-
Bioengineered Dec 2021The study was designed to explore the effects of Withaferin A (WFA) on hyperuricemia-induced kidney injury and its action mechanism. Potassium oxonate (PO) was employed...
The study was designed to explore the effects of Withaferin A (WFA) on hyperuricemia-induced kidney injury and its action mechanism. Potassium oxonate (PO) was employed to establish the hyperuricemic mouse model. The pathological changes of renal tissue were evaluated by hematoxylin-eosin and masson trichrome staining. The levels of creatinine, blood urea nitrogen (BUN), uric acid (UA) and xanthine oxidase (XOD) were detected using corresponding commercial kits. Expressions of collagen-related and apoptosis-associated proteins in renal tissues were, respectively, evaluated by immunofluorescence and western blotting. Cell apoptosis was detected by TUNEL assay, and transporter expressions using western blotting. Followed by WFA, NRK-52E cells were treated with UA before evaluation of apoptosis and fibrosis. Results indicated that WFA ameliorated renal damage, improved kidney function, and decreased levels of creatinine, BUN, UA, and XOD in PO-induced hyperuricemic mice. Furthermore, WFA significantly prevented renal fibrosis and increased the expression of collagen-related proteins. Similarly, WFA markedly inhibited renal apoptosis, accompanied by changes of apoptosis-related proteins. Importantly, expression of transporters responsible for the secretion of organic anion transporter 1 (OAT1), OAT3, ATP-binding cassette subfamily G member 2 (ABCG2) was remarkably enhanced whereas that of urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) was reduced in renal tissues of mice with hyperuricemia. study revealed that WFA notably ameliorated UA-induced cell fibrosis and apoptosis. Taken together, WFA improves kidney function by decreasing UA via regulation of XOD and transporter genes in renal tubular cells.
Topics: Animals; Apoptosis; Disease Models, Animal; Fibrosis; Hyperuricemia; Kidney; Kidney Diseases; Male; Mice; Mice, Inbred C57BL; Oxonic Acid; Withanolides; Xanthine Oxidase
PubMed: 33517833
DOI: 10.1080/21655979.2021.1882761 -
The International Journal of Biological... May 2016To provide an assessment by meta-analysis of the relationship between the expression variations of 5-fluorouracil metabolic enzymes and clinical outcomes in patients... (Meta-Analysis)
Meta-Analysis Review
PURPOSE
To provide an assessment by meta-analysis of the relationship between the expression variations of 5-fluorouracil metabolic enzymes and clinical outcomes in patients with gastric cancer treated with S-1.
METHOD
Databases were searched electronically from inception to April 19th, 2015. Studies in gastric cancer patients treated with S-1 investigating the expression variations of 5-fluorouracil metabolic enzymes were included after having been identified systematically. Pooled odds ratios (OR) for the objective response rate (ORR) and median survival ratio were calculated using the Review Manager 5.3 and Stata 12.0 software separately.
RESULTS
A total of 555 patients in 10 studies met our inclusion criteria. There was a significant difference in ORR between patients with high/+ and low/- expression of orotate phosphoribosyl transferase (OPRT) (OR = 8.06; 95% CI, 4.06-16.02; p<0.001) and dihydropyrimidine dehydrogenase (DPD) (OR = 1.95; 95% CI, 1.21-3.13; p = 0.006). There was no significant difference in ORR between different expression levels of thymidylate synthase (TS) and thymidine phosphorylase (TP). Although patients with low/- TS expression, low/- TP expression and high/+ DPD expression showed a trend towards longer survival, no statistical significance was found. The median OS was significantly longer in patients with high/+ expression of OPRT (p = 0.076).
CONCLUSIONS
OPRT and DPD expression can be treated as a potential predictive biomarker for S-1 response in gastric cancer patients. Further investigation is warranted.
Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Drug Combinations; Fluorouracil; Humans; Orotate Phosphoribosyltransferase; Oxonic Acid; Stomach Neoplasms; Tegafur; Thymidine Phosphorylase; Thymidylate Synthase
PubMed: 27012156
DOI: 10.5301/jbm.5000202 -
The Oncologist 2011The product Teysuno™ (S-1) contains tegafur, a prodrug of 5-fluorouracil (5-FU), and two modulators of 5-FU metabolism, gimeracil and oteracil. The main clinical study... (Review)
Review
The European Medicines Agency review of Tegafur/Gimeracil/Oteracil (Teysuno™) for the treatment of advanced gastric cancer when given in combination with cisplatin: summary of the Scientific Assessment of the Committee for medicinal products for human use (CHMP).
The product Teysuno™ (S-1) contains tegafur, a prodrug of 5-fluorouracil (5-FU), and two modulators of 5-FU metabolism, gimeracil and oteracil. The main clinical study in this application was a randomized controlled study comparing S-1 plus cisplatin with 5-FU plus cisplatin. In this study, median overall survival times of 8.6 months and 7.9 months for S-1 plus cisplatin and 5-FU plus cisplatin, respectively, were observed (hazard ratio, 0.92; 95% confidence interval, 0.80-1.05). The Committee for Medicinal Products for Human Use of the European Medicines Agency concluded that S-1 in combination with cisplatin (75 mg/m²) was noninferior to 5-FU plus cisplatin (100 mg/m²) in patients with advanced gastric cancer and adopted a positive opinion recommending the marketing authorization for this product for the treatment of advanced gastric cancer when given in combination with cisplatin. The recommended dose of S-1 is 25 mg/m² (expressed as tegafur content) twice a day, for 21 consecutive days followed by 7 days rest (one treatment cycle), in combination with 75 mg/m² cisplatin i.v. administered on day 1. This treatment cycle is repeated every 4 weeks. The most common side effects reported in the pivotal study were anemia, neutropenia, vomiting, diarrhea, abdominal pain, weight decrease, anorexia, and fatigue. The objective of this paper is to summarize the scientific review of the application leading to approval in the EU. The full scientific assessment report and the summary of product characteristics are available on the European Medicines Agency website (http://www.ema.europa.eu).
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Drug Administration Schedule; Drug Approval; European Union; Humans; Oxonic Acid; Practice Guidelines as Topic; Pyridines; Randomized Controlled Trials as Topic; Stomach Neoplasms; Tegafur; Treatment Outcome
PubMed: 21963999
DOI: 10.1634/theoncologist.2011-0224 -
Medicine Dec 2018The present study aims to assess the efficacy and safety of S-1 plus cisplatin as concurrent chemoradiation (experimental group [EG]) compared with standard concurrent... (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
The present study aims to assess the efficacy and safety of S-1 plus cisplatin as concurrent chemoradiation (experimental group [EG]) compared with standard concurrent chemoradiation regimens (control group[CG]) in patients with local advanced non-small cell lung cancer.
METHODS
The Cochrane library, pubmed, and Ovid (elsevier) were retrieved. The included randomized controlled trials (RCT) were evaluated, and the statistical analysis was performed using RevMan 5.3 software. Cochrane handbook was applied to evaluate the methodological quality. Statistical significance was considered as P <.05.
RESULTS
There were 5 randomized control trials identified eligible for the meta-analysis. Meta-analysis of the pooled date suggested that overall survival (OS) (HR, 0.81; 95% CI, 0.58-1.13; P = .21, heterogeneity P = 1.00, I = 0%), progressives free survival (PFS) (HR, 0.82; 95% CI, 0.62-1.09; P = .18, heterogeneity P = .83, I = 0%) and 1,2,3-year OS (1-year OS: RR 1.03; 95% CI: 0.92-1.15, p = 0.59), (2-year OS: RR 1.14; 95% CI: 0.98-1.34, P = .09), (3 -year OS: RR 1.14; 95% CI: 0.90-1.44, P = .29) were not significantly different. The combination of S-1 and cisplatin had lower grade 3 or 4 leukocytopenia, neutropenia, (RR = 0.54, 95% CI: 0.38-0.75, P = .0003; RR = 0.23,95% CI: 0.14-0.36, P <.00001;, respectively). The rates of nausea, diarrhea, thrombocytopenia, pneumonitis, anorexia, anemia, febrile neutropenia were much the same in the 2 groups (RR = 1.35, 95% CI: 0.68-2.68, P = .38; RR = 1.85, 95% CI: 0.61-5.60, P = .28; RR = 1.67, 95% CI: 0.88-3.17, P = .12; RR = 1.19, 95% CI: 0.44-3.21, P = .73; RR = 1.35, 95% CI: 0.68-2.68, P = .38; RR = 0.86, 95% CI:0.55-1.34, P = .50; RR = 0.63, 95% CI:0.35-1.14, P = .13;, respectively).
CONCLUSIONS
This meta-analysis of 5 randomized control trails demonstrates that EG results similar OS, PFS, and 1,2,3-year OS, compared with CG, with lower risk of leukocytopenia, neutropenia.
Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cisplatin; Drug Combinations; Humans; Oxonic Acid; Radiotherapy; Randomized Controlled Trials as Topic; Tegafur
PubMed: 30557998
DOI: 10.1097/MD.0000000000013441 -
American Journal of Physiology. Renal... Oct 2008Endothelial dysfunction is a characteristic feature during the renal damage induced by mild hyperuricemia. The mechanism by which uric acid reduces the bioavailability...
Endothelial dysfunction is a characteristic feature during the renal damage induced by mild hyperuricemia. The mechanism by which uric acid reduces the bioavailability of intrarenal nitric oxide is not known. We tested the hypothesis that oxidative stress might contribute to the endothelial dysfunction and glomerular hemodynamic changes that occur with hyperuricemia. Hyperuricemia was induced in Sprague-Dawley rats by administration of the uricase inhibitor, oxonic acid (750 mg/kg per day). The superoxide scavenger, tempol (15 mg/kg per day), or placebo was administered simultaneously with the oxonic acid. All groups were evaluated throughout a 5-wk period. Kidneys were fixed by perfusion and afferent arteriole morphology, and tubulointerstitial 3-nitrotyrosine, 4-hydroxynonenal, NOX-4 subunit of renal NADPH-oxidase, and angiotensin II were quantified. Hyperuricemia induced intrarenal oxidative stress, increased expression of NOX-4 and angiotensin II, and decreased nitric oxide bioavailability, systemic hypertension, renal vasoconstriction, and afferent arteriolopathy. Tempol treatment reversed the systemic and renal alterations induced by hyperuricemia despite equivalent hyperuricemia. Moreover, because tempol prevented the development of preglomerular damage and decreased blood pressure, glomerular pressure was maintained at normal values as well. Mild hyperuricemia induced by uricase inhibition causes intrarenal oxidative stress, which contributes to the development of the systemic hypertension and the renal abnormalities induced by increased uric acid. Scavenging of the superoxide anion in this setting attenuates the adverse effects induced by hyperuricemia.
Topics: Aldehydes; Angiotensin II; Animals; Antioxidants; Arterioles; Body Weight; Cyclic N-Oxides; Disease Models, Animal; Glomerular Filtration Rate; Hypertension, Renal; Hyperuricemia; Kidney Glomerulus; Male; NADPH Oxidase 4; NADPH Oxidases; Oxidative Stress; Oxonic Acid; Rats; Rats, Sprague-Dawley; Renal Circulation; Spin Labels; Superoxides; Tyrosine
PubMed: 18701632
DOI: 10.1152/ajprenal.00104.2008 -
Annals of the Royal College of Surgeons... Apr 2017Introduction Radiotherapy is not commonly used for the treatment of gastric cancer in Japan, where surgery is the standard local treatment. We report the results of...
Introduction Radiotherapy is not commonly used for the treatment of gastric cancer in Japan, where surgery is the standard local treatment. We report the results of chemoradiotherapy in patients with advanced or recurrent gastric cancer which was deemed difficult to treat surgically. Methods Twenty-one patients with gastric cancer (including sixteen with advanced/recurrent gastric cancer and five with poor general condition) underwent chemo-radiotherapy, for whom the therapeutic efficacy, toxicity and survival period were analysed. Results The tumour response to chemoradiotherapy was categorised as complete, partial, stable or progressive in 5, 9, 3, and 4 patients, respectively, with an overall response rate of 67%. No serious complications such as gastrointestinal perforation or bleeding occurred, and no cardiac, hepatic or renal dysfunction developed during the follow-up period. The mean survival time was 19.8 months (range, 3-51 months). One patient died of another disease, 18 died of primary cancer and the cause of death was unknown in 2 patients. Conclusions Chemoradiotherapy appears to be an effective treatment for localised gastric cancer without distant metastases, but further studies are needed to determine the indications for chemoradiotherapy and late adverse effects, as well as the chemotherapy regimens to be used.
Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Chemoradiotherapy; Cisplatin; Drug Combinations; Female; Fluorouracil; Humans; Japan; Male; Neoplasm Recurrence, Local; Oxonic Acid; Radiotherapy, Conformal; Retrospective Studies; Stomach Neoplasms; Survival Rate; Tegafur
PubMed: 27659357
DOI: 10.1308/rcsann.2016.0305 -
Journal of B.U.ON. : Official Journal... 2020To explore the efficacy and safety of apatinib (an anti-angiogenic drug) combined with S-1 (a fluorouracil drug) in the third-line chemotherapy for advanced gastric...
PURPOSE
To explore the efficacy and safety of apatinib (an anti-angiogenic drug) combined with S-1 (a fluorouracil drug) in the third-line chemotherapy for advanced gastric cancer, and to analyze the factors influencing the prognosis.
METHODS
Eighty-four patients with advanced gastric cancer, who did not respond to second-line or above chemotherapy and were treated in our hospital were enrolled and divided into Apatinib+S-1 group (n=42) and S-1 group (n=42), based on different treatments applied. Next, the clinical responses and adverse reactions of patients were observed and recorded. The patients were followed up through the outpatient service and telephone to record their survival and disease progression. Additionally, the factors affecting the prognosis of patients were analyzed.
RESULTS
The objective response rate (ORR) and disease control rate (DCR) in the Apatinib+S-1 group were 9.5% (4/42) and 71.4% (30/42), respectively, which were significantly higher than those in the S-1 group. The main adverse reactions after therapy included neutropenia, thrombocytopenia, anemia, stomatitis, hypertension, proteinuria, hand-foot syndrome and gastrointestinal reaction, which were mostly of grade I-II. The incidence rates of hypertension, proteinuria and hand-foot syndrome were 42.9%, 26.2%, and 23.8%, respectively, in the Apatinib+S-1 group, which were overtly higher than those in the S-1 group. There was no statistically significant difference in the overall survival (OS) of patients between two groups (p=0.063), while the progression free survival (PFS) of patients was overtly longer in the Apatinib + S-1 group than that in S-1 group. Univariate analysis of PFS showed that the PFS of patients with high differentiation of tumor or post-treatment proteinuria or hand-foot syndrome was evidently higher than that of patients without high differentiation of tumor or post-treatment proteinuria or hand-foot syndrome.
CONCLUSION
Patients with advanced gastric cancer achieve relatively satisfactory short-term therapeutic effects after treatment with apatinib combined with S-1 in the third-line therapy, whose PFS is notably better than those treated with S-1 alone, and they are tolerant to adverse reactions. Highly differentiated tumors and post-treatment proteinuria and hand-foot syndrome are predictable factors for the PFS of patients.
Topics: Aged; Antimetabolites, Antineoplastic; Drug Combinations; Female; Humans; Male; Middle Aged; Oxonic Acid; Prognosis; Protein Kinase Inhibitors; Pyridines; Stomach Neoplasms; Tegafur
PubMed: 32521896
DOI: No ID Found -
Journal of B.U.ON. : Official Journal... 2021To investigate the clinical efficacy and safety of apatinib combined with tegafur-gimeracil-oteracil potassium (S-1) in the second-line treatment of advanced gastric...
PURPOSE
To investigate the clinical efficacy and safety of apatinib combined with tegafur-gimeracil-oteracil potassium (S-1) in the second-line treatment of advanced gastric cancer.
METHODS
A total of 126 patients with advanced gastric cancer admitted to our hospital from January 2017 to September 2018 were enrolled as the research objects, none of whom underwent surgery. For these patients, second-line treatment was recommended due to the failure of first-line treatment. According to the different therapeutic options, patients were categorized into S-1 group (n=63) and Apatinib group (S-1 combined with apatinib, n=63), and drugs were administered orally. The clinical efficacy, serological indicators, adverse reactions and immune function were compared between the two groups. Besides, the survival status of patients was recorded through follow-up.
RESULTS
In S-1 group and Apatinib group, the objective response rate (ORR) was 30.2% (19/63) vs. 50.8% (32/63) and the disease control rate (DCR) was 54.0% (34/63) vs. 74.6% (47/63), respectively. The results indicated that Apatinib group was superior to S-1 group in terms of ORR and DCR, suggesting statistically significant differences (p=0.018, p=0.016). Compared with those before treatment, the serum levels of carbohydrate antigen 19-9 (CA19-9), carcinoembryonic antigen (CEA), and tumor supplied group of factors (TSGF) in the two groups of patients were prominently reduced after treatment (p<0.05). After treatment, CA19-9 and TSGF levels were remarkably lower in Apatinib group than those in S-1 group (p=0.008, p=0.023), and there was no statistically significant difference in the CEA level between the two groups (p=0.057). After treatment, the quality of life of patients was improved notably in Apatinib group compared with that in S-1 group (p=0.002). Adverse reactions mainly involved hematological toxicity, nausea and vomiting, abnormal renal function, impairment of hepatic function, neurotoxicity, hypertension and hand-foot syndrome, most of which were in grade I-II and relieved after symptomatic treatment and could be tolerated for continued treatment. Serious adverse reactions in grade III-IV occurred rarely. No statistically significant difference was found in the incidence rate of adverse reactions between the two groups of patients (p>0.05). Besides, according to the follow-up results, median overall survival (OS) was 8.1 months vs. 10.7 months and median progression-free survival (PFS) was 4.2 months vs. 5.3 months, respectively, in S-1 group and Apatinib group. The results of log-rank test demonstrated that Apatinib group was superior to S-1 group with respect to OS, showing a statistically significant difference (p=0.028), and no statistically significant difference was found in PFS between the two groups of patients (p=0.159).
CONCLUSION
In the second-line treatment of advanced gastric cancer, apatinib combined with S-1 is superior to S-1 alone in term of clinical efficacy, and its adverse reactions can be tolerated. Apatinib combined with S-1 can prominently improve the quality of life, reduce the serum tumor marker levels and prolong the OS of patients, but it cannot extend the PFS.
Topics: Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Drug Combinations; Female; Humans; Male; Middle Aged; Neoplasm Staging; Oxonic Acid; Pyridines; Retrospective Studies; Stomach Neoplasms; Tegafur; Treatment Outcome
PubMed: 34268954
DOI: No ID Found -
World Journal of Surgical Oncology Apr 2021Adjuvant tegafur-gimeracil-oteracil (S-1) is commonly used for gastric cancer in Asia, and tegafur-uracil (UFT) is another oral fluoropyrimidine when S-1 is unavailable....
BACKGROUND
Adjuvant tegafur-gimeracil-oteracil (S-1) is commonly used for gastric cancer in Asia, and tegafur-uracil (UFT) is another oral fluoropyrimidine when S-1 is unavailable. The real-world data of adjuvant UFT has less been investigated.
METHODS
Patients with pathological stage II-IIIB (except T1) gastric cancer receiving adjuvant UFT or S-1 monotherapy after D2 gastrectomy were included. Usage of UFT or S-1 was based on reimbursement policy of the Taiwanese healthcare system. The characteristics, chemotherapy completion rates, and 5-year recurrence-free survival (RFS) and overall survival (OS), were compared between these two groups.
RESULTS
From 2005 to 2016, 86 eligible patients were included. Most tumor characteristics were similar between the UFT group (n = 37; age 59.1 ± 13.9 years) and S-1 group (n = 49; age 56.3 ± 10.7 years), except there were significantly more Borrmann type III/IV (86.5% versus 67.3%; p = 0.047) and T4 (56.8% versus 10.2%; p < 0.001) lesions in the UFT group than in the S-1 group. The chemotherapy complete rates were similar in the two groups. The 5-year RFS was 56.1% in the UFT group and 59.6% in the S-1 group (p = 0.71), and the 5-year OS was 78.3% in the UFT group and 73.1% in the S-1 group (p = 0.48). The hazard ratio of adjuvant chemotherapy (S-1 versus UFT) on RFS was 1.25 (95% confidence interval = 0.53-2.94) when Borrmann type and T and N stages were adjusted.
CONCLUSIONS
This small cohort study showed adjuvant UFT, and S-1 monotherapy had a comparable long-term outcome for pathological stage II-IIIB gastric cancer following D2 gastrectomy.
Topics: Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Cohort Studies; Disease-Free Survival; Drug Combinations; Female; Humans; Middle Aged; Neoplasm Staging; Oxonic Acid; Prognosis; Stomach Neoplasms; Tegafur; Treatment Outcome; Uracil
PubMed: 33865416
DOI: 10.1186/s12957-021-02233-2 -
Scientific Reports Jun 2020Although hyperuricemia has been shown to be associated with the progression of cardiovascular disorder and chronic kidney disease (CKD), there is conflicting evidence as...
Although hyperuricemia has been shown to be associated with the progression of cardiovascular disorder and chronic kidney disease (CKD), there is conflicting evidence as to whether xanthine oxidase (XO) inhibitors confer organ protection besides lowering serum urate levels. In this study, we addressed the cardio-renal effects of XO inhibition in rodent CKD model with hyperuricemia. Sprague-Dawley rats underwent 5/6 nephrectomy and received a uricase inhibitor oxonic acid for 8 weeks (RK + HUA rats). In some rats, a XO inhibitor febuxostat was administered orally. Compared with control group, RK + HUA group showed a significant increase in albuminuria and renal injury. Febuxostat reduced serum uric acid as well as urinary albumin levels. Histological and immunohistochemical analysis of the kidney revealed that febuxostat alleviated glomerular, tubulointerstitial, and arteriolar injury in RK + HUA rats. Moreover, in the heart, RK + HUA showed individual myofiber hypertrophy and cardiac fibrosis, which was significantly attenuated by febuxostat. We found that renal injury and the indices of cardiac changes were well correlated, confirming the cardio-renal interaction in this model. Finally, NF-E2-related factor 2 (Nrf2) and the downstream target heme oxygenase-1 (HO-1) protein levels were increased both in the heart and in the kidney in RK + HUA rats, and these changes were alleviated by febuxostat, suggesting that tissue oxidative stress burden was attenuated by the treatment. These data demonstrate that febuxostat protects against cardiac and renal injury in RK + HUA rats, and underscore the pathological importance of XO in the cardio-renal interaction.
Topics: Animals; Cardiotonic Agents; Disease Models, Animal; Febuxostat; Heart; Hyperuricemia; Kidney Diseases; Kidney Function Tests; Male; Myocardium; Nephrectomy; Oxidative Stress; Oxonic Acid; Protective Agents; Rats, Sprague-Dawley; Xanthine Oxidase
PubMed: 32518351
DOI: 10.1038/s41598-020-65706-6