• Clear cell renal cell carcinoma
• FOXM1
• Immunity
• Immunotherapy
• Prognosis

• YJXYY202204-YSB36 Jiangsu Provincial Research Hospital

• Polymorphisms
• SNPs
• chemotherapy
• colorectal cancer
• hypersensitivity
• toxicity

• Biomarker
• Gene expression
• Transcriptomics

• Daphnia/genetics
• Daphnia/drug effects
• Daphnia/metabolism
• Animals
• Copper/toxicity
• Zinc/toxicity
• Water Pollutants, Chemical/toxicity
• Transcriptome/drug effects
• Gene Expression Profiling
• Daphnia magna

• Örebro University

The two common methylenetetrahydrofolate reductase (MTHFR) polymorphisms 677G>A and 1298A>C may have been affecting 5-FU toxicity in cancer patients for decades. Drug efficacy has also been shown by previous studies to be affected. In this study, we investigated the effects of these polymorphisms on 5-FU hematological toxicity and treatment efficacy, to provide enhanced pharmacological treatment for cancer patients.

This is a retrospective study involving 52 Thai colorectal cancer patients who were treated with 5-FU based therapy, using TaqMAN real-time PCR to genotype the MTHFR polymorphisms (677G>A and 1298A>C). The toxicity and response rate were assessed using standardized measures.

Neutropenia was significantly more likely to be experienced (P=0.049, OR=7.286, 95% CI=0.697-76.181) by patients with the MTHFR 677G>A polymorphism, in the same way as leukopenia (P =0.036, OR=3.333, 95%CI=2.183-5.090) and thrombocytopenia (P<0.001, OR=3.917, 95%CI=2.404-6.382). The MTHFR 1298A>C polymorphism had no statistical association with hematological toxicity in 5-FU treatment. The response rate to 5-FU was not significantly affected by these two polymorphisms.

The MTHFR polymorphism 677G>A is a significant risk factor for developing leukopenia, neutropenia and thrombocytopenia as toxic effects of 5-FU therapy in cancer patients. Therefore, patients receiving 5-FU-based therapy should be aware of their polymorphisms as one risk factor for experiencing severe toxicity.

• Thymidylate Synthase/metabolism
• Thymidylate Synthase/genetics
• Fluorouracil/pharmacology
• Colorectal Neoplasms/drug therapy
• Colorectal Neoplasms/metabolism
• Colorectal Neoplasms/pathology
• Colorectal Neoplasms/genetics
• Humans
• N-Acetylglucosaminyltransferases/metabolism
• N-Acetylglucosaminyltransferases/genetics
• Animals
• Mice
• Apoptosis/drug effects
• Cell Line, Tumor
• Antimetabolites, Antineoplastic/pharmacology
• Protein Processing, Post-Translational/drug effects
• Xenograft Model Antitumor Assays
• Glycosylation/drug effects
• Pyrans
• Thiazoles

• Case-Control Studies
• Colonic Neoplasms
• Colorectal Neoplasms/drug therapy
• Colorectal Neoplasms/genetics
• Fluorouracil
• Genetic Predisposition to Disease
• Genotype
• Humans
• Methylenetetrahydrofolate Reductase (NADPH2)/genetics
• Polymorphism, Single Nucleotide/genetics

New approaches to assessing the “enzyme–ligand” complementarity, taking into account hydrogens, have been proposed. The approaches are based on the calculation of three-dimensional maps of the electron density of the receptor–ligand complexes. The action of complementarity factors, first proposed in this article, has been demonstrated on complexes of human dihydrofolate reductase (DHFR) with ligands. We found that high complementarity is ensured by the formation of the most effective intermolecular contacts, which are provided due to predominantly paired atomic–atomic interactions, while interactions of the bifurcate and more disoriented type are minimized. An analytical docking algorithm based on the proposed receptor–ligand complementarity factors is proposed.

• 3D maps of electron density
• complementarity
• dihydrofolate reductase
• docking

The overall efficacy of neoadjuvant chemoradiotherapy (NACT) for locally advanced gastric cancer (LAGC) has been recognized. However, the response rate of NACT is limited due to tumor heterogeneity. For patients who are resistant to NACT, not only the operation timing will be postponed, patients will also suffer from the side effects of it. Thus, it is important to develop a comprehensive strategy and screen out patients who may be sensitive to NACT. This article summarizes the related research progress on the sensitivity prediction of NACT for GC in the following aspects: microRNAs, metabolic enzymes, exosomes, other biomarkers; inflammatory indicators, and imageological assessments. The results showed that there were many studies on biomarkers, but no unified conclusion has been drawn. The inflammatory indicators are related to the survival and prognosis of patients under NACT. For imageological assessments such as CT, MRI, and PET, with careful integration and optimization, they will have unique advantages in early screening for patients who are sensitive to NACT.

• biomarkers
• gastric cancer
• imageological assessments
• inflammatory indicators
• neoadjuvant chemotherapy

• AlteQ approach
• DHFR activity
• DHFR-ligand complexes
• Electron density
• quantum theory of atoms

Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme influencing the metabolism of fluoropyrimidines. The relevance of MTHFR polymorphisms with the clinical response to fluoropyrimidine-based chemotherapy has been explored, but the results remain controversial. Thus, a meta-analysis was performed to provide a comprehensive estimate in this account. Relevant studies were identified through PubMed, Embase and Web of Science databases from inception up to May 2017. Odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were applied to assess the strength of association. A total of 2118 colorectal cancer patients from 21 studies were included in the meta-analysis. Overall, there was no significant association between MTHFR C677T (rs1801133) or A1298C (rs1801131) polymorphisms and the clinical response to fluoropyrimidine-based chemotherapy under all of the three genetic models (allele model, dominant model, and recessive model) and stratification analysis, except for the retrospective study subgroup in the dominant model of MTHFR C677T and the “5-Fu + FA” treatment group in the allele contrast of MTHFR A1298C. No or moderate heterogeneity was observed in all genetic models. This meta-analysis suggested that MTHFR polymorphisms could not be considered as reliable factors for predicting the clinical response to fluoropyrimidine-based chemotherapy in colorectal cancer patients.

• MTHFR
• chemotherapy response
• fluoropyrimidine
• meta-analysis
• polymorphism

• Colorectal cancer
• one-carbon metabolism
• polymorphisms
• survival

• R01 CA189184 NIH HHS
• U01CA206110 NIH HHS
• R01 CA207371 NIH HHS
• R01 CA207371 NCI NIH HHS

In colorectal cancer chemotherapy, the current standard of care includes combination therapy with 5-fluorouracil (5-FU) and leucovorin (LV). However, the factors that determine the LV-mediated enhancement of 5-FU antitumor activity are not fully understood. Therefore, we investigated the roles of thymidine synthase (TYMS), folate receptor 1 (FOLR1), dihydrofolate reductase (DHFR), phosphoribosylglycinamide formyltransferase (GART), methylenetetrahydrofolate dehydrogenase (MTHFD1), and methylenetetrahydrofolate reductase (MTHFR) in LV-mediated enhancement of 5-fluoro-2′-deoxyuridine (FdUrd) cytotoxicity in vitro as a model of 5-FU antitumor activity. These genes were downregulated in DLD-1 and HCT116 human colorectal cancer cells by using small-interfering RNA. Reduced expression of TYMS mRNA significantly increased FdUrd cytotoxicity by 100- and 8.3-fold in DLD-1 and HCT116 cells, respectively. In contrast, reducing the expression of FOLR1, DHFR, GART, MTHFD1, and MTHFR decreased FdUrd cytotoxicity by 2.13- to 12.91-fold in DLD-1 cells and by 3.52- to 10.36-fold in HCT116 cells. These results demonstrate that folate metabolism is important for the efficacy of FdUrd. Overall, the results indicate that it is important to clarify the relationship between folate metabolism-related molecules and 5-FU treatment in order to improve predictions of the effectiveness of 5-FU and LV combination therapy.

Capecitabine, a fluoropyrimidine prodrug, has been a frequently chosen ligand for the last one and half decades to inhibit thymidylate synthase (TYMS) for treatment of colorectal cancer. TYMS is a key enzyme for de novo synthesis of deoxythymidine monophosphate and subsequent synthesis of DNA. Recent years have also seen the trait of modifying ligands using halogens and trifluoromethyl (–CF₃) group to ensure enhanced drug performance. In this study, in silico modification of capecitabine with Cl, Br, I atoms and –CF₃ group has been performed. Density functional theory has been employed to optimize the drug molecules and elucidate their thermodynamic and electrical properties such as Gibbs free energy, enthalpy, electronic energy, dipole moment and frontier orbital features (HOMO–LUMO gap, hardness and softness). Flexible and rigid molecular docking have been implemented between drugs and the receptor TYMS. Both inter- and intra-molecular non-covalent interactions involving the amino acid residues of TYMS and the drug molecules are explored in details. The drugs were superimposed on the resolved crystal structure (at 1.9 Å) of ZD1694/dUMP/TYMS system to shed light on similarity of the binding of capecitabine, and its modifiers, to that of ZD1694. Together, these results may provide more insights prior to synthesizing halogen-directed derivatives of capecitabine for anticancer treatment.

• Antimetabolites, Antineoplastic/therapeutic use
• Breast Neoplasms/drug therapy
• Breast Neoplasms/genetics
• Female
• Humans
• Methotrexate/therapeutic use
• Methylenetetrahydrofolate Reductase (NADPH2)/genetics
• NAD(P)H Dehydrogenase (Quinone)/genetics
• Neoplasm Staging
• Polymorphism, Single Nucleotide
• Treatment Outcome

• 3' Untranslated Regions
• 5' Untranslated Regions
• Adult
• Aged
• Aged, 80 and over
• Alleles
• Allelic Imbalance
• Female
• Fluorouracil/therapeutic use
• Genotype
• Humans
• Leukocytes, Mononuclear
• Male
• Middle Aged
• Neoplasms/drug therapy
• Neoplasms/genetics
• Polymorphism, Genetic
• Thymidylate Synthase/biosynthesis
• Thymidylate Synthase/genetics

Resistance to 5-fluorouracil (5-FU), an important anticancer drug, is a serious challenge in the treatment of pancreatic cancer. Equilibrative nucleoside transporter 1 and multidrug-resistance protein (MRP) 5 and MRP8, rather than P-glycoprotein, play important roles in 5-FU transport. Thymidylate synthase, dihydropyrimidine dehydrogenase, methylenetetrahydrofolate reductase and thymidine phosphorylase are four key enzymes involved in 5-FU metabolism. Other metabolic enzymes, including uridine monophosphate synthetase, also contribute to chemoresistance. Intracellular signaling pathways are an integrated network, and nuclear factor kappa-light-chain-enhancer of activated B cells, AKT and extracellular signal-regulated kinases are signaling pathways that are particularly relevant to 5-FU resistance. In addition, recent reports indicate that STAT-3 is a crucial survival protein. Proteomic assays provide a powerful tool for identifying target proteins and understanding the role of microRNAs and stromal factors to facilitate the development of strategies to combat 5-FU resistance.

• 5-fluorouracil
• Resistance
• Transporters
• Metabolic enzyme
• Signaling pathway
• Stromal factors
• MicroRNA
• Proteomic investigation

• Animals
• Antimetabolites, Antineoplastic/metabolism
• Antimetabolites, Antineoplastic/therapeutic use
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Apoptosis/drug effects
• Apoptosis/genetics
• Cell Cycle/drug effects
• Cell Cycle/genetics
• Cell Proliferation/drug effects
• Cell Proliferation/genetics
• DNA Repair/drug effects
• DNA Repair/genetics
• Drug Resistance, Neoplasm/drug effects
• Drug Resistance, Neoplasm/genetics
• Fluorouracil/metabolism
• Fluorouracil/therapeutic use
• Gene Expression Regulation, Enzymologic
• Gene Expression Regulation, Neoplastic
• Humans
• Membrane Transport Proteins/genetics
• Membrane Transport Proteins/metabolism
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Pancreatic Neoplasms/drug therapy
• Pancreatic Neoplasms/genetics
• Pancreatic Neoplasms/metabolism
• Pancreatic Neoplasms/pathology
• Proteomics/methods

• 5-fluorouracil
• MTHFR polymorphism
• clinical trial
• folate
• pharmacogenetics
• rectal cancer
• survival
• toxicity

• Adult
• Aged
• Aged, 80 and over
• Disease-Free Survival
• Female
• Fluorouracil/administration & dosage
• Folic Acid
• Genetic Association Studies
• Genetic Predisposition to Disease
• Glycine Hydroxymethyltransferase/genetics
• Humans
• Male
• Methylenetetrahydrofolate Reductase (NADPH2)/genetics
• Middle Aged
• Pharmacogenetics
• Polymorphism, Single Nucleotide
• Rectal Neoplasms/genetics
• Rectal Neoplasms/pathology
• Reduced Folate Carrier Protein/genetics
• Thymidylate Synthase/genetics

• U10 CA046113 NCI NIH HHS
• CA58882 NCI NIH HHS
• U10 CA32102 NCI NIH HHS
• R01 CA105145 NCI NIH HHS
• U10 CA032102 NCI NIH HHS
• N01 CA038926 NCI NIH HHS
• U10 CA180888 NCI NIH HHS
• U10 CA180819 NCI NIH HHS
• U10 CA058882 NCI NIH HHS
• CA46113 NCI NIH HHS
• U10 CA038926 NCI NIH HHS

Methylentetrahydrofolate reductase (MTHFR) plays a major role in folate metabolism and consequently could be an important factor for the efficacy of a treatment with 5-fluorouracil. Our aim was to evaluate the prognostic and predictive value of two well characterized constitutional MTHFR gene polymorphisms for primarily resected and neoadjuvantly treated esophagogastric adenocarcinomas.

569 patients from two centers were analyzed (gastric cancer: 218, carcinoma of the esophagogastric junction (AEG II, III): 208 and esophagus (AEG I): 143). 369 patients received neoadjuvant chemotherapy followed by surgery, 200 patients were resected without preoperative treatment. The MTHFR C677T and A1298C polymorphisms were determined in DNA from peripheral blood lymphozytes. Associations with prognosis, response and clinicopathological factors were analyzed retrospectively within a prospective database (chi-square, log-rank, cox regression).

Only the MTHFR A1298C polymorphisms had prognostic relevance in neoadjuvantly treated patients but it was not a predictor for response to neoadjuvant chemotherapy. The AC genotype of the MTHFR A1298C polymorphisms was significantly associated with worse outcome (p = 0.02, HR 1.47 (1.06-2.04). If neoadjuvantly treated patients were analyzed based on their tumor localization, the AC genotype of the MTHFR A1298C polymorphisms was a significant negative prognostic factor in patients with gastric cancer according to UICC 6^th edition (gastric cancer including AEG type II, III: HR 2.0, 95% CI 1.3-2.0, p = 0.001) and 7^th edition (gastric cancer without AEG II, III: HR 2.8, 95% CI 1.5-5.7, p = 0.003), not for AEG I. For both definitions of gastric cancer the AC genotype was confirmed as an independent negative prognostic factor in cox regression analysis. In primarily resected patients neither the MTHFR A1298C nor the MTHFR C677T polymorphisms had prognostic impact.

The MTHFR A1298C polymorphisms was an independent prognostic factor in patients with neoadjuvantly treated gastric adenocarcinomas (according to both UICC 6^th or 7^th definitions for gastric cancer) but not in AEG I nor in primarily resected patients, which confirms the impact of this enzyme on chemotherapy associated outcome.

• Antineoplastic Combined Chemotherapy Protocols/adverse effects
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Camptothecin/adverse effects
• Camptothecin/analogs & derivatives
• Camptothecin/therapeutic use
• Female
• Fluorouracil/adverse effects
• Fluorouracil/therapeutic use
• Glucuronosyltransferase/genetics
• Humans
• Irinotecan
• Male
• Methotrexate/adverse effects
• Methotrexate/therapeutic use
• Methylenetetrahydrofolate Reductase (NADPH2)/genetics
• Neoplasms/drug therapy
• Neoplasms/genetics
• Pharmacogenetics
• Polymorphism, Genetic
• Sensitivity and Specificity
• Toxicogenetics

• Genetic polymorphisms
• Methylenetetrahydrofolate reductase
• Saudi
• hypertension

• Antimetabolites, Antineoplastic/therapeutic use
• Colorectal Neoplasms/drug therapy
• Colorectal Neoplasms/genetics
• Czech Republic
• Disease-Free Survival
• Ferredoxin-NADP Reductase/genetics
• Fluorouracil/therapeutic use
• Genotype
• Humans
• Methylenetetrahydrofolate Reductase (NADPH2)/genetics
• Polymorphism, Genetic

• Antimetabolites, Antineoplastic/adverse effects
• Antimetabolites, Antineoplastic/pharmacokinetics
• Antimetabolites, Antineoplastic/therapeutic use
• Dihydrouracil Dehydrogenase (NADP)/genetics
• Dihydrouracil Dehydrogenase (NADP)/metabolism
• Fluorouracil/adverse effects
• Fluorouracil/pharmacokinetics
• Fluorouracil/therapeutic use
• Humans
• Methylenetetrahydrofolate Reductase (NADPH2)/genetics
• Methylenetetrahydrofolate Reductase (NADPH2)/metabolism
• Polymorphism, Genetic
• Thymidine Phosphorylase/genetics
• Thymidine Phosphorylase/metabolism
• Thymidylate Synthase/genetics
• Thymidylate Synthase/metabolism

• Antineoplastic Agents/pharmacology
• Apoptosis/drug effects
• Blotting, Western
• Cell Line, Tumor
• Cell Proliferation/drug effects
• Cell Separation
• Cyclooxygenase 2/drug effects
• Cyclooxygenase 2/metabolism
• Cyclooxygenase Inhibitors/pharmacology
• Enzyme-Linked Immunosorbent Assay
• Flow Cytometry
• Fluorouracil/pharmacology
• HT29 Cells
• Humans
• Indomethacin/pharmacology
• Methylenetetrahydrofolate Dehydrogenase (NADP)/genetics
• Microscopy, Fluorescence
• Nitrobenzenes/pharmacology
• Polymorphism, Genetic
• Reverse Transcriptase Polymerase Chain Reaction
• Sulfonamides/pharmacology
• Thymidylate Synthase/genetics

• 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase/genetics
• Adolescent
• Child
• Child, Preschool
• Female
• Ferredoxin-NADP Reductase/genetics
• Folic Acid/genetics
• Folic Acid/metabolism
• Genetic Predisposition to Disease
• Glycine Hydroxymethyltransferase/genetics
• Humans
• Infant
• Infant, Newborn
• Male
• Membrane Transport Proteins/genetics
• Methylenetetrahydrofolate Reductase (NADPH2)/genetics
• Nicotinamide N-Methyltransferase/genetics
• Polymorphism, Restriction Fragment Length
• Polymorphism, Single Nucleotide
• Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics
• Reverse Transcriptase Polymerase Chain Reaction
• Risk Factors
• Thymidylate Synthase/genetics

The activity of dihydropyrimidine dehydrogenase (DPD), the key enzyme of pyrimidine catabolism, is thought to be an important determinant for the occurrence of severe toxic reactions to 5-fluorouracil (5-FU), which is one of the most commonly prescribed chemotherapeutic agents for the treatment of solid cancers. Genetic variation in the DPD gene (DPYD) has been proposed as a main factor for variation in DPD activity in the population. However, only a small proportion of severe toxicities in 5-FU based chemotherapy can be explained with such rare deleterious DPYD mutations resulting in severe enzyme deficiencies. Recently, hypermethylation of the DPYD promoter region has been proposed as an alternative mechanism for DPD deficiency and thus as a major cause of severe 5-FU toxicity.

Here, the prognostic significance of this epigenetic marker with respect to severe 5-FU toxicity was assessed in 27 cancer patients receiving 5-FU based chemotherapy, including 17 patients experiencing severe toxic side effects following drug administration, none of which were carriers of a known deleterious DPYD mutation, and ten control patients. The methylation status of the DPYD promoter region in peripheral blood mononuclear cells was evaluated by analysing for each patient between 19 and 30 different clones of a PCR-amplified 209 base pair fragment of the bisulfite-modified DPYD promoter region. The fragments were sequenced to detect bisulfite-induced, methylation-dependent sequence differences.

No evidence of DPYD promoter methylation was observed in any of the investigated patient samples, whereas in a control experiment, as little as 10% methylated genomic DNA could be detected.

Our results indicate that DYPD promoter hypermethylation is not of major importance as a prognostic factor for severe toxicity in 5-FU based chemotherapy.

• Adult
• Age Factors
• Age of Onset
• Aged
• Carcinoma/genetics
• Case-Control Studies
• Female
• Gallbladder Neoplasms/genetics
• Gene Frequency
• Genetic Predisposition to Disease
• Humans
• Male
• Methylenetetrahydrofolate Reductase (NADPH2)/genetics
• Middle Aged
• Polymorphism, Single Nucleotide/physiology
• Risk Factors
• Sex Factors