Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.1.21 (thymidine kinase)
7,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

(E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) is a potent inhibitor of herpes simplex virus type 1 (HSV-1) and varicella-zoster virus (VZV). Its mechanism of action is based on a specific conversion to its 5'-mono- and 5'-diphosphate derivative by HSV-1- and VZV-encoded thymidine kinase, and after further conversion to its 5'-triphosphate derivative, inhibition of the viral DNA polymerase and eventual incorporation into the viral DNA. Recently, a new structural class of bicyclic pyrimidine nucleoside analogues (designated BCNAs) with highly specific and selective anti-VZV activity in cell culture has been discovered. The compounds need a long alkyl or alkylaryl side-chain at the base moiety for pronounced biological activity. This property makes these compounds highly lipophilic. They are also endowed with fluorescent properties when exposed to light with short UV wavelength. In striking contrast to BVDU, the members of this class of compounds are active only against VZV, but not against any other virus, including the closely related HSV-1, HSV-2 and cytomegalovirus. The most active compounds inhibit VZV replication at subnanomolar concentrations and are not toxic at high micromolar concentrations. The compounds lose their antiviral activity against thymidine kinase (TK)-deficient VZV strains, pointing to a pivotal role of the viral TK in their activation (phosphorylation). Kinetic studies with purified enzymes revealed that the compounds were recognized by VZV TK as a substrate, but not by HSV-1 TK, nor by cytosolic or mitochondrial TK. VZV TK is able to phosphorylate the test compounds not only to their corresponding 5'-mono- but also to their 5'-diphosphate derivatives. These data may readily explain and rationalize the anti-VZV selectivity of the BCNAs. There is no clear-cut correlation between the antiviral potency of the compounds and their affinity for VZV TK, pointing to a different structure/activity relationship of the eventual antiviral target of these compounds. The compounds are stable in solution and, in contrast to BVDU, not susceptible to degradation by thymidine phosphorylase. The bicyclic pyrimidine nucleoside analogues represent an entirely new class of highly specific anti-VZV compounds that should be further pursued for clinical development.
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PMID:Chemotherapy of varicella-zoster virus by a novel class of highly specific anti-VZV bicyclic pyrimidine nucleosides. 1208 70

Bicyclic pyrimidine nucleoside analogues (BCNAs) represent highly potent and selective inhibitors of varicella-zoster virus (VZV) replication in cell culture. The compounds inhibit a variety of clinical VZV strains, in the higher picomolar range, whilst being non-toxic at micromolar concentrations. The compounds do not inhibit the closely related simian varicella virus or any other viruses, including herpes simplex virus type 1 (HSV-1), HSV-2 and cytomegalovirus. The BCNAs owe at least part of their antiviral selectivity to a specific activation/phosphorylation by the VZV-encoded thymidine kinase (TK) and associated thymidylate kinase (dTMP-K) activity, while being not recognized by the closely related HSV-1-encoded TK/dTMP-K enzyme. In addition, the 5'-monophosphates of BCNAs are neither a substrate nor an inhibitor of the cellular dTMP-K, and are not subject of back-conversion to the corresponding nucleosides by 5'-deoxynucleotidases. In contrast to the anti-HSV-1/VZV drug (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU), the BCNAs are not catabolized by human (erythrocyte) or bacterial (Escherichia coli) thymidine phosphorylase to release the free bicyclic pyrimidine base. Also, unlike BVU (the free base of BVDU), the BCNA bases do not inhibit dihydropyrimidine dehydrogenase. Consequently, the catabolism of the anticancer drug 5-fluorouracil (5-FU) is not influenced by the BCNA base in cell-free enzyme assays or in mice that were exposed to combinations of 5-FU with BCNAs or their free base. BCNAs have a good oral bioavailability and, owing to their highly lipophilic nature, are assumed to be able to cross the blood-brain barrier efficiently. Given the above-mentioned favourable properties, BCNAs may represent a promising novel class of highly selective anti-VZV drugs that should be further pursued for clinical application.
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PMID:Bicyclic pyrimidine nucleoside analogues (BCNAs) as highly selective and potent inhibitors of varicella-zoster virus replication. 1209

The bicyclic furo[2,3-d]pyrimidine nucleoside analogues represent an entirely new class of fused furopyrimidine derivatives with unprecedented selectivity for varicella-zoster virus (VZV). From extensive structure-activity relationship (SAR) studies, the 6-(p-alkylphenyl)substituted furopyrimidine derivatives Cf 1742 and Cf 1743 emerged as the most potent inhibitors of VZV replication: they were found to inhibit both laboratory VZV strains and clinical VZV isolates at subnanomolar concentrations, while not being toxic to the host cells at 100,000-fold higher concentrations. Although the precise mechanism of action of these compounds remains to be elucidated, it is clear that for their antiviral activity they depend on phosphorylation by the VZV-encoded thymidine kinase. The furo[2,3-d]pyrimidine nucleoside analogues are not susceptible to degradation by human or bacterial thymidine phosphorylase, which may otherwise release the free aglycone. Also, the latter is not inhibitory to dihydropyrimidine dehydrogenase, an enzyme involved in the degradation of thymine, uracil, and the anticancer agent 5-fluorouracil. Further development of the furo[2,3-d]pyrimidine nucleoside analogues as new therapeutic modalities for the treatment of VZV infections (i.e., varicella and herpes zoster) seems highly justified.
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PMID:Highly potent and selective inhibition of varicella-zoster virus replication by bicyclic furo[2,3-d]pyrimidine nucleoside analogues. 1264 10

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disease caused by loss-of-function mutations in the gene encoding thymidine phosphorylase (TP). TP deficiency alters the metabolism of the nucleosides thymidine and deoxyuridine, which, in turn, produces abnormalities of mitochondrial DNA (mtDNA) including depletion, deletions, and point mutations. MNGIE is the best characterized of the expanding number of mitochondrial disorders caused by alterations in the metabolism of nucleosides/nucleotides. Because mitochondria contain their own machinery for nucleoside and nucleotide metabolism and have physically separate nucleotide pools, it is not surprising that disorders of these pathways cause human diseases. Other diseases in this group include mtDNA depletion syndromes caused by mutations on the nuclear genes encoding the mitochondrial thymidine kinase and deoxyguanosine kinase; autosomal dominant progressive external ophthalmoplegia with multiple deletions of mtDNA due to mutations in the genes encoding the muscle-isoform of mitochondrial ADP/ATP translocator; and mitochondrial DNA depletion due to toxicities of nucleoside analogues. Mutations in the deoxynucleotide carrier, a transporter of deoxynucleoside diphosphates, have been identified as a cause of congenital microcephaly. However, alterations of mtDNA have not yet been established in this disorder. Future studies are likely to reveal additional diseases and provide further insight into this new subject.
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PMID:Alteration of nucleotide metabolism: a new mechanism for mitochondrial disorders. 1294 May 7

The aim of this study was to determine the most suitable iodonucleoside analogs for use in tissue proliferation imaging by means of single photon emission tomography (SPECT). In this study, 5-[(125)I]iodo-(2-deoxy-2-fluoro-4-thio-beta-D-arabinofuranosyl)uracil ([(125)I]FITAU, 1E) and 5-[(125)I]iodo-1-methyl-(2-deoxy-2-bromo-beta-D-arabinofuranosyl)uracil ([(125)I]IMBAU, 1F) were synthesized and their biological data were compared with previously published results regarding 4'-thio nucleoside analogs and the reference compound 5-[(125)I]iodo-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)uracil ([(125)I]FIAU, 1D). 5-Iodo-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)uracil (FIAU, 2D), 5-iodo-(2-deoxy-2-fluoro-4-thio-beta-D-arabinofuranosyl)uracil (FITAU, 2E), and 5-iodo-1-methyl-(2-deoxy-2-bromo-beta-D-arabinofuranosyl)uracil (IMBAU, 2F) were successfully labeled with (125)I and their in vitro cytosolic thymidine kinase (TK(1)) phosphorylation, recombinant thymidine phosphorylase enzymatic catabolism, TK(1)-dependent cell uptake, and in vivo biodistribution in normal mice were evaluated. Five compounds (1B, 1C, 1D, 1E, and 1F) were stable against C-N glycoside degradation induced by recombinant thymidine phosphorylase. However, 5-[(125)I]iodo-2'-deoxyuridine ([(125)I]IUdR, 1A) was not shown to be stable against such degradation. The TK(1) assay showed that [(125)I]FIAU (1D) expressed 16% of the phosphorylation potential of [(125)I]IUdR (1A). Furthermore, [(125)I]FITAU (1E) was shown to have reduced phosphorylation potential, in comparison with that of [(125)I]IUdR (1A) (<0.01). [(125)I]IMBAU (1F) did not show any phosphorylation. In vitro cell uptake and in vivo proliferation-selective uptake of each nucleoside was largely dependent on its potential as a TK(1) substrate. Neither [(125)I]FITAU (1E) nor [(125)I]IMBAU (1F) were shown to have distinct TK(1)-dependent cell uptake and retention in the proliferating tissues. From these results, we concluded that [(125)I]FITAU (1E) and [(125)I]IMBAU (1F) are not effective as imaging agents of cell proliferation. The biological data obtained with these nucleosides were compared, and requirements for the design of pharmaceutically useful radioiodinated nucleoside analogs were also considered.
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PMID:Development of radioiodinated nucleoside analogs for imaging tissue proliferation: comparisons of six 5-iodonucleosides. 1449 26

TAS-102 is a new oral anti-cancer drug preparation, composed of a 1:0.5 mixture (on a molar basis) of alpha,alpha,alpha-trifluorothymidine (FTD) and 5-chloro-6-[1-(2-iminopyrrolidinyl)methyl]-2,4(1H,3H)-pyrimidinedione hydrochloride (TPI). TAS-102 currently undergoing clinical trials, has been demonstrated to have at least two mechanisms, inhibition of TS and incorporation into DNA. We hypothesized that the thymidine metabolism enzyme may be a crucial factor that affects the antitumor activity of TAS-102. In the present study, we measured the enzyme activity of thymidine kinase (TK), thymidine phosphorylase (TP) and thymidilate synthase (TS) in human cancer xenografts to investigate the contribution of these enzymes to the sensitivity of TAS-102. Antitumor activity of TAS-102 appears to be associated with TK, tumor growth and TS. However, the most related factors in this study were the TK and TP ratio. There was a significant correlation (p=0.04) between tumor growth inhibition and this ratio. These results suggested that the activation and degradation pattern of FTD plays an important role in the efficacy of TAS-102 and that it is possible to use the TK/TP ratio to predict response to TAS-102 therapy. We also studied the influence of TPI on the capacity of exogenous dThd to reverse FTD-dependent growth inhibition. Thymidine (dThd) levels rescued the effect of FTD in vitro and significantly increased in serum after administration of TAS-102 or TPI alone but not FTD alone. This may suggest the possibility of a decrease in antitumor effect. However, our study indicated that the therapeutic index was clearly increased by FTD combined with TPI, compared with FTD alone, suggesting FTD-induced toxicity to sensitive host tissue can be selectively reversed with dThd. In conclusion, TK and TPI effects on TP play important roles in the cytotoxic action of TAS-102, and it is possible to use the TK/TP ratio to predict more precisely individual resistance or sensitivity.
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PMID:Thymidine kinase and thymidine phosphorylase level as the main predictive parameter for sensitivity to TAS-102 in a mouse model. 1471 72

TAS-102 is a combination drug consisting of alpha,alpha,alpha-trifluorothymidine (FTD) and thymidine phosphorylase inhibitor (TPI). FTD is converted to F3TMP by thymidine kinase and inhibits the thymidylate synthetase (TS) activity by binding to TS. In addition, FTD triphosphate form, F3TTP is incorporated into DNA, which leads to cytocidal effects. Therefore, the incorporation of FTD into DNA is expected to be an important factor, discriminating it from 5-FU showing TS inhibitory activity as their main mechanism of action. To assess a clinically more effective regimen protocol, the intracellular metabolism and the incorporation of FTD into DNA were investigated using human cancer cell lines in vitro and in vivo. FTD was incorporated into DNA in a time-dependent manner, but not in a concentration-dependent manner. FTD was the most efficiently incorporated into DNA after treatment with a several-micro molar level of FTD for around 8 h. The intracellular F3TTP was rapidly eliminated from tumor cells, as soon as FTD was washed out from the culture medium, whereas the FTD incorporated into DNA was retained by 80% or more even at 24 h after a washing-out procedure. When TAS-102 was administered into tumor-bearing mice once daily or three times daily at 3-h intervals at a dose of 150 mg/kg/day for one or 3 consecutive days, incorporation of FTD into tumor DNA by divided dosing significantly higher than that of single dosing. Based on our findings, the antitumor effects of TAS-102 against 3 different human cancer cell xenografts into mice were examined. The divided daily dosing resulted in enhancement of the antitumor effects of TAS-102 without any additional side effects. It is concluded that multiple daily dosing may result in better clinical benefits of TAS-102, when compared with single daily dosing and TAS-102 is a promising candidate for not only FU-sensitive but also FU-resistant cancer patients.
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PMID:An optimal dosing schedule for a novel combination antimetabolite, TAS-102, based on its intracellular metabolism and its incorporation into DNA. 1471 31

The antiviral drug 2',3'-didehydro-3'-deoxythymidine (D4T; also know as stavudine and Zerit), which is used against human immunodeficiency virus (HIV), causes delayed toxicity (peripheral neuropathy) in long-term use. After examining a series of 2',3'-didehydro-3'-deoxy-4'-substituted thymidine (4'-substituted D4T) analogs, 4'-ethynyl D4T was found to have a fivefold-better antiviral effect and to cause less cellular and mitochondrial toxicity than D4T. The antiviral activity of this compound can be reversed by dThd but not by dCyd. The compound acted synergistically with beta-L-2',3'-deoxy-3'-thiacytidine (also known as lamivudine) and beta-L-2',3'-dideoxy-2',3'-didehydro-5-fluorocytidine (also known as elvucitabine) and additively with 2',3'-dideoxyinosine (also known as didanosine and Videx) and 3'-azido-3'-deoxythymidine (also known as Retovir and zidovudine) against HIV. 4'-Ethynyl D4T is phosphorylated by purified human thymidine kinase 1 (TK-1) from CEM cells with a faster relative V(max) and a lower K(m) value than D4T. The efficiency of TK-1 in the phosphorylation of 4'-ethynyl D4T is fourfold better than that of D4T. While D4T is broken down by the catabolic enzyme thymidine phosphorylase, the level of breakdown of 4'-ethynyl D4T was below detection. Since 4'-ethynyl D4T has increased anti-HIV activity and decreased toxicity and interacts favorably with other currently used anti-HIV drugs, it should be considered for further development as an anti-HIV drug.
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PMID:Novel 4'-substituted stavudine analog with improved anti-human immunodeficiency virus activity and decreased cytotoxicity. 1510 15

Thymidine analogs containing o-carboranylalkyl groups at the 3-position were screened as potential substrates for human thymidine kinase 1 (TK1), an enzyme that is selectively expressed in a variety of rapidly proliferating cells, including tumor cells. On the basis of previous studies, 12 of these were identified as potential delivery agents for boron neutron capture therapy, a therapeutic method used for the treatment of high-grade brain tumors. Compound 4 with a pentylene spacer between the o-carborane cage and the thymidine scaffold and compound 10, which has an additional dihydroxypropyl substituent at the o-carborane cage, were the best substrates for TK1 with kcat/Km values of 27% and 36% relative to that of thymidine, respectively. These compounds showed partial competitive inhibition for thymidine phosphorylation by TK1. Neither compound was a substrate of recombinant human thymidine phosphorylase nor were their respective 5'-monophosphates substrates of 5'-deoxynucleotidase 1, thereby indicating potential in vivo stability. The octanol/water partition coefficient for compound 10 was 2.09, suggesting that it has excellent physiochemical properties for crossing the blood brain barrier and penetrating brain tissue. The in vitro cytotoxic effect of the 12 analogs was moderate to low in mammalian cell cultures with IC50 values between 10 and 160 micromol/L. Compounds 4 and 10 were taken up selectively and retained by the murine fibroblast L929 cell line, in contrast to its TK1-deficient variant. These findings suggest that compound 10 is a promising candidate for selective delivery of boron-10 to malignant cells, and additional in vivo studies are planned to evaluate it for boron neutron capture therapy of brain tumors.
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PMID:Evaluation of human thymidine kinase 1 substrates as new candidates for boron neutron capture therapy. 1534 16

(E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU, Brivudin, Zostex, Zerpex, Zonavir), now more than 20 years after its discovery, still stands out as a highly potent and selective inhibitor of herpes simplex virus type 1 (HSV-1) and varicella-zoster virus (VZV) infections. It has been used in the topical treatment of herpetic keratitis and recurrent herpes labialis and the systemic (oral) treatment of herpes zoster (zona, shingles). The high selectivity of BVDU towards HSV-1 and VZV depends primarily on a specific phosphorylation of BVDU to its 5'-diphosphate (DP) by the virus-encoded thymidine kinase (TK). After further phosphorylation (by cellular enzymes), to the 5'-triphosphate (TP), the compound interferes as a competitive inhibitor/alternate substrate with the viral DNA polymerase. The specific phosphorylation by the HSV- and VZV-induced TK also explains the marked cytostatic activity of BVDU against tumor cells that have been transduced by the viral TK genes. This finding offers considerable potential in a combined gene therapy/chemotherapy approach for cancer. To the extent that BVDU or its analogues (i.e., BVaraU) are degraded (by thymidine phosphorylase) to (E)-5-(2-bromovinyl)uracil (BVU), they may potentiate the anticancer potency, as well as toxicity, of 5-fluorouracil. This ensues from the direct inactivating effect of BVU on dihydropyrimidine dehydrogenase, the enzyme that initiates the degradative pathway of 5-fluorouracil. The prime determinant in the unique behavior of BVDU is its (E)-5-(2-bromovinyl) substituent. Numerous BVDU analogues have been described that, when equipped with this particular pharmacophore, demonstrate an activity spectrum characteristic of BVDU, including selective anti-VZV activity.
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PMID:(E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU). 1538 33


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