Synthesis and biological activities of chlorin e6-based conjugate of fluorouracil as dual-mode antitumor photosensitizer / 药学实践杂志

Objective To design and synthesize the conjugate (compound 1) of chlorin e6 (compound 3) with fluorouracil (5-Fu) as novel pH-responsive dual-mode antitumor photosensitizer by acyl hydrazone bond coupling, based on literature reports that combination of 5-Fu and photosensitizer possess synergistic anti-tumor effect, and investigate its photodynamic antitumor activity and mechanism. Methods Lead compound 3 was obtained by alkali degradation with 25% KOH-CH3OH on pheophorbide a (compound 4) which was prepared through acid hydrolysis of chlorophyll a in crude chlorophyll extracts from silkworm excrement. Reflux reaction of 5-Fu with P2S5 in pyridine formed crude 4-thio-5-fluorouracil which was followed to react with hydrazine hydrate (N2H4·H2O) in CH3OH to give 5-fluorouracil-4-hydrazone (compound 2). Then, treatment of compound 3 i.e. acid alkali degradation product of chlorophyll a in silkworm excrement with EDC·HCl generated its 171- and 152 cyclic anhydride which was followed to directly react with intermediate compound 2 to successfully get title compound 1. In addition, its pH-responsive 5-Fu release and photodynamic antitumor activity and their mechanisms in vitro were investigated. Results Compound 1 could responsively release 5-Fu at pH 5.0, with a cumulative release rate of 60.3% within 24 h. It exhibited much higher phototoxicity against melanoma B16-F10 and liver cancer HepG2 cells than talaporfin and its precursor compound 3, with IC50 value being 0.73 μmol/L for B16-F10 cells and 0.90 μmol/L for HepG2 cells, respectively. Upon light irradiation, it also could significantly induce cell apoptosis and intracellular ROS level and block cell cycle in S phase. Its structure was confirmed by UV, 1H-NMR, ESI-MS and elemental analysis data. Conclusion The conjugate compound 1 of compound 3 and 5-Fu has the advantages of strong PDT anticancer activity, high therapeutic index (i.e. dark toxicity/phototoxicity ratio) and responsively release 5-Fu at pH 5.0 etc. which shows “unimolecular” dual antitumor effects of PDT and chemotherapy and is worthy of further research and development.

Mechanism of HMGB1 in scarring after glaucoma drainage valve implantation / 国际眼科杂志(Guoji Yanke Zazhi)

AIM: To explore the dynamic expression of high mobility group box 1(HMGB1)in scar tissues after glaucoma drainage valve implantation, and to further reveal the role and possible mechanism of HMGB1 in scarring after glaucoma surgery.METHODS: A total of 60 New Zealand white rabbits were randomly divided into control group(n=20), model group(n=20, silicone implantation under conjunctival sac)and model with drug administration group(n=20, silicone implantation under conjunctival sac combined with 5-fluorouracil injection). The conjunctival tissues were collected at 4 and 8 wk after surgery. HE staining and Masson staining were used to detect the proliferation and distribution of fibroblasts and collagen fibers in conjunctival tissues. Immunohistochemistry was utilized to detect the distribution and changes of HMGB1, transforming growth factor(TGF)-β1, Smad3 and α-smooth muscle actin(SMA)in conjunctival tissues. RT-PCR and Western blot were adopted to detect the mRNA and protein expression of HMGB1, TGF-β1, Smad3 and α-SMA in conjunctival tissues.RESULTS: HE staining and Masson staining showed that the proliferation of inflammatory cells, fibroblasts and collagen fibers in the model group was significantly higher than that in the control group at both 4 and 8 wk. Meanwhile, the proliferation of fibroblasts and collagen fibers in the model with drug administration group was significantly lower than that in the model group. Immunohistochemical staining showed that the expression of HMGB1, TGF-β1, Smad3 and α-SMA protein was observed in the conjunctival tissues of the model group both 4 and 8 wk, with brown and significantly deeper staining of the model group at 8 wk. Meanwhile, the positive staining in the model with drug administration group at both 4 and 8 wk was significantly lower than that in the model group. There was positive correlations between the number of fibroblasts stained with HE and the expression of HMGB1 in the conjunctival tissue of the model group at both 4 and 8 wk(r=0.602, 0.703, all P<0.05). RT-PCR and Western blot revealed that the mRNA and protein expression levels of HMGB1, TGF-β1, Smad3 and α-SMA in the model group were significantly higher than those in the control group at both 4 and 8 wk(all P<0.05). Meanwhile, the mRNA and protein expression levels of HMGB1, TGF-β1, Smad3 and α-SMA in the model with drug administration group were significantly lower than those in the model group(all P<0.05). There was positive correlations between mRNA expressions of HMGB1 and TGF-β1, Smad3 in the model group and the model with drug administration group(all P<0.05).CONCLUSION: The expression of HMGB1 increased at a time-dependent manner after glaucoma valve implantation. HMGB1 acts an indispensable role in the initiation and progression of scar formation after glaucoma surgery, which may be involved in the regulation of TGF-β/Smad signaling pathway.

Protective Autophagy in 5-Fluorouracil-Resistant Colorectal Cancer Cells and ERK-RSK-ABCG2 Linkage / Autofagia Protectora en Células de Cáncer Colorrectal Resistentes al 5-Fluorouracilo y Enlace ERK-RSK-ABCG2

SUMMARY: To evaluate the anti-cancer effects of yeast extract on resistant cells, autophagy and necroptosis were investigated in 5-fluorouracil (5-FU)-resistant colorectal cancer cells. Further underlying characteristics on drug resistance were evaluated, focused on ERK-RSK-ABCG2 linkage. SNU-C5 and 5-FU resistant SNU-C5 (SNU-C5/5-FUR) colorectal cancer cells were adopted for cell viability assay and Western blotting to examine the anti-cancer effects of yeast extract. Yeast extract induced autophagy in SNU-C5 cells with increased Atg7, Atg12-5 complex, Atg16L1, and LC3 activation (LC3-II/LC3-I), but little effects in SNU-C5/5-FUR cells with increased Atg12-5 complex and Atg16L1. Both colorectal cancer cells did not show necroptosis after yeast extract treatment. Based on increased ABCG2 and RSK expression after yeast extract treatment, drug resistance mechanisms were further evaluated. As compared to wild type, SNU-C5/5-FUR cells showed more ABCG2 expression, less RSK expression, and less phosphorylation of ERK. ABCG2 inhibitor, Ko143, treatment induces following changes: 1) more sensitivity at 500 mM 5-FU, 2) augmented proliferation, and 3) less phosphorylation of ERK. These results suggest that protective autophagy in SNU-C5/5-FUR cells with increased ABCG2 expression might be candidate mechanisms for drug resistance. As the ERK responses were different from each stimulus, the feasible mechanisms among ERK-RSK-ABCG2 should be further investigated in 5-FU-resistant CRC cells.

Para evaluar los efectos anticancerígenos del extracto de levadura en células resistentes, se investigaron la autofagia y la necroptosis en células de cáncer colorrectal resistentes al 5-fluorouracilo (5-FU). Además se evaluaron otras características subyacentes de la resistencia a los medicamentos centrándose en el enlace ERK-RSK-ABCG2. Se usaron células de cáncer colorrectal SNU-C5 (SNU-C5/5-FUR) resistentes a SNU-C5 y 5- FU para el ensayo de viabilidad celular y la transferencia Western para examinar los efectos anticancerígenos del extracto de levadura. El extracto de levadura indujo autofagia en células SNU-C5 con mayor activación de Atg7, complejo Atg12-5, Atg16L1 y LC3 (LC3-II/LC3-I), pero pocos efectos en células SNU-C5/5-FUR con aumento de Atg12-5 complejo y Atg16L1. Ambas células de cáncer colorrectal no mostraron necroptosis después del tratamiento con extracto de levadura. Se evaluaron los mecanismos de resistencia a los medicamentos. en base al aumento de la expresión de ABCG2 y RSK después del tratamiento con extracto de levadura.En comparación con las de tipo salvaje, las células SNU-C5/5-FUR mostraron más expresión de ABCG2, menos expresión de RSK y menos fosforilación de ERK. El tratamiento con inhibidor de ABCG2, Ko143, induce los siguientes cambios: 1) más sensibilidad a 5-FU 500 mM, 2) proliferación aumentada y 3) menos fosforilación de ERK. Estos resultados sugieren que la autofagia protectora en células SNU-C5/5-FUR con mayor expresión de ABCG2 podría ser un mecanismo candidato para la resistencia a los medicamentos. Como las respuestas de ERK fueron diferentes de cada estímulo, los mecanismos factibles entre ERK-RSK- ABCG2 deberían investigarse más a fondo en células CCR resistentes a 5-FU.

Uma Causa Rara e Tratamento da Fibrilação Ventricular: Toxicidade do 5-Fluorouracil / A Rare Cause and Management of Ventricular Fibrillation: 5-Fluorouracil Toxicity

Resumo Um homem de 65 anos com histórico de carcinoma de língua procurou o pronto-socorro com contrações insensíveis estando em casa. Ele estava em terapia com 5-fluorouracil (5-FU) na época. O paciente foi desfibrilado e intubado porque a fibrilação ventricular (FV) se desenvolveu durante o monitoramento no pronto-socorro. A ecocardiografia mostrou que a fração de ejeção do ventrículo esquerdo (FEVE) era de 70% e a espessura do septo interventricular era de 15 mm. A angiografia coronária não revelou qualquer estenose crítica. A ressonância magnética cardíaca (RMC) não mostrou anormalidade de perfusão, fibrose ou cicatriz sugestiva de envolvimento cardíaco. Foi sugerido que a arritmia do paciente estava relacionada principalmente à cardiotoxicidade induzida pelo 5-FU. O fato de as causas secundárias terem sido proeminentes em nosso caso, de nenhuma patologia cardíaca óbvia que pudesse causar arritmia ter sido encontrada no exame detalhado e de a arritmia não ter recorrido durante a internação hospitalar, que durou até 15 dias, nos levou a acreditar que esse paciente poderia receber alta sem um cardioversor-desfibrilador implantável. Nosso caso foi apresentado para contribuir com a literatura.

Treatment outcomes of alternating chemoradiotherapy for nasopharyngeal carcinoma: a single-center safety and efficacy study

Abstract Objective To evaluate the efficacy and safety of Alternating Chemoradiotherapy (ACRT) using cisplatin and 5-Fluorouracil (5-FU) in patients with nasopharyngeal carcinoma. Methods This was a retrospective study in which patients' clinical records were reviewed to identify patients with a new diagnosis of nasopharyngeal carcinoma at our institution between January 2005 and January 2019. Thirty-seven eligible patients were identified; of these, the clinical details of 27 patients treated with ACRT were evaluated. Patient outcomes, including overall survival and progression-free survival, and adverse events were assessed. Results Of these initial 37 patients, 1, 10, 13, 10, and 3 were staged as I, II, III, IVA, and IVB, respectively, as defined by the 8th edition of the TNM classification system. Twenty-seven patients received ACRT comprising sequential administration of chemotherapy, radiotherapy (wide field), chemotherapy, radiotherapy (shrinking field), and chemotherapy. The 5-year overall survival and progression-free survival rates were 83.7% and 88.9%, respectively. Treatment compliance was 93%, which is comparable to that of previous reports. Conclusion ACRT using cisplating and 5-fluorouracil was well tolerated with acceptable efficacy. Level of Evidence IVa

5-Fluorouracil as a targeted lacrimal gland therapy for chronic Stevens-Johnson syndrome: A pilot study

Purpose: The surgical technique of periglandular 5?fluorouracil (5?FU) injection and its effects on the morphology and function of the main lacrimal gland of patients with severe dry eye disease due to Stevens–Johnson syndrome (SJS) are reported. Methods: 5?FU, as a potential antifibrotic agent, is given in the dose of 0.1 ml (50 mg/ml), subconjunctivally into the periglandular fibrosed area of the palpebral lobe of the main lacrimal gland. The injection is given using 30G needle into the subconjunctival plane and not into the substance of palpebral lobe. Results: Eight eyes (eight lobes) of seven chronic SJS patients (mean age, 32.5 years, <5 mm Schirmer) received the injection. All eight lobes demonstrated a visible reduction in the conjunctival congestion and scarring over the lobar area. The mean OSDI scoring improved from 65.3 to 51.1. Three patients with mean pre?injection Schirmer I values of 4 mm showed a mean change of 1 mm at four weeks following a single injection. The tear flow rate per lobe for the above three patients improved from 0.22, 0.12, and 0.16 ?l/min to 0.31, 0.12, and 0.21 ?l/min, respectively. Another patient with pre?injection Schirmer of 4 mm showed no change in tear flow. Three eyes with zero baseline Schirmer values (no visible secretory opening) had no improvement in tearing or ocular surface staining. Conclusion: Local 5?FU injection alters morphology of the conjunctiva overlying the palpebral lobe in SJS patients, but fails to show any significant effect on tear secretion.

Spectrum-effect relationship of total anthraquinone extract of Cassia seeds against fluorouracil-induced liver injury in mice / 南方医科大学学报

OBJECTIVE@#To investigate the spectrum-effect relationship between the total anthraquinone extract of Cassia seeds and fluorouracil (5-Fu)-induced liver injury in mice and identify the effective components in the extract.@*METHODS@#A mouse model of liver injury was established by intraperitoneal injection of 5-Fu, with bifendate as the positive control. The serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and myeloperoxidase (MPO), superoxide dismutase (SOD) and total antioxidant capacity (T-AOC) in the liver tissue were detected to investigate the effect of the total anthraquinone extract of Cassia seeds (0.4, 0.8 and 1.6 g/kg) on liver injury induced by 5-Fu. HPLC fingerprints of 10 batches of the total anthraquinone extracts were established to analyze the spectrum- effectiveness of the extract against 5- Fu- induced liver injury in mice and screen the effective components using the grey correlation method.@*RESULTS@#The 5- Fu- treated mice showed significant differences in liver function parameters from the normal control mice (P < 0.05), suggesting successful modelling. Compared with those in the model group, serum ALT and AST activities were decreased, SOD and T- AOC activities significantly increased, and MPO level was significantly lowered in the mice treated with the total anthraquinone extract (all P < 0.05). HPLC fingerprints of the 31 components in the total anthraquinone extract of Cassia seeds showed good correlations with the potency index of 5-Fu-induced liver injury but with varying correlation strengths. The top 15 components with known correlations included aurantio-obtusina (peak 6), rhein (peak 11), emodin (peak 22), chrysophanol (peak 29) and physcion (peak 30).@*CONCLUSION@#The effective components in the total anthraquinone extract of Cassia seeds, including aurantio-obtusina, rhein, emodin, chrysophanol, and physcion, are coordinated to produce protective effects against 5-Fu-induced liver injury in mice.

Hydroxysafflor yellow A inhibits proliferation, migration, and chemoresistance of colorectal cancer cells through Akt/mTOR-autophagy pathway / 中国中药杂志

In recent years, the clinical treatment of colorectal cancer(CRC) has made great progress, but chemoresistance is still one of the main reasons for reducing the survival rate of patients with colorectal cancer. Therefore, ameliorating chemotherapy resis-tance is an urgent problem to be solved. The purpose of this study was to investigate the regulatory role and related molecular mechanisms of hydroxysafflor yellow A(HSYA) in colorectal cancer cell proliferation, migration, and 5-fluorouracil(5-FU) chemoresistance. In this study, HCT116 and HT-29 cells were used as research subjects. Firstly, methyl thiazolyl tetrazolium(MTT) assay and colony formation assay were used to detect and analyze the effect of HSYA on the proliferation of CRC cells. Secondly, the effect of HSYA on the cell cycle in CRC cells was analyzed by cell cycle assay. Furthermore, the effect of HSYA on the migration of CRC cells was analyzed by wound-healing assay and Transwell assay. Based on the above, the influences of HSYA on 5-FU chemoresistance of CRC cells and related molecular mechanisms were explored and analyzed. The results showed that HSYA significantly inhibited the proliferation and migration of CRC cells, and arrested the cell cycle in G_0/G_1 phase. In addition, HSYA significantly ameliorated the chemoresistance of CRC cells to 5-FU. The results of acridine orange staining and Western blot showed that the autophagy activity of CRC cells in the HSYA and 5-FU combined treatment group was significantly higher than that in the 5-FU single drug treatment group. As compared with the 5-FU single drug treatment group, the phosphorylation levels of protein kinase B(Akt) and mammalian target of rapamycin(mTOR) in the HSYA and 5-FU combined treatment group were significantly reduced, indicating that the Akt/mTOR signaling pathway in the combined treatment group was down-regulated in CRC cells. In conclusion, HSYA may upregulate autophagy activity through the Akt/mTOR signaling pathway, thereby inhibiting the proliferation and migration of CRC cells and ameliorating the chemoresistance to 5-FU.

Adjuvant effects of Saccharomyces cerevisiae in the treatment of experimental periodontitis in rats undergoing chemotherapy

Abstract Surgical procedures, radiotherapy, and chemotherapy, individually or in association, are current oncological treatments. Among the most used chemotherapy drugs, 5-fluorouracil (5FU) is an antimetabolite with a broad spectrum of action. This study evaluated the effects of probiotics (PRO) as an adjuvant to the treatment of experimental periodontitis (EP) in rats immunosuppressed with 5FU. Methodology 108 rats were randomly allocated to six different groups: EP; SS - systemic treatment with saline solution (SS); 5FU - systemic treatment with 5FU; 5FU+PRO - systemic treatment with 5FU, followed by the local administration of Saccharomyces cerevisiae ; 5FU+SRP - systemic treatment with 5-FU, followed by scaling and root planing (SRP); and 5FU+SRP+PRO - systemic treatment with 5FU followed by local treatments with SRP and PRO. Immunosuppression was obtained at two points: at the time of ligature installation and after 48 h. Six animals from each group were euthanized at seven, 15, and 30 d and hemimandibles were collected and processed for histopathological, histometric, and immunohistochemical analysis. Data were subjected to statistical analysis (α=5%). Results At 7 d, the 5FU+PRO group showed less bone resorption and better structured connective tissue compared with the EP, SS, 5FU+SRP, and 5FU+SRP+PRO groups. At 15 d, the 5FU+SRP group showed a greater intensity of the inflammatory response (p<0.05). At 30 d, the 5FU+SRP+PRO group showed better structured bone tissue and a higher percentage of bone tissue (PBT) than the EP, SS, 5FU, and 5FU+PRO groups (p<0.05). Conclusion The use of Saccharomyces cerevisiae as monotherapy or as an adjuvant to periodontal therapy may have a positive effect on bone repair in immunosuppressed conditions.

Application of 5-fluorouracil and bandage contact lens in pterygium excision combined with autogenous limbal stem cell transplantation / 国际眼科杂志(Guoji Yanke Zazhi)

AIM:To assess the clinical efficacy of 5-fluorouracil(5-FU)and bandage contact lens in the pterygium excision combined with autogenous limbal stem cell transplantation(ALSCT)in treating patients with pterygium.METHODS:Random controlled clinical trial. A total of 71 patients(71 eyes)of pterygium who treated at the department of ophthalmology in Qinhuangdao Haigang Hospital between May 2021 and November 2022 were included. They were divide into three groups, including 23 eyes received pterygium excision combined with ALSCT in group A, 24 eyes that were administered with 5-FU intraoperatively and postoperatively in group B, and 24 eyes that received both bandage contact lens and 5-FU in group C. Furthermore, comfort levels at 1, 3, 7, 14d postoperatively, corneal epithelial healing at 1, 3, 7, 14d and 1mo postoperatively, treatment outcomes and complications at 3～6mo postoperatively were compared among the three groups of patients.RESULTS:The comfort levels at 1, 3 and 7d postoperatively and corneal healing at 1 and 3d postoperatively of the group C were better than those of the groups A and B. There were no statistical significant differences in the comfort levels at 14d after surgery and corneal healing at 14d and 1mo after surgery among the three groups of patients. Over a 3～6mo follow-up period, group A experienced recurrence in 3 eyes, group B had 1 recurrence, while group C had no recurrence. There were no statistically significant differences in complication rates among the three groups of patients.CONCLUSIONS: The application of 5-FU combined with bandage contact lens can enhance postoperative comfort levels, promote corneal epithelial healing, and improve the success rate in pterygium excision combined with ALSCT.

Protective effect of polysaccharides isolated from the seeds of Cuscuta chinensis Lam. on 5-fluorouracil-induced intestinal mucositis in mice

Purpose: To evaluate the protective effect of Cuscuta chinensis Lam. polysaccharides (PCCL) on 5-fluorouracil-(5-FU)-induced intestinal mucositis (IM) in mice. Methods: PCCL was orally administered at a dose of 20 mg·kg­1 for 7 days and its protective effect on 5-FU-induced IM (5-FU, 50 mg·kg­1 for 5 days) was evaluated by monitoring changes in body weight, degree of diarrhea, levels of tissue inflammatory factors (tumor necrosis factor α, interleukin 6, and interleukin 1ß levels), apoptosis rates, and the expression levels of caspase-3, Bax and Bcl-2. Results: The severity of mucosal injury (as reflected by body weight changes, degree of diarrhea, height of villi, and damage to crypts) was significantly attenuated by PCCL administration. PCCL also reduced the levels of tissue inflammatory factors, the apoptosis rate, and the expression of caspase-3 and Bax, and increased Bcl-2 expression. Conclusions: PCCL administration may be significantly protective against 5-FU-induced IM by inhibiting apoptosis and regulating the abnormal inflammation associated with it.

Liver regeneration after extensive hepatectomy in rats: effect of preoperative chemotherapy with intravenous 5-fluorouracil

Purpose: To evaluate the effect of preoperative intravenous chemotherapy with 5-fluorouracil on liver regeneration in an experimental model of major hepatectomy in rats. Methods: Wistar rats were divided into two groups of 20 animals each and submitted to 70% hepatectomy 24 h after intravenous injection of 5-fluorouracil 20 mg/kg (fluorouracil group, FG) or 0.9% saline (control group, CG). After hepatectomy, each group was subdivided into two subgroups of 10 animals each according to the day of sacrifice (24 h or 7 days). Liver weight during regeneration, liver regeneration rate using Kwon formula, and the immunohistochemical markers proliferating cell nuclear antigen (PCNA) and Ki-67 were used to assess liver regeneration. Results: At early phase (24 h after hepatectomy) it was demonstrated the negative effect of 5-fluorouracil on liver regeneration when assessed by Kwon formula (p < 0.0001), PCNA analysis (p = 0.02). With regeneration process complete (7 days), it was possible to demonstrate the sustained impairment of chemotherapy with 5-fluorouracil on hepatocytes regeneration phenomenon when measured by Kwon formula (p = 0.009), PCNA analysis (p = 0.0001) and Ki-67 analysis (0.001). Conclusions: Preoperative chemotherapy with intravenous 5-fluorouracil negatively affected the mechanisms of liver regeneration after major hepatectomy in rats.

Causal analysis on infusion timeout of 5-fluorouracil powder injection infusion pumps and the optimization for dispensing methods / 中国实用护理杂志

Objective:To analyze the cause of infusion timeout of 5-fluorouracil (5-FU) powder injection infusion pumps, and conduct research on the dispensing methods, then provide a basis for clinical dispensing.Methods:The dissolution effect of 5-FU in different solvents were tested in the lab. The effect of different solvents on infusion timeout of infusion pumps, and the factors related to infusion timeout of the pumps were explored by analyzing the clinical data which was collected in Cancer Hospital of Shantou University Medical College from May 20 to July 20, 2020.Results:The dissolving capacity to 5-FU of different solvents sorted by the influence in a descending manner as follows: water for injection> 5% glucose injection (5%GS) >0.9% sodium chloride injection (0.9%NS) . Infusion timeout value of water for injection group (15.03 ± 8.62)% was lower than that of 0.9%NS group (36.78 ± 4.81)%, (0.9%NS+ water for injection) group (22.50 ± 7.22)%, 5%GS group (25.53 ± 6.21)% and (5%GS+ water for injection) group (24.78 ± 4.36)% ( t values were 2.50-5.27, all P<0.05). The timeout value of 0.9%NS group was higher than that of other groups ( t values were 3.65-5.27, all P<0.05). There were differences in infusion timeout between intravenous infusion group (23.07 ± 8.98)% and arterial infusion groups (60.60 ± 58.64)% ( H=10.18, P=0.001). There was a positive correlation between drug concentration and infusion timeout( r=0.29, P=0.013), and a negative correlation between total liquid volume and infusion timeout ( r=-0.59, P<0.01). Infusion timeout of pumps was partly (67.3%) affected by drug concentration, total liquid volume and infusion route. Conclusions:The research shows that infusion timeout of 5-FU powder injection infusion pumps is related to drug concentration, total liquid volume and infusion route. It is suggested that the percentage of water for injection, drug concentration, total liquid volume, and infusion route should be considered when 5-FU powder injection infusion pumps are prepared.

Efficacy and safety of nedaplatin versus cisplatin plus fluorouracil for treatment of esophageal neoplasms: A systematic review and meta-analysis / 中国胸心血管外科临床杂志

@#Objective    To systematically evaluate the efficacy and safety of nedaplatin versus cisplatin combined with fluorouracil in the treatment of esophageal neoplasms. Methods    PubMed, EMbase, Web of Science, The Cochrane Library, CNKI, WanFang, VIP and CBM databases were searched by computer to investigate the randomized controlled studies about the clinical effects of nedaplatin combined with fluorouracil versus cisplatin combined with fluorouracil in the treatment of esophageal neoplasms. The retrieval time was from the establishment of the database to January 2021. And meta-analysis was performed using RevMan 5.4. Results    A total of 12 randomized controlled studies involving 744 patients were included. The results of meta-analysis showed that the total effective rate of the nedaplatin group was better than that of the cisplatin group (P<0.05). The incidence of nausea, vomiting, diarrhea and renal impairment in the nedaplatin group was lower than that in the cisplatin group (P<0.05), but the incidence of leukopenia and hemoglobin decline was higher than that in the cisplatin group (P<0.05). There was no statistical difference in the incidence of liver injury, or platelet decline between the two groups (P>0.05). Conclusion    Nedaplatin combined with fluorouracil has more advantages than cisplatin combined with fluorouracil in the treatment of esophageal cancer, the incidence of nausea, vomiting and diarrhea is lower, and the damage to kidney function is also smaller.

Effect of hypoxia on HIF -1 α/MDR1/VEGF expression in gastric cancer cells treated with 5 -fluorouracil / 中南大学学报(医学版)

OBJECTIVES@#Fluorouracil chemotherapeutic drugs are the classic treatment drugs of gastric cancer. But the problem of drug resistance severely limits their clinical application. This study aims to investigate whether hypoxia microenvironment affects gastric cancer resistance to 5-fluorouracil (5-FU) and discuss the changes of gene and proteins directly related to drug resistance under hypoxia condition.@*METHODS@#Gastric cancer cells were treated with 5-FU in hypoxia/normoxic environment, and were divided into a Normoxic+5-FU group and a Hypoxia+5-FU group. The apoptosis assay was conducted by flow cytometry Annexin V/PI double staining. The real-time reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting were used to detect the expression level of hypoxia inducible factor-1α (HIF-1α), multidrug resistance (MDR1) gene, P-glycoprotein (P-gp), and vascular endothelial growth factor (VEGF) which were related to 5-FU drug-resistance. We analyzed the effect of hypoxia on the treatment of gastric cancer with 5-FU.@*RESULTS@#Compared with the Normoxic+5-FU group, the apoptosis of gastric cancer cells treated with 5-FU in the Hypoxia+5-FU group was significantly reduced (P<0.05), and the expression of apoptosis promoter protein caspase 8 was also decreased. Compared with the the Normoxic+5-FU group, HIF-1α mRNA expression in the Hypoxia+5-FU group was significantly increased (P<0.05), and the mRNA and protein expression levels of MDR1, P-gp and VEGF were also significantly increased (all P<0.05). The increased expression of MDR1, P-gp and VEGF had the same trend with the expression of HIF-1α.@*CONCLUSIONS@#Hypoxia is a direct influencing factor in gastric cancer resistance to 5-FU chemotherapy. Improvement of the local hypoxia microenvironment of gastric cancer may be a new idea for overcoming the resistance to 5-FU in gastric cancer.

Curcuma longa extract protects against 5-fluorouracil-induced oral mucositis in hamsters

Abstract Curcumin, contained at Turmeric (Curcumalonga), can exert many beneficial pleiotropic activities in the gastrointestinal tract. This study evaluated the antioxidant and anti-inflammatory activity of C. longa on 5-fluorouracil (5-FU)-induced oral mucositis (OM) in hamsters. Phytochemical analysis of crude C. longa extract (CLE) was performed to detect the presence of curcumin by TLC and HPLC. Golden Syrian hamsters were orally pre-treated with CLE (5, 50, or 100mg/kg). Cheek pouch samples were subjected to macroscopic and histopathological evaluation. ELISA was performed to quantify the inflammatory cytokines IL-1ß and TNF-α. Superoxide dismutase (SOD), glutathione (GSH) and malondialdehyde (MDA) levels were assessed by ultraviolet-visible spectroscopy analysis. Behavior analysis was conducted by the open field test. Curcumin content in the CLE was 0.55%m/m ± 0.0161 (2.84%). The group treated with 5mg/kg CLE showed healing evidence with macroscopic absence of ulceration (p<0.05) and microscopic aspect of re-epithelialization, discrete inflammatory infiltrate and absence of edema. Treatment with 5mg/kg CLE significantly increased GSH levels, and reduced MDA levels and SOD activity (p˂0.05), and decreased IL-1ß (p˂0.05) and TNF-α (p˂0.01) levels. A significant reduction in walking distance, ambulation, speed, and rearing was observed for motor activity. Curcumin reduced oxidative stress, inflammation, and motor activity in hamsters with 5-FU-induced OM.

Micro ribonucleic acid-448 regulates zinc finger e-box binding homeobox 1 to inhibit the growth of breast cancer cells and increase their sensitivity to chemotherapy

Abstract Objective: This study aimed to investigate the effect of Zinc Finger E-box Binding Homeobox 1 (ZEB1) regulation by Micro Ribonucleic acid (miR)-448 on Breast Cancer (BC) cells and their sensitivity to chemotherapy. Methods: miR-448 and ZEB1 mRNA levels in BC and normal tissues were detected by qPCR, and ZEB1 protein was detected by Western Blotting (WB). The correlation between miR-448 and tumor metastasis, clinical staging, and ZEB1 expression was analyzed. MCF-7 cells were transfected or co-transfected with the miR-448 mimic, oe-ZEB1, or their negative controls. Changes in miR-448 and ZEB1 expression were detected by qPCR and WB. Cell proliferation was determined by CCK-8 assays, invasion changes were analyzed by Transwell assays, and apoptosis was detected by flow cytometry. Results: miR-448 expression in BC tissues was lower than that in normal tissues, while ZEB1 expression was increased in the former. ZEB1 expression was lower in BC patients with lymph node metastasis than in those without. In patients with clinical stage I-III BC, miR-448 expression decreased with an increase in tumor stage, which was negatively correlated with ZEB1 expression. Upregulation of miR-448 expression can suppress MCF-7 cell proliferation and invasion and promote apoptosis. Upregulation of ZEB1 expression in cells overexpressing miR-448 can partially reverse the inhibition of BC cell growth induced by miR-448. miR-448 can enhance the sensitivity of cells toward paclitaxel and 5-fluorouracil. Conclusions: miR-448 suppresses cell proliferation and invasion and promotes apoptosis by targeting ZEB1. Moreover, it can increase the sensitivity of cells toward paclitaxel and 5-fluorouracil.

Effects of irbesartan combined with 5-fluorouracil on the proliferation and ERK/PPARγ signaling pathway of Lewis lung cancer cells / 中国药房

OBJECTIVE To explore the effects of irbesartan（Irb）combined with 5-fluorouracil（5-FU）on the proliferation and extracellular signal-regulated kinase （ERK）/peroxidase proliferator-activated receptor γ（PPARγ）signaling pathway of Lewis lung cancer cells. METHODS Lewis lung cancer cells from mice were divided into normal control （NC）group，Irb low-dose （LD）group（1×10－3 mmol/L），Irb high-dose （HD）group（1×10－1 mmol/L），5-FU group （10 μmol/L），Irb LD+ 5-FU group （Irb 1×10－3 mmol/L+5-FU 10 μmol/L）and Irb HD+ 5-FU group （Irb 1×10－1 mmol/L+5-FU 10 μmol/L）. MTT method was used to measure the activity of cell proliferation in each group. Plate colony formation experiment was used to determine the number of cell colonies formed in each group ；Western blot method was used to detect the expression levels of proliferating cell nuclear antigen （PCNA），p53，ERK1/2，p-ERK1/2 and PPAR γ protein in each group. RESULTS Compared with the NC group ，the cell proliferation activity ，the number of colonies formed and the protein levels of PCNA ，p-ERK1/2，and PPARγ were significantly reduced in the other five groups ，and the protein level of p 53 was significantly increased （P＜0.05）；the protein expression of ERK1/2 had no significant difference （P＞0.05）. The changes of above indexes in Irb LD+ 5-FU group and Irb HD+ 5-FU group were more significant than Irb LD group ，Irb HD group and 5-FU group （P＜0.05）. CONCLUSIONS Irb combined with 5-FU can inhibit the proliferation of Lewis lung cancer cell ，and the effect is better than that of the two alone. The mechanism may be related to the inhibition of ERK/PPARγ signal pathway.

Screening of genes related to the prognosis of gastric cancer and the efficacy of 5-fluorouracil based on bioinformatics method / 肿瘤研究与临床

Objective:To screen biomarkers related to the prognosis of gastric cancer and the efficacy of 5-fluorouracil based on the bioinformatics method.Methods:Gastric cancer datasets like GSE54129, GSE79973 and GSE51725 based on GPL570 platform were downloaded from Gene Expression Omnibus (GEO) database. Genes related to the overall survival (OS) of the top 500 gastric cancer patients were downloaded from GEPIA2 online gene expression profile.GEO2R was used to identify the differentially expressed genes (DEG) between gastric cancer tissues and adjacent normal tissues, STRING database was used to build protein-protein interaction networks (PPI) and to identify the key genes, the enrichment analysis of gene ontology (GO)and Kyoto Encyclopedia of Genes and Genomes (KEGG) was made by using OmicShare. Kaplan-Meier Plotter was used to calculate the value of key genes in predicting the OS of gastric cancer patients. All patients were divided into the high expression group and low expression group according to the optimal cut-off value of gene expression level.Results:A total of 59 DEG were screened, including 39 up-regulated genes and 20 down-regulated genes. The key up-regulated genes including homeodomain transcription factors 2(PITX2), hepatocyte growth factor (HGF), fibroblast growth factor 1 (FGF1), transforming growth factor β 2 (TGFB2), thromobospondin 1 (THBS1) were analyzed by using PPI. Survival analysis results showed that the OS of gastric cancer patients with low expression of FGF1, HGF, PITX2 and TGFB2 genes was better (all P < 0.01); the OS of gastric cancer patients with low expression of THBS1 gene was poor, while the difference was not statistically significant ( P > 0.05). The patients with low expression of RIEG1 gene who received 5-fluorouracil-based chemotherapy regimen had the better OS ( P < 0.01),while those with THBS1 and HGF low expression had the worse OS ( P < 0.05). It was found that key genes might promote the development of gastric cancer by participating in the regulation of TGF- β signaling pathway, Rap1 signaling pathway, MAPK signaling pathway, PI3K-Akt signaling pathway, Hippo signaling pathway, Ras signaling pathway and focal adhesion pathway. Conclusions:Bioinformatics analysis shows that the expressions of FGF1, HGF, PITX2 and TGFB2 genes are related to the prognosis of gastric cancer, and the expressions of RIEG1, THBS1 and HGF are related to the efficacy of 5-fluorouracil, which may be used as a predictive marker of fluorouracil chemosensitivity in patients with gastric cancer.

Bioresponsive immune-booster-based prodrug nanogel for cancer immunotherapy

The combination of chemotherapy and immunotherapy motivates a potent immune system by triggering immunogenic cell death (ICD), showing great potential in inhibiting tumor growth and improving the immunosuppressive tumor microenvironment (ITM). However, the therapeutic effectiveness has been restricted by inferior drug bioavailability. Herein, we reported a universal bioresponsive doxorubicin (DOX)-based nanogel to achieve tumor-specific co-delivery of drugs. DOX-based mannose nanogels (DM NGs) was designed and choosed as an example to elucidate the mechanism of combined chemo-immunotherapy. As expected, the DM NGs exhibited prominent micellar stability, selective drug release and prolonged survival time, benefited from the enhanced tumor permeability and prolonged blood circulation. We discovered that the DOX delivered by DM NGs could induce powerful anti-tumor immune response facilitated by promoting ICD. Meanwhile, the released mannose from DM NGs was proved as a powerful and synergetic treatment for breast cancer in vitro and in vivo, via damaging the glucose metabolism in glycolysis and the tricarboxylic acid cycle. Overall, the regulation of tumor microenvironment with DOX-based nanogel is expected to be an effectual candidate strategy to overcome the current limitations of ICD-based immunotherapy, offering a paradigm for the exploitation of immunomodulatory nanomedicines.