Disease relevance of TYMS

• These data suggest that genetic amplification of TYMS is a major mechanism of 5-FU resistance in vivo and have important implications for the management of colorectal cancer patients with recurrent disease [1].
• Patients with metastases containing TYMS amplification had a substantially shorter median survival (329 days) than those without amplification (1,021 days, P <0.01) [1].
• The TYMS 6 base pair (bp)(-)6bp- (homozygous for 6bp deletion), IVS6 -68C>T, and 1053C>T genotypes (all in complete linkage disequilibrium) were all inversely associated with NHL (TYMS; odds ratio [OR] = 0.57; 0.34-0.94), particularly with diffuse large cell lymphoma (DLCL; OR = 0.29; 0.10-0.82) [2].
• In conclusion, the TYMS polymorphisms, especially the TS3'UTR polymorphism, are associated with GC risk, especially the non-cardiac gastric cancer, and the TSER 2R and TS3'UTR 6 bp alleles may jointly play a role in the etiology of GC in the southern Chinese population [3].
• Increased risks for NHL [odds ratio (OR), 1.48; 95% confidence intervals (CI), 1.12-1.97], and marginal zone lymphoma (OR, 3.38; 95% CI, 1.30-8.82) were associated with the TYMS 2R/3R variant [4].

Psychiatry related information on TYMS

• In contrast, the patients in the TS H-group survived longer than those in the L-group when limited to stage I and MTHFR T-group (p = 0.052) [5].
• Procedural learning during the serial reaction time task (SRTT) is used as a model of neural plasticity to illustrate the applications of TMS [6].
• The effects of TMS on target absent trials are interpreted in terms of fronto-parietal connections and the role of frontal cortex in decision-making [7].
• A double blind study showing that two weeks of daily repetitive TMS over the left or right temporoparietal cortex reduces symptoms in patients with schizophrenia who are having treatment-refractory auditory hallucinations [8].
• 5 Hz repetitive TMS increases anticipatory motor activity in the human cortex [9].

High impact information on TYMS

• Thymidylate synthase (TS, EC 2.1.1.45) catalyzes the reductive methylation of dUMP by CH2H4folate to produce dTMP and H2folate [10].
• Included is a discussion of available sources and assays for TS, a description of the enzyme's chemical mechanism and crystal structure, and a summary of data obtained from mutagenesis experiments [10].
• Methotrexate-resistant Leishmania tropica contain two separate regions of DNA amplification, one encoding the bifunctional thymidylate synthetase-dihydrofolate reductase (TS-DHFR) characteristic of protozoans and the other of yet unknown function [11].
• Thymidylate synthase expression and response to neoadjuvant chemotherapy in patients with advanced head and neck cancer [12].
• Fluorouracil: active in ZD1694 (tomudex)-resistant cell lines with markedly elevated thymidylate synthase levels [13].

Chemical compound and disease context of TYMS

• Polymorphisms in the thymidylate synthase and serine hydroxymethyltransferase genes and risk of adult acute lymphocytic leukemia [14].
• A phase III comparative evaluation of a direct inhibitor of TS (ZD1694) with an indirect inhibitor (5-FU/LV) has been completed and showed similar activity but reduced toxicity in favor of ZD1694 [15].
• Preclinical and clinical results in advanced and adjuvant colorectal cancers confirmed that the therapeutic efficacy of fluoropyrimidines, with thymidylate synthase (TS) as a primary target, can be improved significantly with leucovorin (LV) modulation [15].
• Prognostic role of thymidylate synthase, thymidine phosphorylase/platelet-derived endothelial cell growth factor, and proliferation markers in colorectal cancer [16].
• DPD and TS expressions were measured by reverse transcription-PCR in surgically resected materials of primary colorectal tumors from 37 patients who went on to receive oral treatment of uracil and tegafur and leucovorin for either synchronous or metachronous metastatic diseases [17].

Biological context of TYMS

• Analysis of TYMS by fluorescence in situ hybridization identified TYMS gene amplification in 23% of 31 5-FU-treated cancers, whereas no amplification was observed in metastases of patients that had not been treated with 5-FU [1].
• The associations of DLCL and FL with TYMS 1494del6 and MTHFR 677TT genotypes, respectively, suggest that folate metabolism may play an important role in the pathogenesis of specific subtypes of NHL [2].
• The TYMS gene has a tandem repeat polymorphism (two repeats or three repeats, designated 2R or 3R, respectively), which may also affect homocysteine concentrations [18].
• Our findings suggest that the TYMS 3'UTR del/del genotype is a significant determinant of elevated RBC folate concentration in a non-smoking population of northwestern European adults and that this genotype confers protection against diseases for which a low folate/high homocysteine phenotype appears to be an etiologic component [19].
• We observed no association between NHL and haplotypes for MTHFR or TYMS [4].

Anatomical context of TYMS

• Mucinous tumours significantly overexpressed both TYMS and GSTP1 relative to nonmucinous tumours and patient-matched normal mucosa [20].
• Marginal increased risks were also observed for diffuse large B cell lymphoma with the TYMS homozygous 6 bp deletion (OR, 1.61; 95% CI, 0.99-2.60) and for follicular lymphoma with RFC 80AA (OR, 1.44; 95% CI, 0.94-2.22) and TYMS 28-bp repeat 2R/3R (OR, 1.45; 95% CI, 0.96-2.2) [4].
• Among non-smokers only, the TYMS 3'UTR ins/del polymorphism was significantly associated with red blood cell folate (RBC folate; P=0.002) and homocysteine (P=0.03) concentrations [19].
• Thymidine kinase, thymidylate synthase, and dihydropyrimidine dehydrogenase profiles of cell lines of the National Cancer Institute's Anticancer Drug Screen [21].
• CONCLUSIONS: We conclude that the majority of differentiated thyroid cancers (74%) express TP and low levels of TS (63% undetectable) [22].

Associations of TYMS with chemical compounds

• In two of four patients, we identified amplification of an approximately 100-kb region on 18p11.32 that was of particular interest because it contained the gene encoding thymidylate synthase (TYMS), a molecular target of 5-FU [1].
• The thymidylate synthase gene ( TYMS or TS) encodes a tightly regulated enzyme that catalyzes the conversion of deoxyuridylate to thymidylate, and contains a tandem repeat polymorphism that affects expression of the enzyme [23].
• Our findings indicate that the TYMS 3R3R genotype is not a determinant of homocysteine in this sample of healthy young Caucasian adults from Northern Ireland [18].
• In ALL, polymorphisms in the genes of folate metabolism are associated with poor prognosis, and the 3R3R TYMS polymorphism in particular is associated with methotrexate resistance [24].
• Growth inhibition by MTX and FdUrd was increased and DHFR and TS activities and expression were correspondingly decreased in Rb transfectants of SaOS-2 cells [25].

Physical interactions of TYMS

• Folinic acid enhances TS inhibition by increasing the intracellular pool of folates that stabilize the 5FU-TS complex [26].
• The DHFR-TS nucleic acid sequence contains no introns and the single 1563-bp open reading frame encodes a 179 residue N-terminal DHFR domain connected by a 55 amino acid junction peptide to a 287 residue C-terminal TS domain [27].
• However, deletion of the two potential E2F binding sites in the human TS promoter did not prevent the virus-induced increase in TS promoter activity [28].
• In this regard, thymidylate synthase interacts with the mRNAs of the c-myc onocogene and the p53 tumor suppressor gene [29].

Regulatory relationships of TYMS

• The effect of MTX on TS activity and DNA synthesis were measured in stimulated normal PBMC and in PBMC obtained from 6 RA patients treated with oral MTX before and 2 hours after intake of their weekly MTX dose [30].
• Relative mRNA amounts of DPD or TS were expressed as the ratios of targeted gene to glyceraldehyde-3-phosphate dehydrogenase reverse transcription-PCR products [17].
• Finally, the CDK inhibitor roscovitine potentiated the cytotoxic activity of ZD9331 in both wt and p21Cip1-/- cells, strongly suggesting a role for p21Cip1-dependent CDK inhibition in cytotoxicity induced by thymidylate synthase inhibition [31].
• p53 and WAF1 are induced and Rb protein is hypophosphorylated during cell growth inhibition by the thymidylate synthase inhibitor ZD1694 (Tomudex) [32].
• Both inducible TS expression and the addition of exogenous thymidine (10 microM) blocked p53 and p21 induction by the antifolates but not by 5-FU in the M7TS90 cell line [33].

Other interactions of TYMS

• This increase in expression was not due to amplification of the DHFR and TS genes [25].
• Thymidylate synthase, thymidine phosphorylase, dihydropyrimidine dehydrogenase expression, and histological tumour regression after 5-FU-based neo-adjuvant chemoradiotherapy in rectal cancer [34].
• The cases that were negative for p53, TS, bcl-2, and GST-pi were more likely to respond to chemotherapy than the cases that were positive for these markers [35].
• Multivariate analysis identified high-level expression in two of the platinum markers (GST-pi and P-gp) and the 5-FU marker TS as independent predictors of early recurrence and death [36].
• Our results suggest that the genotyping for the TYMS polymorphisms may become a useful indicator in determining the appropriate dose of MTX in patients with RA [37].

Analytical, diagnostic and therapeutic context of TYMS

• Prognostic value of tumoral thymidylate synthase and p53 in metastatic colorectal cancer patients receiving fluorouracil-based chemotherapy: phenotypic and genotypic analyses [38].
• Formalin-fixed, paraffin wax-embedded pre-operative biopsies (n = 14) and surgical resection specimens (n = 40) from patients with rectal carcinoma (clinical UICC stage II/III) receiving neo-adjuvant 5-FU-based chemoradiotherapy were studied for TS-, TP-, and DPD-gene expression by quantitative TaqMan real-time PCR after laser microdissection [34].
• TS protein expression was evaluated by immunohistochemistry using a polyclonal TS antibody [39].
• TS and TP as measured by various assays were correlated with overall and disease-free survival in this patient group [16].
• Moreover, intra-tumoural TS- and TP-gene expression in surgical rectal specimens after neo-adjuvant chemoradiotherapy correlates significantly with histopathological tumour regression when microdissection is applied [34].

References