Enhancement Of Thymidylate Synthase Inhibition

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Transient inhibition of DNA synthesis by 5-fluorodeoxyuridine

ate synthase ternary complex (2, 3). In addition, exposure of cells to fluoropyrimidines before antifolates results in antag- onism (4) due to cessation of thymidylate synthesis with the consequent failure to accumulate dihydrofolate polygluta- mates and reduce the level of cellular tetrahydrofolate cofac- tors (5).

CDK inhibitor enhances the sensitivity to 5-fluorouracil in

The target enzyme of 5-FU is thymidylate synthase (TS). TS is a folate-dependent enzyme that is essential for DNA synthesis and DNA repair. TS often functions as an oncogene (2) and inhibition of the TS reaction results in the cessation of cellular proliferation and growth. Thus, TS represents an important target for cancer chemotherapy


some very signifi cant rate enhancement. The enzyme OMP decarboxylase (EC fulfi lls this life-critical function, enhancing the rate of OMP decar-boxylation by some 10 17-fold, so that the reaction half-life of the enzyme-catalyzed reaction (0.018 seconds) displays the rapidity necessary for living

Mechanism of Cell Death following Thymidylate Synthase

strongly suggests that growth inhibition following thymidylate synthase inhibition is mediated through an increase in intracellular dill', leading to uracil misincorporation into DNA, its subsequent excision, and result ant strand breakage. INTRODUCTION TS2 is a key enzyme of DNA synthesis and therefore a prime target for cancer chemotherapy.

Agent, ZD9331: A Water-Soluble, Nonpolyglutamatable

based inhibitors of thymidylate synthase (TS) that are trans-ported into cells via a saturable, carrier-mediated system (reduced folate carrier, or RFC) but are not substrates for folylpolygiutamate synthetase. ZD9331 is the y-tetrazole an-alogue of 2-desamino-2,7-dimethyl-N #{176}-propargyl-2 fluoro-

Sequential treatment with SN-38 followed by 5-fluorouracil

the enhancement of apoptotic cell death by this sequential treatment. This synergism was observed in 4 out of 5 SCLC cell lines tested. The effects of 5-FU and SN-38 on thymidylate synthase (TS) protein expression, an important determinant of 5-FU sensitivity, were assessed by Western blot analysis in H69 cells. Treatment with SN-38 for 24 h

MLH1 Deficiency Enhances Radiosensitization with 5

Jun 05, 2008 5 -monophosphate (FdUMP), which is a potent inhibitor of thymidylate synthase (TS) resulting in depletion of dTTP and subsequently inhibition of DNA synthesis. Previous studies have determined that the radiosensitizing effect of FdUrd correlates with dTTP depletion but is not dependent on cytotoxicity (Davis et al., 1995).

Research Article Solubility Enhancement of Synthesized

of action of drug mainly involves the inhibition of thymidylate synthase receptor that prevents the growth of cancerous cells.8The evaluation of toxic action of the synthesized compound is very important prior to formulation and toxicity test on animal models is a key stage to ensure the safer dose of the compound. Acute


Inhibition of BRCA2 and Thymidylate Synthase Creates Multidrug Sensitive Tumor Cells via the Induction of Combined Complementary Lethality Mateusz Rytelewski1,2, Peter J Ferguson2,3, Saman Maleki Vareki1,2, Rene Figueredo2, Mark Vincent2,3 and James Koropatnick1 5

Intracellular quantitative detection of human thymidylate

cells that ectopically express a human thymidylate synthase (hTS) enzyme engineered to sustain the FRET-based monitoring of hTS-inhibitor binding at the cell lysate level. 1University of Modena and Reggio Emilia, Department of Life Sciences, Via Giuseppe Campi 183, Modena, 41125, Italy.

Enhancement of anti-tumor effects of 5-fluorouracil on

its anti-tumor effects through the inhibition of RNA/ DNA processing and thymidylate synthase [4]. In recent years, 5-FU proved to be beneficial in treating advanced HCC in the FOLFOX4 regimen (including infusional 5-FU, leucovorin, and oxaliplatin), which increased the overall survival of HCC patients by 1.47 months [5].

Pemetrexed Disodium: A Novel Antifolate Clinically Active

and raltitrexed, inhibition of thymidylate synthase (TS) is the primary mechanism of action [13, 14] (Fig. 2). TS, a folate-dependent enzyme, catalyzes the transformation of deoxyuri-dine monophosphate to deoxythymidine monophosphate. Inhibition of TS results in a decrease in the available thymi-dine necessary for DNA synthesis leading to a

Enhancement of 5-Fluorouracil cytotoxicity by Pyridoxal 5

Jun 01, 2018 tetra hydro pteroylglutamate (CH2-H4PteGlu) in amounts required to improve inhibition of thymidylate synthase by 5-fluorouracil (FUra) through ternary complex stabilization. The hypothesis relates to the low affinity for cofactor of the PLP-dependent serine hydroxymethyl transferase (SHMT), the enzyme that

Antisense Thymidylate Synthase Electrogene Transfer to

diolabeled iododeoxyuridine; thymidylate synthase inhibitor J Nucl Med 2004; 45:478 484 I ododeoxyuridine (IdUrd) is a halogenated thymidine an-alog that competes with thymidine in the biosynthesis of DNA. Cytotoxicity is dependent on its cellular uptake, activation, and subsequent incorporation into DNA (1,2).

RESEARCH ARTICLE Open Access Prognostic significance of 5

thymidylate synthase (TS), which is the enzyme that cat-alyzes the methylation of deoxyuridine monophosphate to deoxythymodine monophosphate, by forming a stable ternary complex with methylene tetrahydrofolate, and the ternary complex leads to the inhibition of DNA syn-thesis [7,8]. Several studies in some cancers including

Elevation of Thymidylate Synthase following 5-Fluorouracil

The inhibition of thymidylate synthase (TS) by the 5-fluorouraciI (5FU) metabolite 5-fluorodeoxyuridine monophosphate can be biochem ically modulated by leucovorin (LV). LV administration increases the level of reduced folates in tissues, which promotes the inhibition of TS. We have studied the antitumor effect, free 5-fluorodeoxyuridine mono-

dUTPase inhibition confers susceptibility to a thymidylate

metabolites. Thymidylate synthase (TS) is the rate‐ limiting enzyme in the conversion of dUMP to dTMP and is responsible for de novo dTTP synthesis. The primary mode of action of 5 ‐FU is believed to be the inhibition of TS, which is mediated by the formation of a ternary complex of 5 ‐fluoro‐2ʹ‐deoxyuridine 5ʹ‐monophosphate

Cornelia Mihai, Ph.D. Curriculum Vitae EDUCATION

Dynamics and Quantum Mechanical Tunneling in w.t. E. coli Thymidylate Synthase , The 12th Biocatalysis and Bioprocessing Conference, University of Iowa, Iowa City, October 27-29, 2003. 3. Nitish Agrawal, Baoyu Hong, Cornelia Mihai, and Amnon Kohen. Enzyme Dynamics and Quantum Mechanical Tunneling in w.t. E. coli Thymidylate Synthase ,

Promotion of Purine Nucleotide Binding to Thymidylate

inhibition of thymidylate synthase (TS; EC, greatly enhances not only the binding of 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP) and dUMP to Escherichia coli TS but also that of dGMP, GMP, dIMP, and IMP. Guanine nucleotide binding was first detected by CD analysis, which revealed a unique spectrum for the TS-dGMP-U89 ternary

Capsaicin Acts Through Reducing P38 MAPK-Dependent

capsaicin, 5-fluorouracil, thymidylate synthase, p38 MAPK, non-small cell lung cancer Received: November 13th, 2020; Accepted: January 15th, 2021. Non-small cell lung cancer (NSCLC) accounts for most lung cancer related deaths worldwide1,2 and 80% of all lung cancer cases.3 Thymidylate synthase (TS), a therapeutic target of

Glycogen Synthase Kinase 3β Inhibitor (2'Z,3'E)-6-Bromo

cytometry. The protein expressions of P-glycoprotein (P-gp), multidrug resistance protein 2 (MRP2), thymidylate synthase (TS), β-catenin, E2F-1 and Bcl-2 were detected by Western blot. β-catenin and P-gp were stained with double immunofluorescence and observed under a confocal microscope.

Adjuvant Chemotherapy for Colon Cancer

antitumor activity of 5-FU through enhancement of the inhibition of thymidylate synthase (7, 8). To evaluate the efficacy of the combination of 5-FU and LV as adjuvant therapy, the National Surgical Adjuvant Breast and Bowel Projects (NSABP) trialists compared a regimen of weekly 5-FU plus high-dose LV (5-FU/LV) to a 5-FU/


Thymidylate Synthase, 255 P-Hydroxydecanoyl Thioester Dehydratase, 260 y-Aminobutyrate Aminotransferase, 262 Kinetics of Slow-Binding and Tight-Binding Inhibition, 268 Slow Binding, 268 Tight Binding, 269 Slow-Binding Inhibition, 270 Dihydrofolate Reductase, 271 Prostaglandin H Synthase, 274 Tight-Binding Inhibition, 280 HMG-CoA Reductase, 280

PERSPECTIVE Inhibition of protein crystallization by

Inhibition of protein crystallization by evolutionary negative design Jonathan P K Doye, Ard A Louis and Michele Vendruscolo University Chemical Laboratory, Lensfield Road, Cambridge CB2 1EW, UK E-mail: [email protected], [email protected] and [email protected] Received 2 October 2003 Accepted for publication 18 December 2003 Published 12 February 2004

A Phase 1 Clinical Trial of Sequential Pralatrexate Followed

ductase and thymidylate synthase. RESULTS: Mucositis was the most common dose-limiting toxicity. When the worst toxicities across all cycles were considered, grade 3 to 4 neutropenia, anemia, and thrombocytopenia were found to have occurred in 14.8%, 14.8%, and 0% of patients, respectively.


Acid Substitution in Human Thymidylate Synthase Franklin G. Berger, and Sondra H. Berger 324 Antiestrogens Inhibit the Replication of the C. Chailleux, F. Mesange, F. Bayard, Retroviral Moloney Murine Leukemia Virus In Vitro A-C. Prats, and J.-C. Faye 328 Metrazole Induces the Sequential Activation of c-fos, Yuan-Shan Zhu, Marina Brodsky,

Thymidylate synthase (TS) ffi2012 Landes Bioscience. Do not

proliferative cdc6, Thymidylate synthase (TS) and cdc25A genes in aortic smooth muscle cells ( aosMC), as seen by real time pCR assays. there is an activation of the stress-induced kinase, JNK1, in V sMCs upon tNFα stimulation.

Transmission of Apoptosis in Human Colorectal Tumor Cells

transfected LS174T-c2 cells. The striking enhancement of thymidylate synthase inhibition that we observed in cells with high TP activity was most probably at the origin of the potentiation of capecitabine antiproliferative efficacy. In addition, this increase of sensitivity was accompanied by a strong overexpression of the CD95-Fas receptor on

BIOGRAPHICAL Name: Edward Chu, MD Birth Date: Home Address

thymidylate synthase associated with multidrug resistance in human breast and colon cancer cell lines. Mol Pharmacol. 1991;39:136-43. PMID: 170499 10. Chu E, Koeller DM, Casey JL, Drake JC, Chabner BA, Elwood PC, Zinn S, Allegra CJ. Autoregulation of human thymidylate synthase messenger RNA translation by thymidylate synthase.

Promotion synthase by apotent folate 1843U89

inhibition of thymidylate synthase (TS; EC, greatly enhances not only the binding of 5-fluoro-2'-deoxyuridine 5'-monophosphate(FdUMP)anddUMPtoEscherichiacoliTS but also that of dGMP, GMP, dIMP, and IMP. Guanine nucleotide binding was first detected by CDanalysis, which revealed a unique spectrum for the TS-dGMP-U89 ternary

For reprints contact: [email protected] Pediatric

Jan 20, 2006 cofactors through inhibition of dihydrofolate reductase (DHFR) (Fig. 1) [17]. MTX polyglutamates and dihydrofo-lates that accumulate as a result of DHFR inhibition also inhibit thymidylate synthase and other enzymes involved in the purine biosynthetic pathway [18, 19]. Smi lai r to other anmetit aboetils, ccitrai detl ermni anst of

BMI1-Mediated Pemetrexed Resistance in Non-Small Cell Lung

Jul 27, 2020 caused the pemetrexed resistance and inhibition of BMI1 by a small molecule inhibitor, PTC-209, or transducing of BMI1-specific shRNAs suppressed cell growth and the expression of thymidylate synthase (TS) in pemetrexed-resistant A549 cells.

Leucovorin enhancement of the effects of the

Leucovorin Enhancement of the Effects of the Fhoropyrimidines on Thymidylate Synthase RICHARD G. MORAN, PHD Exposure of tumor cells to reduced folates before or with the fluoropyrimidines, 5-fluorouracil or 5-fluoro- 2'deoxyuridine, results in a substantial increase in the activity of these drugs. Available evidence suggests

Enhancement of 5-Fluorouracil Cytotoxicity by Pyridoxal 5

amounts required to improve inhibition of thymidylate synthase by 5-fluorouracil (FUra) through ternary complex stabilization. The hypothesis relates to the low affinity for cofactor of the PLP-dependent serine hydroxymethyl transferase (SHMT), the enzyme that catalyzes formation of CH 2-H 4PteGlu by transfer of the Cb of serine to H 4PteGlu

UCN-O1 Suppresses Thymidylate Synthase Gene Expression and

inhibitor, suppressed thymidylate synthase (TS) protein ex-pression in a dose-dependent manner with near complete suppression at 1 LM after a 24-h exposure in human gastric cancer cell line SK-GT5. Other protein kinase C/cydin-dependent kinase inhibitors, including fiavopiridol and safingol, had a similar effect on TS protein expression, but to

Autophagy Inhibition Promotes 5-Fluorouraci-Induced Apoptosis

the inhibition of thymidylate synthase and the incorporation of its active metabolites into RNA and DNA so as to influence the uracil metabolism and eventually lead to apoptosis in the cancer cell [3]. In the past decades, 5-FU-based combination therapies are standard treatments for many patients diagnosed with various

Clinical significance of polyglutamylation in primary central

inhibition by LV, resulting in long-lasting inhibition of thymidylate synthase [14, 22, 24]. Therefore, MTX treat-ment can selectively kill cancer cells in which polygluta-mylation has occurred, whereas normal cells with lower levels of polyglutamylation are rescued with LV [8]. In this context, we hypothesized that the therapeutic re-

Molecularly Evolved Thymidylate Synthase Inhibits 5

Thymidylate synthase plays a central role in the de novo biosynthesis of deoxythymidine 50-monophosphate (dTMP), an essential precursor for DNA synthesis. The enzyme catalyzes reductive methylation of deoxyuridine 50-mono-phosphate (dUMP) by (6R,S)-N5,N10-methylene-5,6,7,8-tetrahydrofolate (CH 2H 4-folate) to produce dTMP and dihydrofolate.