Uridine Triacetate for Severe Fluoropyrimidine Cardiotoxicity in a Patient With Thymidylate Synthase Gene Variants.
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ABSTRACT:
SUBMITTER: Raber I
PROVIDER: S-EPMC8352086 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Fluoropyrimidines (FP) are the backbone chemotherapy in colorectal cancer (CRC) treatment; however, their use is associated with cardiotoxicity, which is underreported. In the present study, we aimed to prospectively determining the incidence rates and related risk factors of FP-induced cardiotoxicity (FIC) in CRC patients and at identifying predictive biomarkers. One hundred and twenty-nine consecutive previously untreated CRC patients underwent active cardiological monitoring, including 5-items simplified questionnaire on symptoms, electrocardiogram (ECG) and plasma sample collection during FP chemotherapy. FIC was defined as the presence of ECG alterations and/or the arising of at least one symptom of chest pain, dyspnoea, palpitations or syncope. The primary objective was the evaluation of FIC incidence. Secondary objectives were the correlation of FIC with well-known cardiological risk factors and the identification of circulating biomarkers (serum levels of TnI, proBNP; miRNA analysis) as predictors of FIC. Twenty out of 129 (15.5%) patients experienced FIC. The most common symptoms were dyspnoea (60%) and chest pain (40%), while only 15% of patients presented ECG alterations, including one acute myocardial infarction. Retreatment with FP was attempted in 90% of patients with a favourable outcome. Despite 48% of patients having cardiological comorbidities, we did not observe an increased FIC in this subgroup. Only the subgroup of females with the habit of alcohol consumption showed an increased risk of FIC. None of the circulating biomarkers evaluated demonstrated a clinical utility as FIC predictors. FIC can be an unexpected, life-threatening adverse event that can limit the subsequent treatment choices in CRC patients. In this prospective study, well-known cardiological comorbidities were not related to higher FIC risk and circulating biomarkers predictive of toxicity could not be found. With careful monitoring, mainly based on symptoms, almost all patients completed the FP treatment.
2023-01-18 | GSE217768 | GEO
Project description:5-Fluorouracil (5-FU) is one of the most commonly used chemotherapeutic agents in solid tumors, including colon, gastric and breast cancers. The pharmacogenetic syndrome of dihydropyrimidine dehydrogenase (DPD) deficiency leading to severe toxicity after administration of 5-flourouracil (5-FU) and capecitabine has been well-recognized. However, the data about the association of the target enzyme, thymidylate synthase (TYMS) with the toxicity of these agents is limited. A 50-year-old Caucasian woman with T2N2M0 Stage IIIB squamous cell rectal cancer after local surgical excision initiated 5-FU therapy with mitomycin-C and radiation therapy in the adjuvant setting. Following the first treatment with 5-FU, she developed grade III mucositis and grade IV neutropenia which delayed her second dose of therapy. Following her second dose of 5-FU, she again developed grade III mucositis, grade II diarrhea, pancytopenia, fever, and rectal bleeding requiring hospitalization. She was treated with blood and platelet transfusion, pegfilgrastim, IV antibiotics, and supportive therapy. Due to her severe clinical toxicity following chemotherapy involving 5-FU, we tested her for both DPD deficiency andTYMS polymorphisms. The patient was found to be homozygous for the TYMS polymorphism 5'TSER genotype 2R/2R*f, which has been associated with increased 5-FU drug sensitivity and susceptibility to 5-FU toxicity. Our case report further underlines the fact that TYMS polymorphism not only predicts response to 5-FU by relating to intratumoral-TYMS mRNA expression but also the toxicity in these patients receiving fluoropyrimidines. In brief, TYMS genotype variations present a dilemma in 5-FU-driven cancer therapy- overexpression leads to decreased drug sensitivity and poor prognosis, while underexpression leads to the manifestation of toxic drug effects that may halt therapy altogether. Future prospective translational studies in a larger population are warranted to validate its role as a predictive and prognostic factor.
| S-EPMC5071174 | biostudies-literature
Project description:BackgroundThymidylate synthase is a housekeeping gene, designated ancient due to its role in DNA synthesis and ubiquitous phyletic distribution. The genomic sequences were characterized coding for thymidylate synthase in two species of the genus Trichinella, an encapsulating T. spiralis and a non-encapsulating T. pseudospiralis.MethodsBased on the sequence of parasitic nematode Trichinella spiralis thymidylate synthase cDNA, PCR techniques were employed.ResultsEach of the respective gene structures encompassed 6 exons and 5 introns located in conserved sites. Comparison with the corresponding gene structures of other eukaryotic species revealed lack of common introns that would be shared among selected fungi, nematodes, mammals and plants. The two deduced amino acid sequences were 96% identical. In addition to the thymidylate synthase gene, the intron-less retrocopy, i.e. a processed pseudogene, with sequence identical to the T. spiralis gene coding region, was found to be present within the T. pseudospiralis genome. This pseudogene, instead of the gene, was confirmed by RT-PCR to be expressed in the parasite muscle larvae.ConclusionsIntron load, as well as distribution of exon and intron phases in thymidylate synthase genes from various sources, point against the theory of gene assembly by the primordial exon shuffling and support the theory of evolutionary late intron insertion into spliceosomal genes. Thymidylate synthase pseudogene expressed in T. pseudospiralis muscle larvae is designated a retrogene.
| S-EPMC4022200 | biostudies-literature
Project description:INTRODUCTION:Fluoropyrimidines (FPDs) are a fundamental component of many chemotherapy regimens. Cardiotoxic adverse events (AEs) such as angina, ischemia, arrhythmias, and cardiomyopathy associated with 5-fluorouracil (5-FU) and capecitabine (CAPE) have been sparingly described in studies, primarily through case reports. Data from the 1990s revealed an estimated incidence of 0.5% to 19%, with cardiovascular fatalities occurring in ?28%. The current use of FPDs includes multiple dosing regimens, oral or intravenous delivery, and administration with additional cardiotoxic therapies. As such, it is imperative to better define the cardiotoxicity risk in the modern treatment era. We comprehensively evaluated the incidence, prevalence, and ascertainment of cardiovascular risk factors and disease within ECOG-ACRIN (Eastern Cooperative Group Cancer Research Group - American College of Radiology Imaging Network) Cancer Research Group clinical trials incorporating 5-FU and CAPE. MATERIALS AND METHODS:Case report forms and clinical study reports from the ECOG-ACRIN Cancer Research Group database of phase II and III clinical trials incorporating 5-FU and CAPE were evaluated. A total of 16 trials from 2002 to 2017 were identified that had used bolus 5-FU (n = 1), continuous infusion 5-FU (n = 10) or CAPE (n = 5). RESULTS:A history of cardiovascular disease was variably defined and was an exclusion criterion in 13 of the 16 studies (81%). The baseline risk factors and history of cardiac disease were specifically collected in only 3 studies (19%). All studies collected cardiovascular AEs using the Common Terminology Criteria for Adverse Events version available at the time of the study. Fewer than half (7 of 16; 44%) of the study case report forms had also specifically requested information on cardiac ischemia/infarction. In the 12 completed studies with clinical study reports, the following AEs were reported: dyspnea, ?16%; arrhythmias, ?6%; and angina, ischemia, and elevated troponin, ?5%. Some trials only recorded cardiac AEs that were possibly associated with the novel drug being studied and not those attributed to the standard of care in the 5-FU/CAPE arm, further decreasing the numerical incidence. CONCLUSION:Inconsistent clinical trial reporting of cardiac AEs precluded accurate and precise delineation of the epidemiology of FPD-related cardiovascular AEs. Prospective knowledge of the definition and natural history will lead to the development of risk factor stratification and prechemotherapy interventions to reduce or prevent cardiotoxicity. We propose that the prospective collection of baseline cardiac data and prespecified cardiac endpoints are necessary to fully understand the incidence and cardiac risk of FDPs.
| S-EPMC6927029 | biostudies-literature
Project description:We demonstrate that human herpesvirus 8, obtained from the lymphoma cell line BC-3 as well as from Kaposi's sarcoma lesions, carries a gene that encodes a functional thymidylate synthase (TS). The particular characteristics of this enzyme are studied and compared to the characteristics of TSs encoded by other organisms.
| S-EPMC136588 | biostudies-literature
Project description:Gene expression was compared between a Tet-OFF transfomant expressing thymidylate synthase trasgene and its parental human colorectal cancer cell line, DLD-1, or the transformant exposed to doxycycline.
2015-03-31 | E-MTAB-3414 | biostudies-arrayexpress
Project description:BackgroundThe fluoropyrimidine drug 5-Fluorouracil (5-FU) and the prodrug capecitabine have been extensively used for treatment of many types of cancer including colorectal, gastric, head and neck. Approximately, 10 to 25% of patients suffer from severe fluoropyrimidine-induced toxicity. This may lead to dose reduction and treatment discontinuation. Pharmacogenetics research could be useful for the identification of predictive markers in chemotherapy treatment. The aim of the study was to investigate the role of five genetic polymorphisms within two genes (DPYD, TYMS) in toxicity and efficacy of fluoropyrimidine-based chemotherapy.MethodsTotal genomic DNA was extracted from 83 cancer patients treated with fluoropyrimidine-based chemotherapy. In this study, three polymorphisms were genotyped in dihydropyrimidine dehydrogenase gene c.1905+1 G>A (DPYD*2A; rs3918290), c.1679 T>G (I560S; DPYD*13; rs55886062), and c.2846A>T (D949V; rs67376798) and two polymorphisms, besides the Variable Number of Tandem Repeat (VNTR) polymorphism and 6-bp insertion/deletion polymorphism in thymidylate synthase gene. The analysis of polymorphisms for rs3918290, rs55886062, rs67376798 and 6-bp insertion/deletion in TYMS was done by Polymerase Chain Reaction-restriction Fragment Length Polymorphism (PCRRFLP) TYMS VNTR analysis. 5-FU-related toxicities such as anemia, febrile neutropenia, neurotoxicity, vomiting, nausea, and mucositis were evaluated according to NCI-CTC criteria version 4.0. T-test and chi-square were used and p-values less than 0.05 were considered statistically significant.ResultsDPYD gene polymorphisms were not observed in this study. The frequency of the TYMS +6 bp allele was 40.35% and the -6 bp allele was 59.65% in this study. The frequency of VNTR 2R allele was 48.75% and 3R allele was 51.15%. Toxicity grade II diarrhea, mucositis, nausea, vomiting, and neurotoxicity was 2.2, 24.1, 15.7, 6, and 51.8%, respectively. Thymidylate synthase ins/del polymorphisms were associated with increased grade III neurotoxicity (p=0.02). Furthermore, anemia grade III was significantly associated with 2R/2R genotype (0.009).ConclusionThymidylate synthase gene polymorphisms may play a key role in fluoropyrimidne -based chemotherapy. Although rare DPYD polymorphisms were not observed in our study, according to large population studies, DPYD gene polymorphisms could be used as a predictive biomarker for patient treatments.
| S-EPMC7368113 | biostudies-literature
Project description:A 978-base-pair gene that encodes thymidylate synthase (TS; 5,10-methylenetetrahydrofolate:dUMP C-methyltransferase, EC 2.1.1.45) from Lactobacillus casei has been synthesized and inserted into Escherichia coli expression vectors. The DNA sequence contains 35 unique restriction sites that are located an average of 28 base pairs apart throughout the entire length of the gene. A ribosome binding site was included 9 base pairs upstream from the translation start site and codon usage was adjusted to ensure efficient translation in E. coli. The TS gene is flanked by unique EcoRI and HindIII restriction sites that render the gene portable to any of several E. coli expression vectors. Catalytically active TS encoded by the synthetic gene is expressed in large amounts (10-20% of the soluble protein) and is indistinguishable from that isolated from L. casei. The utility of the synthetic gene for mutagenesis is demonstrated by a single experiment in which His-199 was replaced with 14 different amino acids. Analysis of the mutants by genetic complementation indicates that TS can tolerate a number of amino acid substitutions at that position and shows that His-199 is not strictly required for catalytic activity.
| S-EPMC53319 | biostudies-other
Project description:Dihydropyrimidine dehydrogenase (DPD) is the major enzyme in the catabolism of fluoropyrimidine chemotherapy. Deficiencies in this enzyme level typically predispose patients to fluoropyrimidine toxicities, and they are often linked to DPYD gene polymorphisms. Other gene polymorphisms such as thymidylate synthase (TYMS) and methylenetetrahydrofolate reductase (MTHFR) may induce similar toxicities. We report a patient with resected stage III colon cancer presenting with severe toxicity to adjuvant capecitabine, a prodrug of 5-fluorouracil (5-FU). Her DPYD gene sequencing was normal. However, the patient was heterozygous for c.1298A>C (p.E429A) in the methylenetetrahydrofolate reductase (MTHFR) gene and c.*450_*455del in the thymidylate synthase (TYMS) gene. The capecitabine dose was reduced in subsequent treatments and then titrated up gradually with no major side effects reported.
| S-EPMC10739331 | biostudies-literature
Project description:Thymidylate synthases (Thy) are key enzymes in the synthesis of deoxythymidylate, 1 of the 4 building blocks of DNA. As such, they are essential for all DNA-based forms of life and therefore implicated in the hypothesized transition from RNA genomes to DNA genomes. Two evolutionally unrelated Thy enzymes, ThyA and ThyX, are known to catalyze the same biochemical reaction. Both enzymes are sporadically distributed within each of the 3 domains of life in a pattern that suggests multiple nonhomologous lateral gene transfer (LGT) events. We present a phylogenetic analysis of the evolution of the 2 enzymes, aimed at unraveling their entangled evolutionary history and tracing their origin back to early life. A novel probabilistic evolutionary model was developed, which allowed us to compute the posterior probabilities and the posterior expectation of the number of LGT events. Simulation studies were performed to validate the model's ability to accurately detect LGT events, which have occurred throughout a large phylogeny. Applying the model to the Thy data revealed widespread nonhomologous LGT between and within all 3 domains of life. By reconstructing the ThyA and ThyX gene trees, the most likely donor of each LGT event was inferred. The role of viruses in LGT of Thy is finally discussed.
| S-EPMC2826268 | biostudies-literature