Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.7 (DNA polymerase)
 17,007 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human thymidine kinase (TK1) is a key enzyme that is up-regulated in cancer cells and phosphorylates thymidine and some of its analogs to their monophosphates. The monophosphates are converted to their di- and triphosphates by the nucleoside kinases, and some of these nucleoside triphosphates are incorporated into DNA by DNA polymerase. The nucleoside analogs are transported into cells by concentrative nucleoside transporter or equilibrative nucleoside transporter. Given the unique property of TK1 and the nucleoside transporter systems, thymidine and its analogs have been radiolabeled for positron emission tomography (PET) imaging of tumor proliferation and DNA synthesis. Because thymidine is catabolized in vivo by thymidine phosphorylase, radiolabeled thymidine has not been successful in PET imaging of tumor proliferation. However, some of its analogs have been radiolabeled and successfully used in PET imaging of cell proliferation as well as DNA synthesis. Much work has been done in synthesis, radiosynthesis, and biological evaluation of these analogs for PET imaging of tumor proliferation. We review the chemistry, radiochemistry, and biological studies published to date, including structure activity relationship and PET imaging of the radiolabeled thymidine analogs. Information on radiolabeling and PET imaging with various nucleoside analogs is presented.
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PMID:Pyrimidine nucleosides in molecular PET imaging of tumor proliferation. 2015 63

Exposure of MOLT4 human T-cell leukemia cells to 6-Mercaptopurine (6-MP) and 6-Thioguanine (6-TG) resulted in acquired resistance associated with attenuated expression of the genes encoding concentrative nucleoside transporter 3 (CNT3) and equilibrative nucleoside transporter 2 (ENT2). To identify other alterations at the RNA and DNA levels associated with 6-MP- and 6-TG resistance, we compared here the patterns of gene expression and DNA copy number profiles of resistant sublines to those of the parental wild-type cells. The mRNA levels for two nucleoside transporters were down-regulated in both of the thiopurine-resistant sublines. Moreover, both of these cell lines expressed genes encoding the enzymes of purine nucleotide composition and synthesis, including adenylate kinase 3-like 1 and guanosine monophosphate synthetase at significantly lower levels than wild-type cells. In addition, expression of the mRNA for a specialized DNA polymerase, human terminal transferase encoded by the terminal deoxynucleotidyl transferase (DNTT) gene, was 122- and 93-fold higher in 6-TG- and 6-MP-resistant cells, respectively. The varying responses to 6-MP- and 6-TG observed here may help identify novel cellular targets and modalities of resistance to thiopurines, as well as indicating new potential approaches to individualization therapy with these drugs.
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PMID:The pattern of gene expression and gene dose profiles of 6-Mercaptopurine- and 6-Thioguanine-resistant human leukemia cells. 2172 52