.CASE SUMMARY A 39-year-old man presented with tearing and pain in the right eye. A biopsy of the tumor invading the sinonasal cavities,right orbit and cranial base confirmed the diagnosis of LA-SNUC. Induction TPF chemotherapy induced remarkable tumor shrinkage and rapidly improved the symptoms. He subsequently received CCRT and achieved complete remission of the disease. The other case is a 21-year-old man who presented with worsening vision. The unresectable tumor involving the nasal septum and cranial base was pathologically diagnosed as SNUC. TPF chemotherapy followed by CCRT yielded complete remission of the disease with preserved visual function. Both patients have been disease-free for44 mo.CONCLUSION Induction TPF chemotherapy followed by CCRT may remarkably improve the outcomes in LA-SNUC patients.

亲肿瘤显像剂5-^(18)F-Fluorouracil(^(18)F-FU)的标记合成研究

用18 F F2 与Uracil的直接标记法合成了 5- 18F -Fluorouracil,探索18F -FU -PET显像对结肠直肠癌肝转移病人化疗前后疗效评价的意义。产品的放射化学纯 >95% ,放射性得率为 60 % ,pH值为 7,无菌性试验和热源试验均为阴性 ,这一结果为临床应用提供了保证。

Interaction between cisplatin,5-fluorouracil and vincristine on human hepatoma cell line (7721)

AIM To evaluate the killing effects of CDDP, 5-Fu and VCR on human hepaoma cell line (7721).METHODS The median-effect principle was used.RESULTS Killing effects of the individual drug were enhanced as the median concentration increased. Antagonism was produced when two drugs were used at a higher concentration (CI＞1), and synergism was achiened when CI＜1. Finally, the effect was influenced by both the ratios of drug concentration and the sequence of administration.CONCLUSION The drug administration order and drug concentrations are significant factors that need to be considered in clinical practice.INTRODUCTIONThe combined chemotherapy for malignant carcinoma is desired to produce efficacious synergism between each drug, alleviate side effects of drugs and delay drug resistance. Clinically, the interaction (namely synergism, summation and antagonism) of different anticancer drugs in combination is usually evaluated by Chou-Talalay′s combination index (i.e., median-effect principle)[1-9]. In this paper the combination effect between Cisplatin (Cis), 5-Fluorouracil (5-Flu) and Vincristine (VCR) on human hepatoma cell line 7721, was analyzed in vitro.

Preparation and distribution of 5-fluorouracil ^(125)I sodium alginate-bovine serum albumin nanoparticles

AIM To prepare 5 FU sodium alginate 125 I bovine serum albumin nanoparticles (BSA NP), to determine the radioactive count in different organs of rats at different time points after oral administration of 5 FU 125 I sodium alginate BSA NP and to calculate the kinetic parameters of its metabolism. METHODS Emulsion solidification method was used to prepare 5 FU 125 I sodium alginate BSA NP, and to determine its diameter under transmission electronic microscope (TEM). Then the rate of NP and external drug releasing velocity were measured. Radioactive counting in different organs of rats was made after oral administration of the NP by GAMA Counter, and the kinetic parameters of drug metabolism were calculated by handling the data with the two department model. RESULTS The average arithmatic diameter of the NP was 166nm ± 34nm , the rate of 5 FU was 32 8% and the cumulative external releasing ratio amounted to 84 0% within 72 hours. The NP was mainly distributed in the liver, spleen, lungs and kidneys after NP oral administration to rats. The micro radioautographic experiment showed that NP was distributed in the Kupffers cells of liver, liver parenchymal cells and the phagocytes of spleen and lungs. The kinetic parameters of matabolism were: T 1/2 =9 42h, C max =2 45×10 7Bq, T max =2 18h, AUC=148×10 9Bq. CONCLUSION NP is difficult to pass through the blood-cerebral barrier,and 125 I sodium alginate-BSA NP enters the body circulation by gastroin testinal passage.

Rosiglitazone enhances fluorouracil-induced apoptosis of HT-29 cells by activating peroxisome proliferator-activated receptor γ

AIM： To examine whether and how rosiglitazone enhances apoptosis induced by fluorouracil in human colon cancer （HT-29） cells. METHODS： Human colon cancer HT-29 cells were cultured in vitro and treated with fluorouracil and/or rosiglitazone. Proliferation and growth of HT-29 cells were evaluated by MTF assay and trypan blue exclusion methods, respectively. The apoptosis of HT-29 cells was determined by acridine orange/ethidium bromide staining and flow cytometry using PI fluorescence staining. The expressions of peroxisome proliferator-activated receptor γ （PPARγ）, Bcl-2 and Bax in HT-29 cells were analyzed by Western blot. RESULTS： Although rosiglitazone at the concentration below 30 μmol/L for 72 h exerted almost no inhibitory effect on proliferation and growth of HT-29 cells, it could significantly enhance fluorouracil-induced HT-29 cell proliferation and growth inhibition. Furthermore, 10 μmol/L rosilitazone did not induce apoptosis of HT-29 cells but dramatically enhanced fluorouracil-induced apoptosis of HT-29 cells. However, rosiglitazone did not improve apoptosis induced by fluorouracil in HT-29 cells pretreated with GW9662, a PPARγ antagonist. Meanwhile, the expression of Bax and PPAR7 was upregulated, while the expression of Bcl-2 was down regulated in HT-29 cells treated with rosiglitazone in a time-dependent manner. However, the effect of rosiglitazone on Bcl-2 and Bax was blocked or diminished in the presence of GW9662. CONCLUSION： Rosiglitazone enhances fluorouracilinduced apoptosis of HT-29 cells by activating PPARγ.

UGT1A1 predicts outcome in colorectal cancer treated with irinotecan and fluorouracil

AIM:To evaluate effects of UDP-glucuronosyltransferase1A1(UGT1A1) and thymidylate synthetase(TS) gene polymorphisms on irinotecan in metastatic colorectal cancer(mCRC).METHODS:Two irinotecan-and fluorouracil-based regimens,FOLFIRI and IFL,were selected as second-line therapy for 138 Chinese mCRC patients.Genomic DNA was extracted from peripheral blood samples before treatment.UGT1A1 and TS gene polymorphisms were determined by direct sequencing and restriction fragment length polymorphism,respectively.Gene polymorphisms of UGT1A1*28,UGT1A1*6 and promoter enhancer region of TS were analyzed.The relationship between genetic polymorphisms and clinical outcome,that is,response,toxicity and survival were assessed.Pharmacokinetic analyses were performed in a subgroup patients based on different UGT1A1 genotypes.Plasma concentration of irinotecan and its active metabolite SN-38 and inactive metabolite SN-38G were determined by high performance liquid chromatography.Differences in irinotecan and its metabolites between UGT1A1 gene variants were compared.RESULTS:One hundred and eight patients received the FOLFIRI regimen,29 the IFL regimen,and one irinotecan monotherapy.One hundred and thirty patients were eligible for toxicity and 111 for efficacy evaluation.One hundred and thirty-six patients were tested for UGT1A1*28 and *6 genotypes and 125 for promoter enhancer region of TS.Patients showed a higher frequency of wild-type UGT1A1*28(TA6/6) compared with a Caucasian population(69.9% vs 45.2%).No significant difference was found between response rates and UGT1A1 genotype,although wild-type showed lower response rates compared with other variants(17.9% vs 24.2% for UGT1A1*28,15.7% vs 26.8% for UGT1A1*6).When TS was considered,the subgroup with homozygous UGT1A1*28(TA7/7) and non-3RG genotypes showed the highest response rate(33.3%),while wild-type UGT1A1*28(TA6/6) with non-3RG only had a 13.6% response rate,but no significant difference was found.Logistic regression showed treatment duration was closely linked to clinical response.In toxicity comparison,UGT1A1*28 TA6/6 was associated with lower incidence of grade 2-4 diarrhea(27.8% vs 100%),and significantly reduced the risk of grade 4 neutropenia compared with TA7/7(7.8% vs 37.5%).Wild-type UGT1A1*6(G/G) tended to have a lower incidence of grade 3/4 diarrhea vs homozygous mutant(A/A) genotype(13.0% vs 40.0%).Taking UGT1A1 and TS genotypes together,lower incidence of grade 2-4 diarrhea was found in patients with non-3RG TS genotypes,when TA6/6 was compared with TA7/7(35.3% vs 100.0%).No significant association with time to progression(TTP) and overall survival(OS) was observed with either UGT1A1 or TS gene polymorphisms,although slightly longer TTP and OS were found with UGT1A1*28(TA6/6).Irinotecan PK was investigated in 34 patients,which showed high area under concentration curve(AUC) of irinotecan and SN-38,but low AUC ratio(SN-38G /SN-38) in those patients with UGT1A1*28 TA7/7.CONCLUSION:A distinct distribution pattern of UGT1A1 genotypes in Chinese patients might contribute to relatively low toxicity associated with irinotecan and 5-fluorouracil in mCRC patients.

Effects of tacrolimus on proliferation, apoptosis, and fluorouracil sensitivity of liver cancer cell line of SMMC-7721

BACKGROUND: The effect of tacrolimus (FK506) and 5- fluorouracil (5-FU) on hepatocellular carcinoma remains elusive. The aim of this study was to assess the effect of ta- crolimus on the proliferation, and apoptosis in liver cancer cell line of SMMC-7721 and its sensitivity to fluorouracil (5- FU). METHODS: The liver cancer cell line of SMMC-7721 was cultured in vitro, and the MTT assay was used to examine the antiproliferative effect of FK506. Flow cytometry (FCM) was used to examine the effect of 5-FU alone or in combination with FK506 on the apoptosis and cell cycle of SMMC-7721 cells. RESULTS: FK506 produced concentration-dependent anti- proliferative effect on SMMC-7721 cells at all experimental concentrations(P <0.05), but no effect on induction of apo- ptosis. 5-FU induced apoptosis in a concentration-depen- dent manner, whereas the percentage of G0/G1-phase cells and proliferation index (PI) were increased with the in- creased concentration of 5-FU. Pretreatment with FK506 for 2 hours enhanced the effect of 5-FU on the induction of apoptosis. CONCLUSIONS: FK506 inhibits the growth of SMMC-7721 cells and enhances their sensitivity to 5-FU. This may be as- sociated with the synergic effect of FK506 and 5-FU in in- ducing apoptosis and G0/G1-phase stasis.

Caspase-8 in apoptosis of hepatoma cell induced by 5-fluorouracil

OBJECTIVE: To explore the relationship between the changes in the activity of caspase-8 and apoptosis of HepG2 cells induced by 5-fluorouracil (5-Fu). METHODS: Human hepatoma HepG2 cells were treated with 5-Fu at the concentrations of 1×10^(-1), 1×10^(-2), 1×10^(-3), 1×10^(-4), 1×10^(-5) mol/L and for 1, 2, 4, 8, 16, 24 hours, respectively. The caspase-8 activity was detected using caspase-8 fluorescent assay kit. The apoptotic rate of HepG2 cells induced by 5-Fu with or without the caspase-8 inhibitor IETD-FMK was measured by flow cytometry. RESULTS: Afer the HepG2 cells were trealed with 10^(-2) mol/L 5-Fu, the caspase-8 activity increased gradually and reached the peak level (313.9±6.9) at 16 hours, then fell down. Compared with the control group, the activity was still significantly higher (274.2±3.9 vs 68.3±3.6, P<0.01). With the increasing concentraion of 5-Fu, the caspase-8 activity was also increased; the activity in high concentration 5-Fu was significantly higher than that in low concentration 5-Fu (370.5±4.7 vs 313.7±6.9; 225.7±5.4 vs 183.3±4.8; 183.3±4.8 vs 124.0±6.2, P<0.01). The caspase-8 activity was the highest at 1×10^(-1) mol/L 5-Fu (370.5±4.7). The caspase-8 activity in low concentration 5-Fu was higher than in the blank control group and inhibitor group (124.0±6.2 vs 68.5±3.4; 124.0±6.2 vs 41.0±2.1, P<0.01). IETD-FMK could block the activation of caspase-8 and reduce the apoptosis of HepG2 cells induced by 5-Fu. The apoptotic rate of HepG2 cells in the 5-Fu group was significantly different from that in the inhibitor group (P<0.01). CONCLUSIONS: 5-Fu can induce apoptosis of HepG2 cells via caspase-8 signal transduction pathway, which can be blocked by IETD-FMK. 5-Fu promotes the increase of caspase-8 activity in a time- or concentration-dependent manner.

Pneumatosis cystoides intestinalis after fluorouracil chemotherapy for rectal cancer

Pneumatosis cystoides intestinalis (PCI) is a relatively rare condition characterized by intraluminal gas in the gastrointestinal tract. Several chemotherapeutic agents have been reported to be associated with PCI, although fluorouracil-related PCI is extremely rare. We report a case of a 76-year old man who received adjuvant chemotherapy for rectal cancer with fluorouracil (FU) and leucovorin (LV). After 1 cycle of the treatment, he presented with diarrhea and abdominal pain. Abdominal radiogram revealed the presence of free air under the diaphragm and intramural gas in the intestine. Laparotomy was performed, showing a suspected diagnosis of perforation in the gastrointestinal tract. Intraoperative findings revealed penumatosis of the intestine without evidence of perforation. He was treated supportively and his symptoms improved. In conclusion, we should consider the possibility of PCI occurring in patients with malignancies during chemotherapy treatment.

Pharmacological Study on Antitumor Activity of 5-Fluorouracil-1-Acetic Acid and Its Rare Earth Complexes

The antitumor activity of 5 fluorouracil 1 acetic acid(HFAA) and its lanthanide complexes(La(FAA) 3, Eu(FAA) 3) were studied. The results show that HFAA, La(FAA) 3 and Eu(FAA) 3 with the concentrations of 1 0×10 -5 ～1 0×10 -2 μg·ml -1 inhibit the colony formation of leukemia cells(L 1210 ) and the growth of transplanted tumor sarcoma 180(S 180 ), hepatic carcinoma(HEPA) and ehrlich ascites tumor(EC) as well. The maximum inhibitory rate of Eu(FAA) 3 for S 180 is 38 4%, that HFAA and La(FAA) 3 for EC are 22 4% and 43 4%, respectively. The life prolongation rate of Eu(FAA) 3 for HEPA bearing mice is as long as 284%.

Glycogen Synthase Kinase 3β Inhibitor (2'Z,3'E)-6-Bromo-indirubin-3'-Oxime Enhances Drug Resistance to 5-Fluorouracil Chemotherapy in Colon Cancer Cells

Objective： To explore the effects and mechanism of glycogen synthase kinase 3β （GSK-313） inhibitor （2＇Z,3＇E）-6-bromo-indirubin-3＇-oxime （BIO） on drug resistance in colon cancer cells. Methods： The colon cancer SW480 and SW620 cells were treated with BIO, 5-fluorouracil （5-FU） and BIO/5-FU, separately. Cell cycle distribution, apoptosis level and efflux ability of rhodamine 123 （Rh123） were detected by flow cytometry. The protein expressions of P-glycoprotein （P-gp）, multidrug resistance protein 2 （MRP2）, thymidylate synthase （TS）, β-catenin, E2F-1 and βcl-2 were detected by Western blot. β-catenin and P-gp were stained with double immunofluorescence and observed under a confocal microscope. Results： BIO up-regulated β-catenin, P-gp, MRP2 and TS, enhanced the efflux ability of Rh123, decreased Bcl-2 protein and gave the opposite effect to E2F-1 protein in SW480 and SW620 ceils. Furthermore, BIO significantly inhibited cell apoptosis, increased S and G2/M phase cells, and reduced the cell apoptosis induced by 5-FU in SW480 cells, whereas the effects were slight or not obvious in SW620 cells. Conclusion： GSK-3β was involved in drug resistance regulation, and activation of β-catenin and inhibition of E2F-1 may be the most responsible for the enhancement of 5-FU chemotherapy resistance induced by GSK-β inhibitor β10 in colon cancer.

Oxaliplatin,Fluorouracil and Leucovorin (FOLFOX) as First-line Chemotherapy for Metastatic or Recurrent Colorectal Cancer Patients

OBJECTIVE To investigate the efficiency and safety of the oxaliplatin, fluorouracil （5-FU） and leucovorin regimen （FOLFOX）in previously untreated patients with metastatic or recurrent colorectal cancer. METHODS Previously untreated patients with metastatic or recurrent colorectal cancer received 100 mg/m^2 of oxaliplatin intravenously （Ⅳ） over 2 h on day 1, and Ⅳ 400 mg/m^2 of leucovorin over 2 h followed by a bolus of 400 mg/m^2 of 5-FU. Then 2,600-3,000 mg/m^2 of 5-FU was administered by continuous infusion over 46 h. RESULTS An evaluated response rate was determined for 97 of 105 treated patients. The overall response rate was 35.1%, 9 patients （9.3%） had a complete response and 25 patients （25.8%） a partial response. Thirtytwo patients （33.0%） developed stable disease and 32.0% of the patients progressed. The median time to progression （TTP） was 7.7 months and the median overall survival 20.5 months. One and 2-year survival rates were 68% and 32%. Toxic effects based on the National Cancer Institute-Common Toxicity Criteria （NCI-CTC）, reaching grade 3/4 were： neutropenia 12.3%, anemia 11.3%, vomiting 4.1% and diarrhea 7.2%. Grade 3 neuropathy was 5.1%. The overall survival rate of patients who had received a radical resection was superior to the patients who had not received a operation, or had received a palliative resection （P=0.0658）. The serum levels of CEA, ALP and LDH had no relationship with survival （P〉0.05）. CONCLUSION The FOLFOX regimen containing oxaliplatin, 5-FU plus leucovorin was an efficacious regimen with good tolerability in previously untreated metastatic or recurrent colorectal cancer patients.

Cooperative inhibitory effect of sinomenine combined with5-fluorouracil on esophageal carcinoma

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.

Influence of L-methionine-deprived total parenteral nutrition with 5-fluorouracil on gastric cancer and host metabolism

AIM: To investigate the influence of L-methionine-deprived total parenteral nutrition with 5-FU on gastric cancer and host metabolism. METHODS: N-methyl-N'-nitro-nitrosoguanidine (MNNG) induced gastric cancer rats were randomly divided into four groups: Met-containing TPN group (n=11), Met-deprived TPN group (n =12), Met-containing TPN+5-FU group (n=11) and Met-deprived TPN+5-FU group (n=12). Five rats in each group were sacrificed after 7 days of treatment and the samples were taken for examination. The remaining rats in each group were then fed separately with normal diet after the treatment until death, the life span was noted. RESULTS: The tumors were enlarged in Met-containing group and shrank in Met-deprived group markedly after the treatment. The DNA index (DI) of tumor cells and the body weight (BW) of rats had no significant change in the two groups, however, the ratio of tumor cells'S phase was increased. The ratio of G2M phase went up in Met-containing group, but down in Met-deprived group. In the other two groups that 5-FU was added, the BW of rats, and the diameter of tumors, the DI of tumor cells, the S and G2M phase ratio of tumor cells were all decreased, particularly in Met-deprived plus 5-FU group. Pathological examination revealed that the necrotic foci of the tumor tissue increased after Met-deprived TPN treatment, and the nucleoli of tumor cells enlarged. In MetTPN+5-FU group, severe nuclear damage was also found by karyopyknosis and karyorrhexis, meanwhile there was slight degeneration in some liver and kidney cells. The serum free Met and Cysteine decreased markedly (P【0.001), while other amino acids, such as serum free serine and glutamine increased significantly (P【0.005). All the rats died of multiple organ failure caused by cancer metastasis. The average survival time was 18.6 days in Met-containing TPN group, 31 days in Met-deprived TPN group, 27.5 days in Met-containing TPN+5-FU group, and 43 days in Met-deprived TPN+5-FU group (P【0.05). CONCLUSION: Met-deprived TPN causes methionine starvation of tumor cells, and can enhance the anti-tumor effect of 5-FU and prolong the life span of gastric cancer bearing rats.

Interleukin-1 receptor antagonist enhances chemosensitivity to fluorouracil in treatment of Kras mutant colon cancer

BACKGROUND Kras mutant colon cancer shows abnormal activation of the nuclear factor kappa-B(NF-κB)pathway,resulting in the proliferation of tumor cells.Treatment with fluorouracil(5-FU)might not achieve the expected inhibition of proliferation of malignant cells based on the fluorouracil-induced activation of the NF-κB pathway.AIM To detect whether interleukin(IL)-1 receptor antagonist(IL-1RA)could increase the chemosensitivity to 5-FU by decreasing the activation of the NF-κB pathway and reducing the proliferation of colon cancer cells.METHODS Western blot analysis was performed to detect the persistent activation of the NF-κB pathway in colon cancer cell lines.Reverse transcription-polymerase chain reaction was used to detect the IL-1RA-reduced expression levels of IL-6,IL-8,IL-17,IL-21 and TLR4 in colon cancer cell lines.We used a xenograft nude mouse model to demonstrate the downregulation of the NF-κB pathway by blocking the NF-κB-regulated IL-1αfeedforward loop,which could increase the efficacy of chemotherapeutic agents in inhibiting tumor cell growth.RESULTS IL-1 receptor antagonist could decrease the expression of IL-1αand IL-1βand downregulate the activity of the NF-κB pathway in Kras mutant colon cancer cells.Treatment with 5-FU combined with IL-1RA could increase the chemosensitivity of the SW620 cell line,and decreased expression of the TAK1/NF-κB and MEK pathways resulted in limited proliferation in the SW620 cell line.CONCLUSION Adjuvant chemotherapy with IL-1RA and 5-FU has a stronger effect than single chemotherapeutic drugs.IL-1RA combined with fluorouracil could be a potential neoadjuvant chemotherapy in the clinic.

Preparation of 5-fluorouracil-loaded chitosan nanoparticles and study of the sustained release in vitro and in vivo

The sustained-release properties of the biodegradable nano-drug delivery systems were used to improve the residence time of the chemotherapeutic agent in the body. These drug delivery systems were widely used to deliver chemotherapeutic drugs. The 5-fluorouracil loaded chitosan nanoparticles prepared in this paper have the above advantage. Here, we found that when the mass ratio of 5-fluorouracil and chitosan was 1:1, the maximum drug loading of nanoparticles was 20.13 ± 0.007%, the encapsulation efficiency was 44.28 ± 1.69%, the particle size was 283.9 ± 5.25 nm and the zeta potential was 45.3 ± 3.23 mV. The prepared nanoparticles had both burst-release and sustained-release phases in vitro release studies.In addition, the inhibitory effect of the prepared nanoparticles on gastric cancer SGC-7901 cells was similar to that of 5-fluorouracil injection, and the blank vector had no obvious inhibitory effect on SGC-7901 cells. In the pharmacokinetic study of rats in vivo, we found that AUC(0-t), MRT(0-t) and t1/2 z of nanoparticles were significantly increased in vivo compared with 5-fluorouracil solution, indicating that the prepared nanoparticles can play a role in sustained-release.