5-fluorouracil Research Articles

Phenoxodiol sensitizes metastatic colorectal cancer cells to 5-fluorouracil- and oxaliplatin-induced apoptosis through intrinsic pathway.

Colorectal cancer (CRC) is one of the most common types of cancer seen in the world. 5-Fluorouracil (5-Fu) plus Oxaliplatin (1-OHP) remains the backbone of CRC chemotherapeutics, but with limited success. Phenoxodiol (Pxd) is an isoflavone analog with antitumor activity against various types of cancers, and sensitizes chemoresistant cancer cells to chemotherapeutics including platinum and taxanes. This study was, therefore, undertaken to examine whether Pxd pre-treatment with conventional chemotherapeutic agent(s) 5-Fu and 1-OHP co-administration be a therapeutic strategy for CRC. Cell viability and cytotoxicity were evaluated using dimethyl-thiazolyl diphenyl tetrazolium bromide (MTT) and lactate dehydrogenase assays. The percentage of apoptotic and necrotic cells were determined by fluorescence microscopy analysis. Besides, active Caspase-3 levels by ELISA and relative mRNA levels of Caspase 3 (CASP3), CASP8 and CASP9 genes were determined by quantitative real-time PCR (qPCR) analysis. The pre-treatment of Pxd followed by 5-Fu and 1-OHP co-administration was more effective at inhibiting cell viability than either chemotherapeutic agents treatment alone. When compared to 5-Fu with 1-OHP alone treatment, Pxd pre-treatment overwhelmingly increased apoptotic Caspase-3 activity levels in CRC cells. Moreover, qPCR analyses showed that CASP3 and CASP9 mRNA levels significantly increased after pre-treatment with Pxd followed by 5-Fu and 1-OHP treatments, compared to 5-Fu with 1-OHP alone. Our results suggested that Pxd enhanced the in vitro antitumor activity of 5-Fu and 1-OHP. Our study also suggested that Pxd may be a potential candidate agent in advanced CRC and inclusion of Pxd to the conventional chemotherapeutic agent(s) could be an effective therapeutic strategy for CRC.

Rat corneal endothelial cell migration during wound repair on the basement membrane depends more on the PI-3K pathway than the cdc-42 pathway or actin stress fibers.

Following a central transcorneal circular freeze injury, organ-cultured rat corneal endothelial cells surrounding the wound reorganize peripheral actin bands into stress fibers and migrate individually into the wound. To ascertain the significance of this rearrangement relative to morphological changes accompanying migration and wound repair, some tissues were incubated overnight in 4μM TRITC-conjugated phalloidin to stabilize actin and prevent its reorganization. After a freeze injury to the endothelium tissues were histologically observed at 24h post-wounding and demonstrated that despite a lack of actin organization, cells responding to the injury appeared morphologically similar to their control counterparts. Tissues cultivated in the presence of either cytochalasin B (CB), soybean agglutinin (SBA), or fluorouracil (FU) and also exhibited actin cytoskeletal disruption. Under these conditions, migration continued despite the absence of detectable stress fibers. For SBA-, CB-, and FU-treated tissues, wound repair did not significantly differ from control preparations although FU-treated tissues showed a slower repair. Electron micrographs confirmed an absence of stress fibers in migrating cells treated with any of these agents. Tissues were also treated with ML 141 and EY294002 to inhibit the cdc-42 and PI-3K pathways, respectively. While cell movement still occurred in the presence of ML 141, migration into the wound was greatly restricted in the presence of EY294002. These results indicate that rat corneal endothelial cell movement in situ does not require actin reorganization into stress fibers, but the functioning of the PI-3K pathway is indispensable for their migration along the basement membrane during wound repair.

Gelatin–rosin gum complex nanoparticles: preparation, characterization and colon targeted delivery of 5-fluorouracil

Gelatin-rosin gum complex nanoparticles (GGRNPs) have been synthesized by complex coacervation method. The particles were extensively characterized using Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), field emission scanning electron microscopy (FESEM), and particle size analysis based on dynamic light scattering (DLS). The GGRNP3 were stable and their average particle size was ~ 153 nm. GGRNPs were evaluated as the carrier matrix for 5-fluoro uracil (5-FU), and the release behavior of 5-FU was examined by swelling and in vitro dissolution tests in simulated gastrointestinal fluid (SGF) for first 2 h followed by 14 h in simulated intestinal fluid (SIF). About 71% drug release was witnessed (SGF = 21%; SIF = 50%) over a time span of 16 h, in contrast to native gelatin or rosin gum where under identical conditions the release exhausted within 7 h and 10 h, respectively. The release profile followed the first-order kinetics and the diffusion exponent (n) values obtained from the Korsemeyer−Peppas model ranged between 0.5 < n < 0.8 (both in SGF and SIF), which indicated non-Fickian diffusion mechanism. A549 cell line was used to carry out MTT assay test for investigating the cell toxicity of the drug-loaded GGRNP3 (D GGRNP3) where DGGRNP3 exhibited greater toxicity as compared to GGRNP3.

Synthesis, COX-2 inhibition and metabolic stability studies of 6-(4-fluorophenyl)-pyrimidine-5-carbonitrile derivatives as anticancer and anti-inflammatory agents

In continuation of previous work on cyanopyrimidine derivatives for cancer and inflammation, eighteen novel amino containing cyanopyrimidine derivatives (4a-p) bearing secondary or tertiary amines and alkyl-thio substitution were synthesized by Biginelli condensation reaction followed by nucleophilic substitution reaction. Two compounds 4 g (NSC: 795,754) and 4o (NSC: 798,988) showed excellent anticancer potency against most of the cell lines. Compound 4 g was selected for five dose-assays and the result of tested compound was given by three response parameters i.e. GI50, TGI and LC50 for each cell line. Compound 4 g exhibited superior anticancer activity against ovarian cancer with GI50-value of 0.33 μM and selectivity index of 4.84 in comparison to 5-fluoro uracil (5-FU) which exhibited GI50-value 4.43 μM. During in-vivo anti-inflammatory study, compound 4 g exhibited 87 % inhibition of inflammation at 3 h which was found superior to the standard drugs ibuprofen (78 %) and celecoxib (52 %). The compounds 4 g and 4o exhibiting both anticancer and anti-inflammatory potential were further studied for their biological target studies and in-vitro metabolic stability assessment. The result showed that compounds 4 g and 4o displaying broad anticancer activity were more selective towards COX-2 as compared to COX-1.

Submicron Particles of Double Network Alginate/Polyacrylamide Hydrogels for Drug Delivery of 5-fluorouracil

The purpose of this study was to prepare a double network (DN) hydrogel made with sodium-alginate (Na-alg) natural polysaccharide and polyacrylamide (PAM) chains that targets control release of anticancer drug. To this aim, the entitled submicron particles of double network hydrogels exhibit exceptional properties. A two-step strategy was used to obtain alginate/PAM hydrogels crosslinked by Ca2+ cations and N,N'-methylenebisacrylamide (MBA) as different types of crosslinker. Particles of DN alginate / PAM were employed for entrapping and releasing the model drug 5-fluorouracil as an anticancer drug. Scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), dynamic light scattering (DLS), swelling properties, drug entrapment efficiency and drug release studies were also done. The particles showed porous structure, good swelling ability and aqueous dispersibility with a size in range of 280 nm. The resulting hydrogel subsequently loaded with 5-fluorouracil and released patterns carried in 7.4 pH and 5.8 pH at temperature of 37 oC. The controlled drug release behavior was noticed and the finding of the study suggested that the Alginate/PAM double network hydrogels is a promising carrier for 5-fluorouracil delivery.

Chemoprevention of keratinocyte carcinoma and actinic keratosis in solid-organ transplant recipients: Systematic review and meta-analyses

To the Editor: Skin cancers account for 40% of malignancies in solid-organ transplant recipients (SOTRs), who have an 80-fold increased risk of squamous cell carcinoma (SCC) and a 16-fold increased risk of basal cell carcinoma (BCC). Systemic chemoprevention is one method to mitigate this amplified risk. Acitretin, for instance, has been used to prevent keratinocyte carcinomas (KC) and actinic keratoses (AK) in SOTRs since 1995,1Bavinck J.N. Tieben L.M. Van der Woude F.J. et al.Prevention of skin cancer and reduction of keratotic skin lesions during acitretin therapy in renal transplant recipients: a double-blind, placebo-controlled study.J Clin Oncol. 1995; 13: 1933-1938Crossref PubMed Google Scholar but its adverse effects include mucositis, liver and lipid abnormalities, and teratogenicity.2George R. Weightman W. Russ G.R. et al.Acitretin for chemoprevention of non-melanoma skin cancers in renal transplant recipients.Australas J Dermatol. 2002; 43: 269-273Crossref PubMed Scopus (130) Google Scholar Nicotinamide, an amide form of vitamin B3, is a newer chemoprophylaxis with fewer adverse effects.3Chen A.C. Martin A.J. Dalziell R.A. et al.A phase II randomized controlled trial of nicotinamide for skin cancer chemoprevention in renal transplant recipients.Br J Dermatol. 2016; 175: 1073-1075Crossref PubMed Scopus (61) Google Scholar Here we report results of a pairwise and network meta-analyses to summarize the current evidence regarding chemoprevention. We selected studies that analyzed the efficacy of systemic chemoprevention to prevent KC/AK in patients who are SOTRs or have a history of 2 or more KCs, or both. We limited our search to placebo-controlled, randomized control trials (RCTs) that reported the number of new KC/AK in both arms. Two authors (L.Y.T., S.Y.C.T.) independently conducted the literature search, screened titles and abstracts for eligibility, and extracted data. Statistical synthesis was performed with RevMan 5.3 software (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark). After the literature search, 6 RCTs with 734 patients were included in the quantitative synthesis (Appendix A, available via Mendeley at https://doi.org/10.17632/m6z2fzkkxn.2). Of the 6 RCTs, 3 studies with 580 patients (range, 17-192 patients) compared nicotinamide to placebo, and 3 studies with 154 patients (range, 19-35 patients) compared acitretin to placebo. Pairwise meta-analysis of all 6 RCTs using a random-effects model demonstrated a significant risk reduction with chemoprevention (Fig 1). The overall mean difference was 0.855 (95% confidence interval, 0.365-1.345; P < .001). In addition, acitretin and nicotinamide were both efficacious, with a combined mean difference of 0.792 (95% confidence interval, 0.298-1.286; P = .00168) for acitretin and a combined mean difference of 4.239 (95% confidence interval, 0.611-7.866; P = .0220) for nicotinamide. A network meta-analysis comparing nicotinamide and acitretin found no significant difference between the 2 treatments (Fig 2, Appendix B).Fig 1Forest plot of the pairwise meta-analysis of randomized controlled trials. The squares indicate the mean difference and are proportional to the weights used in the meta-analysis. The horizontal lines represent the 95% confidence interval (CI). The diamond indicates the weighted mean difference, and the lateral tips of the diamond indicate the associated 95% CI.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Fig 2Network graph and league table of the network meta-analysis. Mean differences and 95% confidence intervals are calculated using a random-effects model. A mean difference >1 means the top-left treatment is better.View Large Image Figure ViewerDownload Hi-res image Download (PPT) This meta-analysis does not address the optimal dosages of the drugs or the frequency of adverse effects. In addition, owing to the limited numbers of eligible RCTs, we are unable to investigate how chemoprevention is influenced by the duration or type of transplantation, duration of systemic chemoprevention, or existing immunosuppressive regimens. Moving forward, topical chemoprevention may be a suitable alternative to systemic chemoprophylaxis in SOTRs. Notably, large RCTs have evaluated topical chemoprevention for actinic keratosis. For instance, the Veterans Affairs Keratinocyte Carcinoma Chemoprevention trial found that topical 5% 5-fluorouracil cream resulted in a 49% relative risk reduction in the number of AK after 6 months and reduced the risk of SCC requiring surgery by 75% after 1 year but did not lower the risk of BCC.4Hyemin P. Hogan D. Eilers D. et al.Long-term efficacy of topical fluorouracil cream 5% for treating actinic keratosis: a randomized clinical trial.JAMA Dermatol. 2015; 151: 952-960Crossref PubMed Scopus (69) Google Scholar,5Weinstock M.A. Thwin S.S. Siegel J.A. et al.Chemoprevention of basal and squamous cell carcinoma with a single course of fluorouracil, 5%, cream: a randomized clinical trial.JAMA Dermatol. 2018; 154: 167-174Crossref PubMed Scopus (54) Google Scholar To our knowledge, this is the first meta-analysis that statistically integrates the current evidence regarding chemoprevention of KC/AK. This study demonstrates that systemic chemoprevention with nicotinamide or acitretin is effective in lowering the risk of KC/AK. Yet, even with the advent of better chemoprevention, regular physician surveillance and sun protection are still key basic strategies that should be practiced by all SOTRs.

Peeling with 70% glicolic acid followed by 5% 5-fluorouracil as well as 5% 5-fluorouracil cream are effective methods for the treatment of actinic keratoses on upper limbs: A randomized clinical trial.

The 5% 5-fluorouracil (5-FU) cream, considered the gold standard topical treatment, and peeling using 70% glycolic acid (GA) followed by 5% 5-FU are methods for the treatment of actinic keratoses (AKs). However, the comparison of these two treatments had not yet been described and therefore was the objective of this study. A randomized clinical trial, intrapatient study in which 17 patients received a type of treatment in the right and left upper limb with 5% 5-FU cream (twice daily) or a peeling application of 70% GA (every 15 days) followed by 5% 5-FU cream. There was a significant reduction of 75% and 85.71% in the mean number of AK lesions and of 74.5% and 85.71% in the size of lesions on the upper limbs of patients treated with peeling and 5% 5-FU cream (P-value ≤.001), respectively. Neither treatment was superior to the other since there was no significant difference (P-value ≥.05) between the treatments, both at the post-intervention period as well as when comparing the difference between the pre and post-intervention periods. The peeling with 70% GA followed by 5% 5-FU as well as 5% 5-FU cream are effective methods for the treatment of AKs on upper limbs.

Erratum: In situ Delivery of Thermosensitive Gel-Mediated 5-Fluorouracil Microemulsion for the Treatment of Colorectal Cancer [Corrigendum

[This corrects the article DOI: 10.2147/DDDT.S111351.].

Fluorouracil and doxorubicin - cardiotoxic cytostatics in the workplace

The aim of the study is to analyze the potential occupational hazards of fluorouracil (FU) and doxorubicin (DOX). The literature review was based on factual and bibliographic scientific databases of the available peer-reviewed journals and the so-called gray literature. In Poland, the process of determining the acceptable levels of occupational exposure for selected anticancer drugs has been underway since 2014, and the basis for determining the maximum allowable concentration values is usually the concentration equivalent to 0.1% of the lowest therapeutic dose found in the literature. In addition, uncertainty coefficients are used, which take into account the mechanism of action of the cytostatics, the dynamics of metabolism, the assessment of classification and labeling for carcinogenic, mutagenic, genotoxic, reproductive toxicity, organ toxicity, the ability to accumulate cytostatics, the assessment of cumulative effects with other cytostatics, the physicochemical form and data completeness. Where possible, the risk of additional cancer is estimated. Directive 2004/37/EC on the protection of workers from the risks related to exposure to carcinogens at work (the carcinogens and mutagens directive ‒ CMD) is a key legal solution in the field of public health in the European Union, focused on the issue of occupational cancer. These cytostatics, FU and DOX, are genotoxic and are classified as hazardous. Life-threatening heart damage is a serious side effect of both FU and DOX. The analysis has shown that the inclusion of dangerous drugs in the list of substances subject to the requirements of the CMD is completely justified. The cytostatics classification and labeling procedure should be harmonized throughout the European Union, which will ensure a reliable and credible risk management in this area. Med Pr. 2020;71(3):363-73.

Local recurrence of clinically observed basal cell carcinomas following complete saucerization or punch removal with negative margins: Retrospective case series from 2010 to 2020

Local recurrence of clinically observed basal cell carcinomas following complete saucerization or punch removal with negative margins: Retrospective case series from 2010 to 2020

Structural characterization of 5-fluorouracil & piperazine new solid forms and evaluation of their antitumor activity

A salt (FP–S) and two co-crystals (FP–C1 and FP-C2) of fluorouracil (FU) with piperazine (PZ) were investigated in terms of bioavailability and their effect on endothelial cells. From structural point of view, the best stability was observed for FP-C2 sample obtained by storage of FP-C1 sample under extreme conditions of temperature and humidity. This result was explained by the strong intermolecular interactions between 5-fluorouracil, piperazine and water, as denoted by the crystallographic analysis of FP-C2 form. Dissolution measurements in water indicate that the most soluble form is the salt, with a dissolution rate about 3 times greater than for the fluorouracil pure compound, while the solubility for co-crystals decreases compared to FU. Toxicity and antitumoral effect of the synthesized compounds were checked on three different cell lines: normal cells (HUVEC endothelial cells) and tumor cells (DLD-1 and HT29, both colorectal adenocarcinoma) and cytotoxicity by the MTT assay and cell proliferation assay. It has been found that the FP-C1 exerts a selective cytotoxic effect on HT29 cells and FP-C2 on DLD-1 cells in contrast to normal endothelial cell line resistance. For FU and FP-S salt, the effect on normal and tumoral cells is similar. The comparative study of the three fluorouracil forms shows that the best antitumor selective response was obtained for the co-crystal forms.

MONARCC: A randomized phase II study of panitumumab monotherapy and panitumumab (pan) plus 5 Fluorouracil (FU) as first-line therapy for RAS and BRAF wild type metastatic colorectal cancer (mCRC): An AGITG clinical trial.

TPS271 Background: Pan added to combination chemotherapy is established first-line therapy for RAS and BRAF wild type mCRC. Elderly patients are not well represented in clinical trials and may be more suited to treatment protocols with lower toxicity risks; FU plus bevacizumab (bev) is commonly used. Treatment related efficacy, toxicity, impact on quality of life and other outcomes of pan based regimens in an elderly population have not been well studied. Methods: A prospective non-comparative randomized phase 2 study. Australian Clinical Trials Registry Number: ACTRN 12618000233224. Main inclusion criteria include: Untreated patients aged 70 years or older; RAS and BRAF wild type; ECOG performance 0-2. Randomisation 1:1, stratified by primary tumour side, performance status, number of metastatic sites; to pan 6mg/kg 2 weekly or panitumumab plus FU 400 mg/m² bolus; leucovorin 200mg/m²; FU 2400mg/m² 48 hour infusion 2 weekly. Primary endpoint is 6-month progression-free survival (PFS). Sample size is 80 patients based on expected 6-month PFS rate of 73% with FU and bev. Using the method of Metha-Cain, if 24 or more patients are progression free at 6 months, the one sided 95% confidence interval includes 73% and we declare similar activity. Secondary endpoints include overall survival; toxicity and overall treatment utility, a composite measure of treatment benefit based on radiology, clinical progress, toxicity and patient reflection of the impact of treatment on their daily lives. Patients undergo a comprehensive health assessment at baseline and limited health assessment at 4 months. Physical activity trackers are worn for 2 weeks at treatment commencement and again at week 16. Tumour tissue and blood samples (at baseline, cycle 3 day 1 and at 24 weeks) will be collected for translational research. First site opened in June 2018. Twelve patients have been recruited to date from 9 sites in Australasia. Eighteen sites were open as at September 2019. Clinical trial information: 12618000233224.

Phase II study of fluorouracil (FU), leucovorin (LV), and nanoliposomal irinotecan (nal-IRI) in previously treated advanced biliary tract cancer (NAPOLI-2).

TPS593 Background: Biliary tract cancers (BTCs) are rare and aggressive malignancies. The current standard of care for advanced BTC is gemcitabine (GEM) plus cisplatin . Although there is no established second-line treatment, regimens such as FOLFOX, XELOX, FOLFIRI, XELIRI, GEM, and capecitabine have activity. Nal-IRI contains IRI free base encapsulated in liposome nanoparticles which shelter IRI from conversion to its active metabolite (SN-38) and increase intratumoral levels of SN-38 compared with IRI. FU/LV/nal-IRI has shown overall survival benefit and acceptable toxicity in patients (pts) with metastatic pancreatic adenocarcinoma following GEM-based therapy in the NAPOLI-1 trial. Methods: This is a single arm, open label, multicenter phase II study of pts with advanced BTC previously treated with gemcitabine plus platinum chemotherapy. Pts will receive nal-IRI 70 mg/m2 IV over 90 minutes, LV 400 mg/m2 IV over 30 minutes, and FU 2400 mg/m2 over 46 hours, every 14 days. The primary objective is to determine progression-free survival (PFS) rate at 4 months (4mo) using RECIST v. 1.1 criteria and central radiology review. Response assessments will occur using imaging every 8 weeks. All pts who receive at least 1 dose of the study treatment will be eligible for the primary analysis. We will substitute pts who screen fail or do not begin treatment. Median PFS reported for pts receiving second-line 5-FU doublet chemotherapy is 3 months with a PFS4mo of 30%. FU/LV/nal-IRI would be of interest if it could increase the PFS4mo to 50% or higher. We will use a 2-stage Simon Minimax design. Using a one-sided α of 0.05 and 80% power, 39 pts will be required to detect a difference in PFS4mo between 30% and 50%. Assuming a dropout rate of 10%, 44 pts will be enrolled across the 5 study sites. Enrollment began in Q2 2019. Clinical trial information: NCT04005339.

Polyurethane-based hydrogels for controlled drug delivery applications

The aim of this paper was to prepare polyurethane-based hydrogels for the controlled release of 5-fluoro uracil. The polyurethane containing azomethine linkage in the main chain was prepared using different diisocyanates such as HDI, LDI or IPDI. A melamine-based amine compound has been used to synthesize polyurethane and this compound has wide range applications. The hydrogels were prepared by using polyurethanes and chitosan for the first time literature and the chemical structure and morphology were also investigated. Wettability, water uptake performance, in-vitro biodegradation, mechanical strength, thermal stability, protein absorption, and antibacterial properties were also evaluated. In the presence of LDI in the structure of the hydrogels, wettability, thermal stability, mechanical strength, in-vitro biodegradation rate and protein absorption performance of the hydrogels were enhanced. Moreover, drug loading and release application of the hydrogels were carried out and LDI containing hydrogels has higher 5-FU loading and release capacity than the other hydrogels.

左亚叶酸钙、5-氟尿嘧啶联合表柔比星对胃癌患者应激反应及VEGF水平的影响

Objective To investigate the effects of calcium levofolinate and 5-fluorouracil combined with epirubicin on stress response and vascular endothelial growth factor (VEGF) level in patients with gastric cancer. Methods A total of 160 patients with gastric cancer treated in Huxi Hospital Affiliated to Jining Medical College from April 2016 to March 2018 were selected as research objects. All the patients were divided into two groups according to the random number table method and each group consisted of 80 cases. The control group was treated with epirubicin, while the study group was treated with calcium levofolinate and 5-fluorouracil combined with epirubicin. The clinical efficacy and adverse reactions of the two groups were observed and compared. The levels of VEGF and quality of life were compared before and after the treatment. The stress response indexes such as cortisol (Cor), norepinephrine (NE) and total antioxidant capacity (TAC) were detected, and the stress levels of the two groups were compared. Results The total effective rate of the study group was 67.5% (54/80), which was significantly better than that of the control group [45.0% (36/80)], and the difference was statistically significant (χ2=8.229, P=0.004). The quality of life of the two groups after the treatment was significantly higher than that before the treatment, and the quality of life scores of the study group were significantly higher than those of the control group (all P<0.001). After the treatment, the levels of Cor, NE and TAC of the study group were (239.27±19.63) μg/L, (258.46±18.31) ng/L, (11.01±0.77) KIU/L, which were significantly lower than those of the control group [(286.35±20.63) μg/L, (294.18±21.95) ng/L, (12.73±1.58) KIU/L], and the differences were statistically significant (t=10.003, P<0.001; t=9.476, P<0.001; t=6.984, P<0.001). After the treatment, the VEGF levels of the two groups were lower than those before the treatment, and the VEGF level of the study group was significantly lower than that of the control group [(39.4±0.9) pg/ml vs. (42.3±1.1) pg/ml, t=18.251, P<0.001]. The total incidences of adverse reactions in the control group and the study group were 82.5% (66/80) and 48.8% (39/80), respectively. The incidence of adverse reactions in the control group was significantly higher than that in the study group, and the difference was statistically significant (χ2=20.197, P<0.001). Conclusion Calcium levofolinate and 5-fluorouracil combined with epirubicin has a good clinical effect in treating patients with gastric cancer. It can not only improve the level of VEGF in the serum of patients, but also can improve the quality of life of patients, reduce the incidence of adverse reactions and body stress response. It has broad application prospects and is worthy of further promotion and application in clinic. Key words: Stomach neoplasms; Vascular endothelial growth factors; Stress response; Epirubicin; Calcium levofolate

Experimental study on the efficacy and toxicity of intraperitoneal injection of 5-fluorouracil to treat PDX model of pseudomyxoma peritonei

Objective To evaluate the efficacy and toxicity of intraperitoneal injection of 5-fluorouracil (5-Fu) in patient derived xenograft (PDX) model of pseudomyxoma peritonei (PMP). Methods One PMP tumor from surgery was used to establish PMP PDX models, which were equally randomized into control (no treatment), vehicle (normal saline, 0.2 ml) and treatment (5-Fu, 50 mg/kg, 0.2 ml) groups. Experimental peritoneal cancer index (ePCI) score, body weight, and pathological examination were performed to evaluate the efficacy and toxicity. Results PDX models replicating human PMP were established and diagnosed as high grade mucinous carcinoma peritonei with signet ring cells. Average ePCI score of treatment group was significantly lower than control and vehicle groups [(0.9±1.2) points vs. (3.6±1.7) points vs. (2.7±1.1) points, F=9.253, P<0.01]. Histopathological study revealed obvious tumor necrosis and reduced signet ring cells in the treatment group. The Ki-67 label index of treatment group was significantly lower than control group and vehicle group [(57.3±15.1)% vs. (72.2±15.1)% vs. (70.0±14.0)%, F=4.923, P<0.05]. The body weight of treatment group was significantly lower than control group and vehicle group [(19.7±2.8) g vs. (22.7±1.8) g vs. (21.9±1.7) g, F=4.654, P<0.05]. Major toxicities in the treatment group were animal death (10.0%), congestive splenomegaly (88.9%), lymphocyte accumulation (77.8%), bile canaliculus hyperplasia and obstruction (22.2%), cholestasis (100.0%), and acidophilic body (55.6%) in the liver. Conclusion In the PDX model of human PMP, intraperitoneal injection of 5-Fu could inhibit tumor proliferation and progression, with lowered ePCI score and reduced Ki-67, and toxicity was mainly on liver. Key words: Pseudomyxoma peritonei; PDX model; 5-Fluorouracil; Intraperitoneal injection; Organ toxicity

Relationship between epithelial cell adhesion molecule and wingless/integrated-β-catenin signaling in colon cancer and the effect of XAV939 on the expression of related markers

Objective To investigate whether activation of Wingless/integrated-β-catenin (Wnt-β-catenin) pathway regulates epithelial cell adhesion molecule (EpCAM) expression in colon cancer and analyze the effect of XAV939 on colon cancer-associated markers. Methods After Wnt-β-catenin signaling was activated, relative expression levels of related genes were determined by quantitative real-time polymerase chain reaction (RT-qPCR). After constructing a mouse colon cancer model, XAV939 and/or 5-Fu were intraperitoneally injected for 1 week. Detection of related molecules expression in colon tissue by Western blotting. Results Compared with the control group, LiCl could significantly stimulate the expression of Wnt-β-catenin signaling pathway genes, and the levels of TACSTD1, DKK1, BAMBI, CCND1 and MYC genes were significantly increased by 1.20-, 2.44-, 4.34-, 2.57-, 1.58 fold (t=12.179, 20.661, 54.378, 19.384, 20.341, P<0.05), respectively. ZnCl2 treatment significantly inhibited the expression of TACSTD1 and CCND1 in HCT116 cells (tTACSTD1=36.467, 9.682, tCCND1=16.130, 17.003, P<0.05), which were down-regulated by about 50.06% and 34.38%, respectively. In the APC gene-deficient cells, the inhibitory effect of ZnCl2 on TACSTD1 and CCND1 was reversed. XAV939 and XAV939+ 5-fluorouracil (5-Fu) treatment significantly up-regulated the expression of Axin in HCT116 cells, which was about 15.97 and 17.2 fold higher than that of the control group (t=19.502, 18.236, P<0.05); and expression of β-catenin, EpCAM, telomerase reverse transcriptase (TERT) and bicorticosteroids and calmodulin dependent protein kinase-like 1 (DCAMKL-1) were down-regulated by 0.75 and 0.72 fold, 0.68 and 0.25 fold, 0.74 and 0.73 fold, 0.27 and 0.34 fold (tβ-catenin=20.412, 22.862, tEpCAM=26.336, 27.111, 82.711, tTERT=19.636, 22.787, 23.678, tDCAMKL-1=81.637, 64.814, P<0.05), respectively. Conclusion XAV939 inhibits tumor cell proliferation by blocking Wnt-β-catenin signaling down-regulation of β-catenin, target gene EpCAM and other related factors of CSC to promote colon cancer prognosis. Key words: Wingless/Integrated-β-catenin pathway; Epithelial cell adhesion molecule; XAV939; Colon cancer

Role of Nuclear Factor Erythroid 2-Related Factor 2 (NRF-2) Mediated Antioxidant Response on the Synergistic Antitumor Effect of L-Arginine and 5-Fluro Uracil (5FU) in Breast Adenocarcinoma.

Breast adenocarcinoma (BAC) in glandular tissue cells have excessive metastasis and invasion capability. The major challenges for the chemotherapy used for the management of BAC include chemoresistance and auto-immunosuppression in BAC. The 5-fluro uracil (5-FU) based therapy promotes the immune activation in BAC by targeting the regulatory T cells and myeloid-derived suppressor cells (MDSC). The beneficial effect of the combination of L-Arginine with 5-FU strives to be established in different pre-clinical and clinical conditions and explored in the scientific literature. L-Arginine induces NO production and potentiates the anticancer effect of 5-FU. NO-mediated signaling is regulated by nuclear factor erythroid 2-related factor 2 (NRF-2) mediated antioxidant response. NRF-2 mediated antioxidant mechanism always suppresses the formation of superoxide (O2-) as well as other reactive oxygen species (ROS). Thus the utilization of NO by O2- will be minimum in this combination therapy. The regulatory role of NRF-2 in regulation to Antioxidant Response Element (ARE) mediated cytoprotective gene expression in BAC remains unexplored. The present review summarizes the role of NRF-2 mediated antioxidant response on the synergistic antitumor effect of L-Arginine and 5-FU in BAC. This review brought new insight into the management of BAC and in the same context, a hypothesis is raised on the use of reduced glutathione (GSH) or N-Acetyl Cysteine as it may be an added adjuvant in the combination of 5- FU and L-Arginine for management of BAC.

Efficacy and safety of Yangzheng Xiaoji capsule combined with radiotherapy and chemotherapy in the treatment of gastric cancer and its influence on immune function

Objective To explore the efficacy and safety of Yangzheng Xiaoji capsule combined with radiotherapy and chemotherapy in the treatment of gastric cancer and its influence on immune function. Methods From October 2016 to October 2018, 80 patients with gastric cancer in the First People's Hospital of Yongkang were divided into two groups according to the random number table, with 40 cases in each group.The control group received conventional radiotherapy plus chemotherapy, namely oxaliplatin, 5-fluorouracil combined with calcium leucovorin conventional chemotherapy.The observation group received Yangzheng Xiaoji capsule on the basis of the control group.The clinical symptoms, objective tumor efficacy, TCM symptoms and signs score, safety, immune function of the two group were observed. Results The total effective rate of the observation group was 87.5%, which was significantly higher than 72.5% of the control group(χ2=3.52, P 0.05), and there were statistically significant differences in WBC, Hb and PLT of the control group before and after treatment(t=4.85, 3.64, 3.85, all P 0.05). There were no statistically significant differences in the levels of CD3＋, CD4＋, CD8＋, CD4＋/CD8＋ of the observation group before and after treatment(t=2.14, 2.08, 1.69, 2.47, all P>0.05), and compared with before treatment, the levels of CD3＋, CD4＋, CD4＋/CD8＋ of the control group were significantly decreased(t=5.12, 4.26, 5.38, all P<0.05), while the level of CD8＋ was significantly increased(t=3.86, P<0.05). After treatment, the levels of CD4＋, CD4＋, CD8＋, CD4＋/CD8＋ of the observation group were significantly better than those of the control group (t=4.79, 3.52, 4.28, 3.61, all P<0.05). Conclusion Yangzheng Xiaoji capsule combined with radiotherapy and chemotherapy can improve the curative effect of patients with gastric cancer, and it has high safety, less toxic and side effects, and can improve the immune function of patients with gastric cancer.It is worthy of promoting. Key words: Stomach neoplasms; Radiotherapy; Antineoplastic combined chemotherapy protocols; Medicine, Chinese Traditional; Signs and symptoms; Safety; Immunity; Comparative effectiveness research

Prognostic value and clinical significance of carbohydrate antigen 125 and carcinoembryonic antigen expression in patients with colorectal carcinoma

Objective To investigate the clinical guiding effect of carbohydrate antigen 125 (CA125) and carcinoembryonic antigen (CEA) on chemotherapy in patients with stage T 4 colorectal cancer after operation. Methods 100 patients with stage T 4 colorectal cancer were analyzed retrospectively. Log-rank test was used to analyze the effects of age, sex, CA125, carbohydrate antigen 199 (CA199), CEA expression and capecitabine plus oxaliplatin (XELOX) and oxaliplatin, leucovorin and 5-fluorouracil (FOLFOX) regimen chemotherapy on the survival time of patients, and the relationship between them was analyzed. Results Log-rank analysis showed that CA125 and CEA expression, and XELOX and FOLFOX chemotherapy regimen had an effect on the survival of patients. The prognosis of patients with rectal cancer with high expression level of CA125 was poor, the median overall survival (OS) was 1 084 days in the patients with high expression of CA125 vs. 1 477 days in the patients with low expression (χ2=4.399, P 0.05). However, in patients with high expression of CA125 or (and) CEA, the median OS in patients treated with XELOX regimen was 951 days vs.1 520 days with FOLFOX chemotherapy regimen (χ2=7.077, P<0.01). Conclusion The expression of CA125 and CEA has an effect on the prognosis of patients with colorectal cancer. In the patients with normal expression of CA125 or/and CEA, there is no significant difference in the survival time between the patients treated with FOLFOX chemotherapy and XELOX chemotherapy, but the efficacy of FOLFOX chemotherapy is better than that of XELOX chemotherapy in patients with high expression of CA125 or/and CEA. Key words: Carbohydrate antigen 125; Carcinoembryonic antigen; Overall survival; Colorectal carcinoma