Evaluating serum level of thymidylate synthase in post burn keloid patients before and after intralesional injection of 5-fluorouracil

Background Keloids are fibrous lesions formed at the site of trauma due to types I and III collagen irregular production. The presence of thymidylate synthase (TS) is a must for DNA synthesis and repairs causing cell death. 5-fluorouracil (5-FU) is a fluorinated pyrimidine analogue acting as an anti-metabolic agent that inhibits thymidylate synthase and interferes with ribo-nucleic acid (RNA) synthesis. Objectives we aimed to evaluate the level of thymidylate synthase in post burn keloid patients before and after intralesional injection of 5-fluorouracil. Methods The study included 20 keloid patients and 20 healthy subjects as a control. Serum TS was estimated using commercially available enzyme-linked immunosorbent assay (ELISA) kits before and after treatment with 5-fluorouracil. Results There was a statistically significant difference in TS levels before and after 5-FU treatment (p < 0.05). Also, results have shown that 5-FU injection has good satisfactory results in treatment of keloid causing reduction in scar volume and symptoms improvement (90% of the patients improved). On the other hand, there was no statistically significant difference in TS levels and the outcomes of the treatment. Conclusion Our findings suggest that intralesional 5-FU injection in keloid has very satisfactory results. However, thymidylate synthase enzyme has a minimal role in evaluating the treatment of keloid, so further studies are required to elaborate the relation between this enzyme and keloid scars.

Visfatin and Resveratrol Differentially Regulate the Expression of Thymidylate Synthase to Control the Sensitivity of Human Colorectal Cancer Cells to Capecitabine Cytotoxicity

Colorectal cancer (CRC) is a highly lethal malignant cancer. Capecitabine, a 5-fluororacil (5-FU) derivate, is its first-line drug, but the resistance of CRC to capecitabine is still the most challenging factor for curing patients. It has been suggested that thymidylate synthase (TYMS) level might affect the capecitabine efficacy in CRC patients, but the mechanism still needs more elucidation. Obesity is a risk factor for CRC. Recently, a correlation between serum visfatin, an obesity-elicited adipokine, and CRC development has been found. Thus, the aim of present study is to examine the visfatin capacity in TYMS expression and in the development of capecitabine resistance of CRC. Moreover, an attractive natural component, i.e., resveratrol, has been proposed in anticancer therapy and has hence been examined in the present study to see its potential capacity in the alleviation of CRC resistance. Our results found that visfatin significantly reduces the CRC sensitivity to capecitabine by controlling the TYMS expression via p38 signaling and Sp1 transcription factor. Moreover, resveratrol could significantly alleviate the visfatin effect on capecitabine-treated CRC cells. These results provided new insights to understand the capecitabine susceptibility of CRC under a visfatin-containing environment and a possible therapeutic application of resveratrol in CRC patients with obesity.

Synthesis and evaluation of vitamin-drug conjugate for its anticancer activity

Cancer is the uncontrolled growth of cells in the human body that has the ability to spread. The purpose of the study is to explore that vitamins can be used as a targeting moiety for new anticancer drugs to address issues like non-selectivity, systemic toxicity. 5-Fluorouracil acetic acid–Vitamin D3 (5FUAC-Vit.D3) conjugate has been synthesized, characterized, and evaluated for its anticancer activity. 5-FUAC-Vit.D3 conjugate was synthesized via esterification mechanism in the presence of N-Hydroxy succinimide (NHS) and 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (EDC) by using HCL as coupling agent. Formation of 5-FUAC-Vit.D3 conjugate via esteric bond and the structure of the compounds were confirmed by spectroscopic data, i.e., IR, NMR, and mass spectra. The docking studies showed that 5-FUAC-Vit.D3 conjugate interacted at Arg-215 and Lys-47 of the human thymidylate synthase proteins, through hydrogen bonding and ionic bonds respectively with a binding score of -8.614 which is higher than only 5-FU (-3.475). So, it was proved that forming 5-FUAC-Vit.D3 conjugate shows greater binding to the target protein.

Cardiotoxicity of Fluoropyrimidines: Epidemiology, Mechanisms, Diagnosis, and Management

Cancer is a growing public health problem; it is responsible annually for millions of deaths worldwide. Fluoropyrimidines are highly effective and commonly prescribed anti-neoplastic drugs used in a wide range of chemotherapy regimens against several types of malignancies. 5-fluorouracil and its prodrugs affect neoplastic cells in multiple ways by impairing their proliferation, principally through the inhibition of thymidylate synthase. Fluoropyrimidine-induced cardiotoxicity was described more than 50 years ago, but many details such as incidence, mechanisms, and treatment are unclear and remain disputed. Severe cardiotoxicity is not only life-threatening, but also leads to withdrawal from an optimal chemotherapy regimen and decreases survival rate. Differences in the frequency of cardiotoxicity are explained by different chemotherapy schedules, doses, criteria, and populations. Proposed pathophysiological mechanisms include coronary vasospasm, endothelial damage, oxidative stress, Krebs cycle disturbances, and toxic metabolites. Such varied pathophysiology of the cardiotoxicity phenomenon makes prevention and treatment more difficult. Cardiovascular disturbances, including chest pain, arrhythmias, and myocardial infarction, are among the most common side effects of this class of anti-neoplastic medication. This study aims to summarize the available data on fluoropyrimidine cardiotoxicity with respect to symptoms, incidence, metabolism, pathophysiological mechanism, diagnosis, management, and resistance.

In silico Repurposing of Anticancer Drug (5-Fluorouracil) as an Antibacterial Agent against Klebsiella pneumoniae

Background: Infections caused by drug resistant microorganisms have been increasing worldwide thereby being one of the major causes of morbidity in the 21st century. Klebsiella pneumoniae is one such bacteria causing lung inflammation, lung injury and death. Emergence of hyper-virulent and drug resistant species such as ESBL and CRKP has made this microbe a serious and urgent threat. The pace of emergence of these species is outgrowing the development of novel drug and vaccine candidates thereby focusing on drug repurposing approach. Objective: 1. Homology Modelling of Thymidylate Synthase. 2. Verification of Modelled Structure. 3. Molecular Docking. 4. Molecular Dynamic Simulation of Docked Complex. 5. In vitro analysis of 5-FU activity against Klebsiella pneumonia. Method: The 3-D structure of Thymidylate Synthase was predicted using Swiss-Model server and validated by in silico approaches. - Determination protein-protein interactions using STRING database. - Molecular docking. - MD simulations of 5-FU with predicted structure of thymidylate synthase. - In vitro antimicrobial drug sensitivity assay at different concentrations. Result: Hydrogen bond was observed in Molecular Docking - Protein-ligand complex remains stable during simulation. - 5-FU shows antimicrobial activity against Klebsiella pneumonia during In vitro study. Conclusion: Both In silico as well as in vitro analysis have indicated that 5-FU can potentially be developed as an antimicrobial agent towards Klebsiella pneumonia