The Role of Thymidine Kinases in the Activation of Pyrimidine Nucleoside Analogues

Madhoun, Ashraf Al

doi:10.2174/1389557043403963

Cited by 53 publications

(36 citation statements)

References 52 publications

(106 reference statements)

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“…There are two forms of TK: A cytosolic (TK1) and a mitochondrial form (TK2) (13). The level of TK1 is very low in non-proliferating cells but increases dramatically at late G1 to late S-phase/early G2 phase during the cell cycle in proliferating cells and tumor cells.…”

Section: Introductionmentioning

confidence: 99%

Elevated thymidine kinase 1 in serum following neoadjuvant chemotherapy predicts poor outcome for patients with locally advanced breast cancer

Huang

Tian

Li³

et al. 2011

Experimental and Therapeutic Medicine

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Abstract.Patients with locally advanced breast cancer (LABC) commonly have an unfavorable prognosis. A molecular predictor for the identification of at-risk patients is urgently required. Thymidine kinase 1 in serum (S-TK1) is an enzyme involved in the synthesis of DNA precursors. In studies using immunohistochemistry, it was reported to be a more useful proliferation marker than Ki-67 in breast, lung and colorectal carcinoma. In the present study, we extended the research of prior breast carcinoma studies by postulating that in patients with LABC, overexpression of S-TK1 following neoadjuvant chemotherapy predicts cancer outcome. An experimental design consisting of 48 patients with LABC was prospectively constructed and analyzed. All patients received neoadjuvant chemotherapy and definitive surgical therapy. Study homogeneity was maintained by standardized treatment, surveillance and compliance protocols. The S-TK1 concentration was detected using the anti-TK1 chicken IgY antibody, using a dot-blot immuno-assay. After a median follow-up of 30 months, the results indicated a statistically significant trend (unadjusted). Patients with high S-TK1 overexpression had a significantly higher incidence of recurrence (P= 0.006) and cancer death (P= 0.0128) than those with low S-TK1 overexpression. A multivariate analysis provided identical results. The hazards ratio for developing recurrence in patients with higher S-TK1 expression was 6-7 times higher than the hazards ratio in patients with lower expression. In conclusion, our results indicate that a high S-TK1 concentration in sera from LABC patients receiving neoadjuvant chemotherapy is predictive of cancer outcome.

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Section: Introductionmentioning

confidence: 99%

Elevated thymidine kinase 1 in serum following neoadjuvant chemotherapy predicts poor outcome for patients with locally advanced breast cancer

Huang

Tian

Li³

et al. 2011

Experimental and Therapeutic Medicine

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“…By far the most commonly used radiotracer in PET imaging is 2-deoxy-2-[ 18 (Figure 1). TK1 is a key enzyme that is upregulated in cancer cells and, in agreement with separate studies [49,50], it is assumed that the concentration of [ 18 …”

Section: Overviewmentioning

confidence: 59%

Nucleoside transporters in PET imaging of proliferating cancer cells using 3ꞌ-deoxy-3ꞌ-[18F]fluoro-L-thymidine

Saidijam¹,

Afshar²,

Ahmad³

et al. 2018

J Diagn Imaging Ther

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The movement of physiologic nucleosides and nucleoside analogue drugs across biological membranes is mediated by nucleoside transport proteins. In cancer, nucleoside transporters have an important role in maintaining the hyperproliferative state of tumours and are important targets for diagnostic and therapeutic agents in the detection, treatment and monitoring of cancers. The nucleoside-based probe 3ꞌ-deoxy-3ꞌ-

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“…It indicates that substitution at the N3 position with the alkyl group changes the shape of a molecule. It was proven that substitution in this position hinders the hydrogen bonding between the N3 nitrogen of pyrimidine base and the main chain carbonyl of residue 178 in the enzyme that is required to tight spacing of the lasso-like loop [32,33,54]. Substitution at deoxyribose is also not favourable.…”

Section: Resultsmentioning

confidence: 99%

“…However, this nucleoside is substituted not only at the 2′ position but also at the 5 position of pyrimidine. The lower activity (higher values of P_VSA_logP_6 and lower values of HATS4v and E3u) of 3′- OH derivatives is probably related to the lack of hydrogen bonds that cannot be formed in the ligand-enzyme complex between the substituted 3′-OH group and the amino group of Gly182 [32,33,[54][55][56]. 2′-Fluoro derivative of deoxythymidine differs from dT mostly in the value of P_VSA_logP_6 while the HATS4v and E3u descriptors remain almost the same.…”

Section: Resultsmentioning

confidence: 99%

Molecular features of thymidine analogues governing the activity of human thymidine kinase

et al. 2018

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Modified uridines seem to be able to work as hypoxic tumour cell radiosensitisers. Before they sensitise cells to ionising radiation, they have to be incorporated into the genomic DNA and the latter process has to be preceded by the phosphorylation of the modified uridine, which in human cells is executed by human thymidine kinase 1 (hTK1). In the current study, we present the quantitative structure-activity relationship (QSAR) model allowing to identify and understand the molecular features of nucleoside derivatives governing the hTK1 kinase activity. The developed model meets all requirements of a reliable QSAR model and is based on only two molecular properties: the shape of the nucleoside determined by atom substitutions and the ability of the molecule to intermolecular interactions with the enzyme. These results have important implications for the rational designing of new hTK1 substrates and should significantly reduce the time and cost of studies on new radiosensitisers.

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The Role of Thymidine Kinases in the Activation of Pyrimidine Nucleoside Analogues

Cited by 53 publications

References 52 publications

Elevated thymidine kinase 1 in serum following neoadjuvant chemotherapy predicts poor outcome for patients with locally advanced breast cancer

Elevated thymidine kinase 1 in serum following neoadjuvant chemotherapy predicts poor outcome for patients with locally advanced breast cancer

Nucleoside transporters in PET imaging of proliferating cancer cells using 3ꞌ-deoxy-3ꞌ-[18F]fluoro-L-thymidine

Molecular features of thymidine analogues governing the activity of human thymidine kinase

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