Thymidine kinase

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Thymidine kinase
2B8T.png
Crystal structure of a tetramer of thymidine kinase from U. urealyticum (where the monomers are color cyan, green, red, and magenta respectively) in complex with thymidine (space-filling model, carbon = white, oxygen = red, nitrogen = blue).[1]
Identifiers
EC number 2.7.1.21
CAS number 9002-06-6
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / EGO
Thymidine kinase
Identifiers
Symbol TK
Pfam PF00265
Pfam clan CL0023
InterPro IPR001267
PROSITE PDOC00524
Thymidine kinase 1, soluble
Identifiers
Symbol TK1
Entrez 7083
HUGO 11830
OMIM 188300
RefSeq NM_003258
UniProt P04183
Other data
Locus Chr. 17 q23.2-25.3
Thymidine kinase 2, mitochondrial
Identifiers
Symbol TK2
Entrez 7084
HUGO 11831
OMIM 188250
RefSeq NM_004614
UniProt O00142
Other data
Locus Chr. 16 [1]

Thymidine kinase is an enzyme, a phosphotransferase (a kinase): 2'-deoxythymidine kinase, ATP-thymidine 5'-phosphotransferase, EC 2.7.1.21.[2][3] It can be found in most living cells. It is present in two forms in mammalian cells, TK1 and TK2. Certain viruses also have genetic information for expression of viral thymidine kinases.

Thymidine kinase catalyses the reaction:

  • Thd + ATP → TMP + ADP

where Thd is deoxythymidine, ATP is adenosine 5’-triphosphate, TMP is deoxythymidine 5’-phosphate and ADP is adenosine 5’-diphosphate.

Thymidine kinases have a key function in the synthesis of DNA and thereby in cell division, as they are part of the unique reaction chain to introduce deoxythymidine into the DNA. Deoxythymidine is present in the body fluids as a result of degradation of DNA from food and from dead cells. Thymidine kinase is required for the action of many antiviral drugs. It is used to select hybridoma cell lines in production of monoclonal antibodies. In clinical chemistry it is used as a proliferation marker in the diagnosis, control of treatment and follow-up of malignant disease, mainly of hematological malignancies.

History[edit]

The incorporation of thymidine in DNA was demonstrated around 1950.[4] Somewhat later, it was shown that this incorporation was preceded by phosphorylation,[5] and, around 1960, the enzyme responsible was purified and characterized.[6][7]

Classification[edit]

Two different classes of thymidine kinases have been identified[8][9] and are included in this super family:

The Prosite pattern recognises only the cellular type of thymidine kinases.

Biochemistry[edit]

Mammals have two isoenzymes, that are chemically very different, TK1 and TK2. The former was first found in fetal tissue, the second was found to be more abundant in adult tissue, and initially they were termed fetal and adult thymidine kinase. Soon it was shown that TK1 is present in the cytoplasm only in anticipation of cell division (cell cycle-dependent),[10][11] whereas TK2 is located in mitochondria and is cell cycle-independent.[12][13] The genes of the two types were localized in the mid-1970s.[14][15] The gene for TK1 was cloned and sequenced.[16] The corresponding protein has a molecular weight of about 25 kD. Normally, it occurs in tissue as a dimer. It can be activated by ATP. After activation, it has been converted to a tetramer. The recombinant TK1 cannot be activated and converted to a tetramer in this way, showing that the enzyme occurring in cells has been modified after synthesis.[17][18][19] TK1 is synthesized by the cell during the S phase of cell division. After cell division is completed, TK1 is degraded intracelluarly, so that it does not pass to body fluids after normal cell division.[20] There is a feed-back regulation of the action of thymidine kinase in the cell: thymidine triphosphate (TTP), the product of the further phosphorylation of thymidine, acts as an inhibitor to thymidine kinase.[18][21][22][23] This serves to maintain a balanced amount of TTP available for nucleic acid synthesis, not oversaturating the system. 5'-Aminothymidine, a non-toxic analogue of thymidine, interferes with this regulatory mechanism and thereby increases the cytotoxicity of thymidine analogues used as antineoplastic drugs.[24][25][26][27][28][29][30]

Genes for virus specific thymidine kinases have been identified in Herpes simplex virus, Varicella zoster virus and Epstein-Barr virus.[31][32][33][34][35][36][37]
2'-Desoxythymidin.svg + ATP ---> 2'-Desoxythymidinmonophosphat.svg + ADP

Deoxythymidine reacts with ATP to give deoxythymidine monophosphate and ADP.

Physiological context[edit]

Deoxythymidine monophosphate, the product of the reaction catalysed by thymidine kinase, is in turn phosphorylated to deoxythymidine diphosphate by the enzyme thymidylate kinase and further to deoxythymidine triphosphate by the enzyme nucleoside diphosphate kinase. The triphosphate is included in a DNA molecule, a reaction catalysed by a DNA polymerase and a complementary DNA molecule (or an RNA molecule in the case of reverse transcriptase, an enzyme present in retrovirus). Deoxythymidine monophosphate is produced by the cell in two different reactions - either by phosphorylation of deoxythymidine as described above or by methylation of deoxyuridine monophosphate, a product of other metabolic pathways unrelated to thymidine, by the enzyme thymidylate synthethase. The second route is used by the cell under normal conditions, and it is sufficient to supply deoxythymidine monophosphate for DNA repair. When a cell prepares to divide, a complete new set-up of DNA is required, and the requirement for building blocks, including deoxythymidine triphosphate, increases. Cells prepare for cell division by making some of the enzymes required during the division. They are not normally present in the cells and are downregulated and degraded afterwards. Such enzymes are called salvage enzymes. Thymidine kinase 1 is such a salvage enzyme, whereas thymidine kinase 2 is not cell cycle-dependent.[38][39][40][41][42][43][44][45][46]

Applications[edit]

Identification of dividing cells[edit]

The first indirect use of thymidine kinase in biochemical research was the identification of dividing cells by incorporation of radiolabeled thymidine and subsequent measurement of the radioactivity or autoradiography to identify the dividing cells. For this purpose tritiated thymidine is included in the growth medium.[47] In spite of errors in the technique, it is still used to determine the growth rate of malignant cells and to study the activation of lymphocytes in immunology.

PET scan of active tumours[edit]

3'-Deoxy-3'-[(18)F]fluorothymidine is a thymidine analogue. Its uptake is regulated by thymidine kinase 1, and it is therefore taken up preferentially by rapidly proliferating tumour tissue. The fluorine isotope 18 is a positron emitter that is used in positron emission tomography (PET). This marker is therefore useful for PET imaging of active tumour proliferation, and compares favourably with the more commonly used marker 2-[(18)F]fluoro-2-deoxy-D-glucose.[48][49][50][51][52]

Selection of hybridomas[edit]

Hybridomas are cells obtained by fusing tumour cells (which can divide infinitely) and immunoglobulin-producing lymphocytes (plasma cells). Hybridomas can be expanded to produce large quantities of immunoglobulins with a given unique specificity (monoclonal antibodies). One problem is to single out the hybridomas from the large excess of unfused cells after the cell fusion. One common way to solve this is to use thymidine kinase negative (TK-) tumour cell lines for the fusion. The thymidine kinase negative cells are obtained by growing the tumour cell line in the presence of thymidine analogues, that kill the thymidine kinase positive (TK+) cells. The negative cells can then be expanded and used for the fusion with TK+ plasma cells. After fusion, the cells are grown in a medium with methotrexate[53] or aminopterin[54] that inhibit the enzyme dihydrofolate reductase thus blocking the de novo synthesis of thymidine monophosphate. One such medium that is commonly used is HAT medium, which contains hypoxanthine, aminopterin and thymidine. The unfused cells from the thymidine kinase-deficient cell line die because they have no source of thymidine monophosphate. The lymphocytes eventually die because they are not "immortal." Only the hybridomas that have "immortality" from their cell line ancestor and thymidine kinase from the plasma cell survive. Those that produce the desired antibody are then selected and cultured to produce the monoclonal antibody.[55][56][57][58][59]

Hybridoma cells can also be isolated using the same principle as described with respect to another gene the HGPRT, which synthesises IMP necessary for GMP nucleotide synthesis in the salvage pathway.

Clinical chemistry[edit]

Thymidine kinase is a salvage enzyme that is only present in anticipation of cell division. The enzyme is not set free from cells undergoing normal division where the cells have a special mechanism to degrade the proteins no longer needed after the cell division.[10] In normal subjects, the amount of thymidine kinase in serum or plasma is therefore very low. Tumour cells release enzyme to the circulation, probably in connection with the disruption of dead or dying tumour cells. The thymidine kinase level in serum therefore serves as a measure of malignant proliferation, indirectly as a measure of the aggressivity of the tumour. It is interesting to note that the form of enzyme present in the circulation does not correspond to the protein as encoded by the gene: the gene corresponds to a protein with molecular weight around 25 kD. It is a dimer with a molecular weight of around 50 kD, if activated by ATP a tetramer with molecular weight around 100 kD.[17] The main fraction of the active enzyme in the circulation has a molecular weight of 730 kD and is probably bound in a complex to other proteins.[60]

The most dramatic increases are seen in hematologic malignancies.[61] The main use of thymidine kinase assay now is in Non-Hodgkin lymphoma. This disease has a wide range of aggressivity, from slow-growing indolent disease that hardly requires treatment to highly aggressive, rapidly growing forms that should be treated urgently. This is reflected in the values of serum thymidine kinase, that range from close to the normal range for slow-growing tumours to very high levels for rapidly growing forms.[62][63][64][65][66][67][68][69]

Also in dogs, lymphomas cause elevations of serum TK levels, indicative of the disease activity and useful for management of the disease.[70][71]

Similar patterns can be seen in other hematological malignancies (leukemia,[72][73][74] myeloma[75][76] myelodysplastic syndrome). A very interesting case is the myelodysplastic syndrome: Some of them rapidly change to acute leukemia, whereas others remain indolent for very long time. Identification of those tending to change to overt leukemia is important for the treatment.[77][78]

Also solid tumours give increased values of thymidine kinase. Reports on this have been published for prostatic carcinoma, where thymidine kinase has been suggested as a supplement to PSA (Prostate Specific Antigen), the tumor marker now most frequently used in prostate cancer. Whereas PSA is considered to give an indication of the tumour mass, thymidine kinase indicates the rate of proliferation.[79][80][81][82] There are also reports of the utility of thymidine kinase measurements in serum in small cell lung cancer,[83][84] in breast cancer [85] and in kidney cancer.[86]

Non-malignant causes for elevation of thymidine kinase in serum are vitamin B12 deficiency, leading to pernicious anemia,[87][88] viral infections (particularly by virus from the herpes group)[88][89][90] and wound healing after trauma and operation.

Therapeutic[edit]

Some drugs are specifically directed against dividing cells. They can be used against tumours and viral diseases (both against retrovirus and against other virus), as the diseased cells replicate much more frequently than normal cells and also against some non-malignant diseases related to excessively rapid cell replication (for instance psoriasis). There are different classes of drugs to control too fast cell division that are directed against thymidine metabolism and thereby involving thymidine kinase:[91][92][93][94]

Chain terminators are thymidine analogues that are included in the growing DNA chain, but modified so that the chain cannot be further elongated. As analogues of thymidine, they are readily phosphorylated to 5'-monophosphates. The monophosphate is further phosphorylated to the corresponding triphosphate and incorporated in the growing DNA chain. The analogue has been modified so that it does not have the hydroxyl group in the 3'-position that is required for continued chain growth. In zidovudine (AZT; ATC: J05AF01) the 3'-hydroxyl group has been replaced by an azido group,[95][96] in Stavudine (ATC: J05AF04) it has been removed without replacement.[97][98] AZT is used as substrate in one of the methods for determination of thymidine kinase in serum.[99] This implies that AZT interferes with this method and may be a limitation: AZT is a standard component of HAART therapy in HIV infection. One common consequence of AIDS is lymphoma and the most important diagnostic application of thymidine kinase determination is for monitoring of lymphoma.

Chemical structures of thymidine kinase substrate analogs
AZT 
Stavudine 
Idoxuridine 
Aciclovir 
Ganciclovir 

Other thymidine analogues, for instance Idoxuridine (ATC: J05AB02) act by blocking base pairing during subsequent replication cycles, thereby making the resulting DNA chain defective.[100] This may also be combined with radioactivity to achieve apoptosis of malignant cells.[101]

Some antiviral drugs, such as acyclovir (ATC: J05AB01) and ganciclovir (ATC: J05AB06) as well as other recently developed nucleoside analogs[102] make use of the specificity for viral thymidine kinase, as opposed to human thymidine kinases.[103] These drugs act as prodrugs, which in themselves are not toxic, but are converted to toxic drugs by phosphorylation by viral thymidine kinase. Cells infected with the virus therefore produce highly toxic triphosphates that lead to cell death. Human thymidine kinase, in contrast, with its more narrow specificity, is unable to phosphorylate and activate the prodrug. In this way, only cells infected by the virus are susceptible to the drug. Such drugs are effective only against viruses from the herpes group with their specific thymidine kinase.[104]

After smallpox was declared eradicated by WHO in December 1979, vaccination programs were terminated. A re-emergence of the disease either by accident or as a result of biological warfare would meet an unprotected population and could result in an epidemic that could be difficult to control. Mass vaccination would be unethical, as the only efficient vaccines against smallpox include live vaccinia virus with severe adverse effects on rare occasions. As one protective measure, large amounts of vaccine are kept in stock, but an efficient drug against smallpox has high priority. One possible approach would be to use the specificity of the thymidine kinase of poxvirus for the purpose, in a similar way that it is used for drugs against herpesvirus. One difficulty is that the poxvirus thymidine kinase belongs to the same family of thymidine kinases as the human thymidine kinases and thereby is more similar chemically. The structure of poxvirus thymidine kinases has therefore been determined to find potential antiviral drugs.[105] The search has however not yet resulted in a usable antiviral drug against poxviruses.

The herpesvirus thymidine kinase gene has also been used as a “suicide gene” as a safety system in gene therapy experiments, allowing cells expressing the gene to be killed using ganciclovir. This is desirable in case the recombinant gene causes a mutation leading to uncontrolled cell growth (insertional mutagenesis). The thymidine kinase produced by these modified cells may diffuse to neighboring cells, rendering them similarly susceptible to ganciclovir, a phenomenon known as the "bystander effect." This approach has been used to treat cancer in animal models, and is advantageous in that the tumor may be killed with as few as 10% of malignant cells expressing the gene.[106][107]

A similar use of the thymidine kinase makes use of the presence in some tumor cells of substances not present in normal cells (tumor markers). Such tumor markers are, for instance, CEA (carcinoembryonic antigen) and AFP (alpha fetoprotein). The genes for these tumor markers may be used as promoter genes for thymidine kinase. Thymidine kinase can then be activated in cells expressing the tumor marker but not in normal cells, such that treatment with ganciclovir kills only the tumor cells.[108][109][110][111][112][113] Such gene therapy-based approaches are still experimental, however, as problems associated with gene transfer have not yet been completely solved.

Incorporation of a thymidine analogue with boron has been suggested and tried in animal models for boron neutron capture therapy of brain tumours.[114][115][116][117][118][119][120][121][122][123][124]

Measurement[edit]

In serum[edit]

The level of thymidine kinase in serum or plasma is so low that the measurement is best based on the enzymatic activity. In commercial assays, this is done by incubation of a serum sample with a substrate analogue. The oldest commercially available technique uses iodo-deoxyuridine wherein a methyl group in thymidine has been replaced with radioactive iodine.[125][126][127] This substrate is well accepted by the enzyme. The monophosphate of iododeoxyuridine is adsorbed on aluminium oxide that is suspended in the incubation medium. After decantation and washing the radioactivity of the aluminium oxide gives a measure of the amount of thymidine kinase in the sample. Kits using this principle are commercially available from the companies Immunotech/Beckman and DiaSorin.

A non-radioactive assay method has been developed by the company Dia-Sorin. In this technique 3'-azido-2',3'-deoxythymidine (AZT)is first phosphorylated to AZT 5'-monophosphate (AZTMP) by TK1 in the sample. AZTMP is measured in an immunoassay with anti-AZTMP antibodies and AZTMP-labeled peroxidase. The assay runs in a closed system on the laboratory robot from DiaSorin[71][99]

Another newly developed technique uses a thymidine analogue, bromo-deoxyuridine, as substrate to the enzyme. The product of the reaction (in microtiter plates) binds to the bottom of the wells in the plate. There it is detected with ELISA technique: The wells are filled with a solution of a monoclonal antibody to bromo-deoxyuridine. The monoclonal antibody has been bound (conjugated) to alkaline phosphatase (an enzyme). After the unbound antibody with attached alkaline phosphatase has been washed away, a solution of a substrate to the alkaline phosphatase, 4-nitrophenyl phosphate, is added. The product of the reaction, 4-nitrophenol, is yellow at alkaline pH and can be measured by photometry.[128] This assay gives a considerably more sensitive determination. It is commercially available from the company Biovica.

Direct determination of the thymidine kinase protein by immunoassay has also been used.[129][130][131] The amounts of thymidine kinase found by this method did not correlate well with the activities and found to have less clinical significance, and the method has been withdrawn from the market.

In tissue[edit]

Thymidine kinase has been determined in tissue samples after extraction of the tissue. No standard method for the extraction or for the assay has been developed and TK determination in extracts from cells and tissues have not been validated in relation to any specific clinical question, see however Romain et al.[132] and Arnér et al.[133] A method has been developed for specific determination of TK2 in cell extracts using the substrate analogue 5-Bromovinyl 2'-deoxyuridine.[134] In the studies referred to below the methods used and the way the results are reported are so different that comparisons between different studies are not possible.

The TK1 levels in fetal tissues during development are higher than those of the corresponding tissues later.[135][136][137]

Certain non-malignant diseases also give rise to dramatic elevation of TK values in cells and tissue: in peripheric lymphocytes during monocytosis[138] and in bone marrow during pernicious anemia.[139][140]

As TK1 is present in cells during cell division, it is reasonable to assume that the TK activity in malignant tissue should be higher than in corresponding normal tissue. This is also confirmed in most studies. A higher TK activity is found in neoplastic than in normal tissue,[135][141][142][143] in brain tumours,[144] in hematological malignancies,[145] in cancer and polyps in colon,[146][147][148][149][150][151] in breast cancer,[152][153][154][155][156][157] in lung cancer,[158][159][160] in gastric cancers,[161] in ovarian cancer,[162] in mesotheliomas,[163] in melanomas[164] and in thyroid tumours.[165][166]

In leukemia[167][168] and in breast cancer [169] therapy that influences the rate of cell proliferation influences the TK values correspondingly.

Immunohistochemical staining for thymidine kinase[edit]

Antibodies against thymidine kinase are available for immunohistochemical detection.[170] Staining for thymidine kinase was a reliable technique for identification of patients with stage 2 breast carcinoma. The highest number of patients identified was obtained by combination of thymidine kinase and Ki-67 staining.[171][172]

The technique has also been validated for lung cancer,[171][173] for colorectal carcinima,[174] for lung cancer[175] and for renal cell carcinoma.[176]

See also[edit]

Further reading[edit]

Three survey articles on different aspcets of thymidine kinase are available from the internet site of Biovica International:

References[edit]

  1. ^ PDB 2B8T; Kosinska U, Carnrot C, Eriksson S, Wang L, Eklund H (December 2005). "Structure of the substrate complex of thymidine kinase from Ureaplasma urealyticum and investigations of possible drug targets for the enzyme". FEBS J. 272 (24): 6365–72. doi:10.1111/j.1742-4658.2005.05030.x. PMID 16336273. 
  2. ^ Kit S (December 1985). "Thymidine kinase". Microbiol. Sci. 2 (12): 369–75. PMID 3939993. 
  3. ^ Wintersberger E (February 1997). "Regulation and biological function of thymidine kinase". Biochem. Soc. Trans. 25 (1): 303–8. PMID 9056888. 
  4. ^ Reichard P, Estborn B (February 1951). "Utilization of desoxyribosides in the synthesis of polynucleotides". J. Biol. Chem. 188 (2): 839–46. PMID 14824173. 
  5. ^ Kornberg A, Lehman IR, Simms ES (1956). "Polydeoxyribonucleotide synthesis by enzymes from Eschrichia coli". Fed. Proc. 15: 291–2. 
  6. ^ Bollum FJ, Van Potter R (August 1958). "Incorporation of thymidine into deoxyribonucleic acid by enzymes from rat tissues". J. Biol. Chem. 233 (2): 478–82. PMID 13563524. 
  7. ^ Weissman SM, Smellie RMS, Paul J (December 1960). "Studies on the biosynthesis of deoxyribonucleic acid by extracts of mammalian cells. IV. The phosphorylation of thymidine". Biochim. Biophys. Acta 45: 101–10. doi:10.1016/0006-3002(60)91430-X. PMID 13784139. 
  8. ^ Boyle DB, Gibbs AJ, Seigman LJ, Both GW, Coupar BE (1987). "Fowlpox virus thymidine kinase: nucleotide sequence and relationships to other thymidine kinases". Virology 156 (2): 355–365. doi:10.1016/0042-6822(87)90415-6. PMID 3027984. 
  9. ^ Lopez-Otin C, Blasco R, Vinuela E, Munoz M, Simon-Mateo C, Bockamp EO (1990). "Sequence and evolutionary relationships of African swine fever virus thymidine kinase". Virology 178 (1): 301–304. doi:10.1016/0042-6822(90)90409-K. PMID 2389555. 
  10. ^ a b Littlefield JW (February 1966). "The periodic synthesis of thymidine kinase in mouse fibroblasts". Biochim. Biophys. Acta 114 (2): 398–403. doi:10.1016/0005-2787(66)90319-4. PMID 4223355. 
  11. ^ Bello LJ (December 1974). "Regulation of thymidine kinase synthesis in human cells". Exp. Cell Res. 89 (2): 263–74. doi:10.1016/0014-4827(74)90790-3. PMID 4457349. 
  12. ^ Berk AJ, Clayton DA (April 1973). "A genetically distinct thymidine kinase in mammalian mitochondria. Exclusive labeling of mitochondrial deoxyribonucleic acid". J. Biol. Chem. 248 (8): 2722–9. PMID 4735344. 
  13. ^ Berk AJ, Meyer BJ, Clayton DA (February 1973). "Mitochondrial-specific thymidine kinase". Arch. Biochem. Biophys. 154 (2): 563–5. doi:10.1016/0003-9861(73)90009-X. PMID 4632422. 
  14. ^ Elsevier SM, Kucherlapati RS, Nichols EA, Creagan RP, Giles RE, Ruddle FH, Willecke K, McDougall JK (October 1974). "Assignment of the gene for galactokinase to human chromosome 17 and its regional localisation to band q21-22". Nature 251 (5476): 633–6. Bibcode:1974Natur.251..633E. doi:10.1038/251633a0. PMID 4371022. 
  15. ^ Willecke K, Teber T, Kucherlapati RS, Ruddle FH (May 1977). "Human mitochondrial thymidine kinase is coded for by a gene on chromosome 16 of the nucleus". Somatic Cell Genet. 3 (3): 237–45. doi:10.1007/BF01538743. PMID 605384. 
  16. ^ Flemington E, Bradshaw HD, Traina-Dorge V, Slagel V, Deininger PL (1987). "Sequence, structure and promoter characterization of the human thymidine kinase gene". Gene 52 (2–3): 267–77. doi:10.1016/0378-1119(87)90053-9. PMID 3301530. 
  17. ^ a b Welin M, Kosinska U, Mikkelsen NE, et al. (December 2004). "Structures of thymidine kinase 1 of human and mycoplasmic origin". Proc. Natl. Acad. Sci. U.S.A. 101 (52): 17970–5. Bibcode:2004PNAS..10117970W. doi:10.1073/pnas.0406332102. PMC 539776. PMID 15611477. 
  18. ^ a b Munch-Petersen B, Cloos L, Jensen HK, Tyrsted G (1995). "Human thymidine kinase 1. Regulation in normal and malignant cells". Adv. Enzyme Regul. 35: 69–89. doi:10.1016/0065-2571(94)00014-T. PMID 7572355. 
  19. ^ Li CL, Lu CY, Ke PY, Chang ZF (January 2004). "Perturbation of ATP-induced tetramerization of human cytosolic thymidine kinase by substitution of serine-13 with aspartic acid at the mitotic phosphorylation site". Biochem. Biophys. Res. Commun. 313 (3): 587–93. doi:10.1016/j.bbrc.2003.11.147. PMID 14697231. 
  20. ^ Zhu C, Harlow LS, Berenstein D, Munch-Petersen S, Munch-Petersen B (2006). "Effect of C-terminal of human cytosolic thymidine kinase (TK1) on in vitro stability and enzymatic properties". Nucleosides Nucleotides Nucleic Acids 25 (9–11): 1185–8. doi:10.1080/15257770600894436. PMID 17065087. 
  21. ^ Van, P. (1963). "Feedback Inhibition of Thymidine Kinase by Thymidine Triphosphate". Experimental cell research 24: SUPPL9:SUP259–62. PMID 14046233.  edit
  22. ^ Severin, E. S.; Itkes, A. V.; Kartasheva, O. N.; Tunitskaya, V. L.; Turpaev, K. T.; Kafiani, C. A. (1985). "Regulation of 2-5 a phosphodiesterase activity by cAMP-dependent phosphorylation: Mechanism and biological role". Advances in enzyme regulation 23: 365–376. doi:10.1016/0065-2571(85)90056-1. PMID 3000146.  edit
  23. ^ Mikkelsen, N. E.; Johansson, K.; Karlsson, A.; Knecht, W.; Andersen, G.; Piskur, J.; Munch-Petersen, B.; Eklund, H. (2003). "Structural Basis for Feedback Inhibition of the Deoxyribonucleoside Salvage Pathway:  Studies of the Drosophila Deoxyribonucleoside Kinase†". Biochemistry 42 (19): 5706–5712. doi:10.1021/bi0340043. PMID 12741827.  edit
  24. ^ Fischer, P. H.; Phillips, A. W. (1984). "Antagonism of feedback inhibition. Stimulation of the phosphorylation of thymidine and 5-iodo-2'-deoxyuridine by 5-iodo-5'-amino-2',5'-dideoxyuridine". Molecular Pharmacology 25 (3): 446–451. PMID 6727866.  edit
  25. ^ Fischer, P. H.; Vazquez-Padua, M. A.; Reznikoff, C. A. (1986). "Perturbation of thymidine kinase regulation: A novel chemotherapeutic approach". Advances in enzyme regulation 25: 21–34. doi:10.1016/0065-2571(86)90006-3. PMID 3812083.  edit
  26. ^ Fischer, P. H.; Vazquez-Padua, M. A.; Reznikoff, C. A.; Ratschan, W. J. (1986). "Preferential stimulation of iododeoxyuridine phosphorylation by 5'-aminothymidine in human bladder cancer cells in vitro". Cancer Research 46 (9): 4522–4526. PMID 3731105.  edit
  27. ^ Fischer, P. H.; Fang, T. T.; Lin, T. S.; Hampton, A.; Bruggink, J. (1988). "Structure-activity analysis of antagonism of the feedback inhibition of thymidine kinase". Biochemical pharmacology 37 (7): 1293–1298. doi:10.1016/0006-2952(88)90785-X. PMID 3355601.  edit
  28. ^ Vazquez-Padua, M. A.; Kunugi, K.; Fischer, P. H. (1989). "Enzyme regulatory site-directed drugs: Study of the interactions of 5'-amino-2', 5'-dideoxythymidine (5'-AdThd) and thymidine triphosphate with thymidine kinase and the relationship to the stimulation of thymidine uptake by 5'-AdThd in 647V cells". Molecular Pharmacology 35 (1): 98–104. PMID 2536472.  edit
  29. ^ Vazquez-Padua, M. A.; Fischer, P. H.; Christian, B. J.; Reznikoff, C. A. (1989). "Basis for the differential modulation of the uptake of 5-iododeoxyuridine by 5'-aminothymidine among various cell types". Cancer Research 49 (9): 2415–2421. PMID 2706629.  edit
  30. ^ Vázquez-Padua, M. A. (1994). "Modulation of thymidine kinase activity: A biochemical strategy to enhance the activation of antineoplastic drugs". Puerto Rico health sciences journal 13 (1): 19–23. PMID 8016290.  edit
  31. ^ McKnight SL (December 1980). "The nucleotide sequence and transcript map of the herpes simplex virus thymidine kinase gene". Nucleic Acids Res. 8 (24): 5949–64. doi:10.1093/nar/8.24.5949. PMC 328064. PMID 6258156. 
  32. ^ Halliburton IW, Morse LS, Roizman B, Quinn KE (August 1980). "Mapping of the thymidine kinase genes of type 1 and type 2 herpes simplex viruses using intertypic recombinants". J. Gen. Virol. 49 (2): 235–53. doi:10.1099/0022-1317-49-2-235. PMID 6255066. 
  33. ^ McDougall JK, Masse TH, Galloway DA (March 1980). "Location and cloning of the herpes simplex virus type 2 thymidine kinase gene". J. Virol. 33 (3): 1221–4. PMC 288658. PMID 6245273. 
  34. ^ Kit S, Kit M, Qavi H, Trkula D, Otsuka H (November 1983). "Nucleotide sequence of the herpes simplex virus type 2 (HSV-2) thymidine kinase gene and predicted amino acid sequence of thymidine kinase polypeptide and its comparison with the HSV-1 thymidine kinase gene". Biochim. Biophys. Acta 741 (2): 158–70. doi:10.1016/0167-4781(83)90056-8. PMID 6317035. 
  35. ^ Sawyer MH, Ostrove JM, Felser JM, Straus SE (February 1986). "Mapping of the varicella zoster virus deoxypyrimidine kinase gene and preliminary identification of its transcript". Virology 149 (1): 1–9. doi:10.1016/0042-6822(86)90081-4. PMID 3004022. 
  36. ^ Littler E, Zeuthen J, McBride AA, Trøst Sørensen E, Powell KL, Walsh-Arrand JE, Arrand JR (August 1986). "Identification of an Epstein-Barr virus-coded thymidine kinase". EMBO J. 5 (8): 1959–66. PMC 1167064. PMID 3019675. 
  37. ^ Kit S, Dubbs DR (April 1963). "Acquisition of thymidine kinase activity by herpes simplex-infected mouse fibroblast cells". Biochem. Biophys. Res. Commun. 11: 55–9. doi:10.1016/0006-291X(63)90027-5. PMID 14033128. 
  38. ^ Schlosser CA, Steglich C, deWet JR, Scheffler IE (February 1981). "Cell cycle-dependent regulation of thymidine kinase activity introduced into mouse LMTK- cells by DNA and chromatin-mediated gene transfer". Proc. Natl. Acad. Sci. U.S.A. 78 (2): 1119–23. Bibcode:1981PNAS...78.1119S. doi:10.1073/pnas.78.2.1119. PMC 319958. PMID 6940130. 
  39. ^ Coppock DL, Pardee AB (August 1987). "Control of thymidine kinase mRNA during the cell cycle". Mol. Cell. Biol. 7 (8): 2925–32. PMC 367911. PMID 3670299. 
  40. ^ Stewart CJ, Ito M, Conrad SE (March 1987). "Evidence for transcriptional and post-transcriptional control of the cellular thymidine kinase gene". Mol. Cell. Biol. 7 (3): 1156–63. PMC 365188. PMID 3561412. 
  41. ^ Piper AA, Tattersall MH, Fox RM (December 1980). "The activities of thymidine metabolising enzymes during the cell cycle of a human lymphocyte cell line LAZ-007 synchronised by centrifugal elutriation". Biochim. Biophys. Acta 633 (3): 400–9. doi:10.1016/0304-4165(80)90198-1. PMID 6260157. 
  42. ^ Pelka-Fleischer R, Ruppelt W, Wilmanns W, Sauer H, Schalhorn A (March 1987). "Relation between cell cycle stage and the activity of DNA-synthesizing enzymes in cultured human lymphoblasts: investigations on cell fractions enriched according to cell cycle stages by way of centrifugal elutriation". Leukemia 1 (3): 182–7. PMID 3669741. 
  43. ^ Sherley JL, Kelly TJ (June 1988). "Regulation of human thymidine kinase during the cell cycle". J. Biol. Chem. 263 (17): 8350–8. PMID 3372530. 
  44. ^ Gross MK, Kainz MS, Merrill GF (August 1987). "The chicken thymidine kinase gene is transcriptionally repressed during terminal differentiation: the associated decline in TK mRNA cannot account fully for the disappearance of TK enzyme activity". Dev. Biol. 122 (2): 439–51. doi:10.1016/0012-1606(87)90308-3. PMID 3596017. 
  45. ^ Kauffman MG, Kelly TJ (May 1991). "Cell cycle regulation of thymidine kinase: residues near the carboxyl terminus are essential for the specific degradation of the enzyme at mitosis". Mol. Cell. Biol. 11 (5): 2538–46. PMC 360023. PMID 1708095. 
  46. ^ Sutterluety H, Bartl S, Karlseder J, Wintersberger E, Seiser C (June 1996). "Carboxy-terminal residues of mouse thymidine kinase are essential for rapid degradation in quiescent cells". J. Mol. Biol. 259 (3): 383–92. doi:10.1006/jmbi.1996.0327. PMID 8676376. 
  47. ^ Johnson HA, Rubini JR, Cronkite EP, Bond VP (1960). "Labeling of human tumor cells in vivo by tritiated thymidine". Lab. Invest. 9: 460–5. PMID 14407455. 
  48. ^ Barthel H, Cleij MC, Collingridge DR, et al. (July 2003). "3'-deoxy-3'-[18F]fluorothymidine as a new marker for monitoring tumor response to antiproliferative therapy in vivo with positron emission tomography". Cancer Res. 63 (13): 3791–8. PMID 12839975. 
  49. ^ Chao KS (December 2006). "Functional imaging for early prediction of response to chemoradiotherapy: 3'-deoxy-3'-18F-fluorothymidine positron emission tomography--a clinical application model of esophageal cancer". Semin. Oncol. 33 (6 Suppl 11): S59–63. doi:10.1053/j.seminoncol.2006.10.011. PMID 17178290. 
  50. ^ Salskov A, Tammisetti VS, Grierson J, Vesselle H (November 2007). "FLT: measuring tumor cell proliferation in vivo with positron emission tomography and 3'-deoxy-3'-[18F]fluorothymidine". Semin Nucl Med 37 (6): 429–39. doi:10.1053/j.semnuclmed.2007.08.001. PMID 17920350. 
  51. ^ de Langen AJ, Klabbers B, Lubberink M, et al. (October 2008). "Reproducibility of quantitative (18)F-3'-deoxy-3'-fluorothymidine measurements using positron emission tomography". Eur. J. Nucl. Med. Mol. Imaging 36 (3): 389–95. doi:10.1007/s00259-008-0960-5. PMID 18931838. 
  52. ^ Shields AF, Lawhorn-Crews JM, Briston DA, et al. (July 2008). "Analysis and reproducibility of 3'-Deoxy-3'-[18F]fluorothymidine positron emission tomography imaging in patients with non-small cell lung cancer". Clin. Cancer Res. 14 (14): 4463–8. doi:10.1158/1078-0432.CCR-07-5243. PMID 18628460. 
  53. ^ Methotrexate - Compound Summary
  54. ^ Aminopterin - Compound Summary
  55. ^ Köhler G, Milstein C (August 1975). "Continuous cultures of fused cells secreting antibody of predefined specificity". Nature 256 (5517): 495–7. Bibcode:1975Natur.256..495K. doi:10.1038/256495a0. PMID 1172191. 
  56. ^ Köhler G, Howe SC, Milstein C (April 1976). "Fusion between immunoglobulin-secreting and nonsecreting myeloma cell lines". Eur. J. Immunol. 6 (4): 292–5. doi:10.1002/eji.1830060411. PMID 825374. 
  57. ^ Köhler G, Milstein C (July 1976). "Derivation of specific antibody-producing tissue culture and tumor lines by cell fusion". Eur. J. Immunol. 6 (7): 511–9. doi:10.1002/eji.1830060713. PMID 825377. 
  58. ^ Köhler G, Pearson T, Milstein C (May 1977). "Fusion of T and B cells". Somatic Cell Genet. 3 (3): 303–12. doi:10.1007/BF01538748. PMID 305123. 
  59. ^ Milstein C, Adetugbo K, Cowan NJ, Kohler G, Secher DS (May 1978). "Expression of antibody genes in tissue culture: structural mutants and hybrid cells". Natl Cancer Inst Monogr (48): 321–30. PMID 107455. 
  60. ^ Karlström AR, Neumüller M, Gronowitz JS, Källander CF (January 1990). "Molecular forms in human serum of enzymes synthesizing DNA precursors and DNA". Mol. Cell. Biochem. 92 (1): 23–35. doi:10.1007/BF00220716. PMID 2155379. 
  61. ^ Doi S, Naito K, Yamada K (March 1990). "Serum deoxythymidine kinase as a progressive marker of hematological malignancy". Nagoya J Med Sci 52 (1–4): 19–26. PMID 2381458. 
  62. ^ Ellims PH, Van der Weyden MB, Medley G (February 1981). "Thymidine kinase isoenzymes in human malignant lymphoma". Cancer Res. 41 (2): 691–5. PMID 7448815. 
  63. ^ Hagberg H, Glimelius B, Gronowitz JS, Killander A, Källander CFR, Schröder T (July 1984). "Biochemical markers in non-Hodgkin's lymphoma stages III and IV and prognosis: a multivariate analysis". Scand J Haematol 33 (1): 59–67. doi:10.1111/j.1600-0609.1984.tb02211.x. PMID 6379852. 
  64. ^ Gronowitz JS, Hagberg H, Källander CFR, Simonsson B (April 1983). "The use of serum deoxythymidine kinase as a prognostic marker, and in the monitoring of patients with non-Hodgkin's lymphoma". Br. J. Cancer 47 (4): 487–95. doi:10.1038/bjc.1983.78. PMC 2011337. PMID 6849793. 
  65. ^ Hallek M, Wanders L, Strohmeyer S, Emmerich B (July 1992). "Thymidine kinase: a tumor marker with prognostic value for non-Hodgkin's lymphoma and a broad range of potential clinical applications". Ann. Hematol. 65 (1): 1–5. doi:10.1007/BF01715117. PMID 1643153. 
  66. ^ Bogni A, Cortinois A, Grasselli G, et al. (1994). "Thymidine kinase (TK) activity as a prognostic parameter of survival in lymphoma patients". J. Biol. Regul. Homeost. Agents 8 (4): 121–5. PMID 7660854. 
  67. ^ Rehn S, Gronowitz JS, Källander C, Sundström C, Glimelius B (May 1995). "Deoxythymidine kinase in the tumour cells and serum of patients with non-Hodgkin lymphomas". Br. J. Cancer 71 (5): 1099–105. doi:10.1038/bjc.1995.213. PMC 2033808. PMID 7734308. 
  68. ^ Suki S, Swan F, Tucker S, et al. (June 1995). "Risk classification for large cell lymphoma using lactate dehydrogenase, beta-2 microglobulin, and thymidine kinase". Leuk. Lymphoma 18 (1–2): 87–92. doi:10.3109/10428199509064927. PMID 8580834. 
  69. ^ Hallek M, Wanders L, Ostwald M, et al. (August 1996). "Serum beta(2)-microglobulin and serum thymidine kinase are independent predictors of progression-free survival in chronic lymphocytic leukemia and immunocytoma". Leuk. Lymphoma 22 (5–6): 439–47. doi:10.3109/10428199609054782. PMID 8882957. 
  70. ^ von Euler H, Einarsson R, Olsson U, Lagerstedt AS, Eriksson S (2004). "Serum thymidine kinase activity in dogs with malignant lymphoma: a potent marker for prognosis and monitoring the disease". J. Vet. Intern. Med. 18 (5): 696–702. doi:10.1892/0891-6640(2004)18<696:STKAID>2.0.CO;2. ISSN 0891-6640. PMID 15515587. 
  71. ^ a b Voneuler, H.; Ohrvik, A.; Eriksson, S. (2006). "A non-radiometric method for measuring serum thymidine kinase activity in malignant lymphoma in dogs". Research in Veterinary Science 80 (1): 17–24. doi:10.1016/j.rvsc.2005.05.001. PMID 16140350.  edit
  72. ^ Källander CFR, Simonsson B, Gronowitz JS, Nilsson K (April 1987). "Serum deoxythymidine kinase correlates with peripheral lymphocyte thymidine uptake in chronic lymphocytic leukemia". Eur. J. Haematol. 38 (4): 331–7. doi:10.1111/j.1600-0609.1987.tb00007.x. PMID 3609253. 
  73. ^ Källander CFR, Simonsson B, Hagberg H, Gronowitz JS (December 1984). "Serum deoxythymidine kinase gives prognostic information in chronic lymphocytic leukemia". Cancer 54 (11): 2450–5. doi:10.1002/1097-0142(19841201)54:11<2450::AID-CNCR2820541123>3.0.CO;2-R. PMID 6498737. 
  74. ^ Rivkina, A.; Vitols, G.; Murovska, M.; Lejniece, S. (2011). "Identifying the stage of new CLL patients using TK, ZAP-70, CD38 levels". Experimental oncology 33 (2): 99–103. PMID 21716207.  edit
  75. ^ Simonsson B, Källander CFR, Brenning G, Killander A, Gronowitz JS, Bergström R (May 1988). "Biochemical markers in multiple myeloma: a multivariate analysis". Br. J. Haematol. 69 (1): 47–53. doi:10.1111/j.1365-2141.1988.tb07601.x. PMID 3289607. 
  76. ^ Simonsson B, Källander CFR, Brenning G, Killander A, Ahre A, Gronowitz JS (October 1985). "Evaluation of serum deoxythymidine kinase as a marker in multiple myeloma". Br. J. Haematol. 61 (2): 215–24. doi:10.1111/j.1365-2141.1985.tb02820.x. PMID 4041368. 
  77. ^ Musto P, Bodenizza C, Falcone A, et al. (May 1995). "Prognostic relevance of serum thymidine kinase in primary myelodysplastic syndromes: relationship to development of acute myeloid leukaemia". Br. J. Haematol. 90 (1): 125–30. doi:10.1111/j.1365-2141.1995.tb03390.x. PMID 7786774. 
  78. ^ Aul C, Germing U, Gattermann N, Söhngen D, Heyll A (September 1996). "[The prognostic significance of serum thymidine kinase in the myelodysplastic syndrome]" [The prognostic significance of serum thymidine kinase in the myelodysplastic syndrome]. Dtsch. Med. Wochenschr. (in German) 121 (37): 1113–8. doi:10.1055/s-2008-1043114. PMID 8925725. 
  79. ^ Larson A, Fritjofsson A, Norlén BJ, Gronowitz JS, Ronquist G (1985). "Prostate specific acid phosphatase versus five other possible tumour markers: a comparative study in men with prostatic carcinoma". Scand. J. Clin. Lab. Invest. Suppl. 179: 81–8. PMID 2417306. 
  80. ^ Letocha H, Eklöv S, Gronowitz S, Norlén BJ, Nilsson S (July 1996). "Deoxythymidine kinase in the staging of prostatic adenocarcinoma". Prostate 29 (1): 15–9. doi:10.1002/(SICI)1097-0045(199607)29:1<15::AID-PROS2>3.0.CO;2-H. PMID 8685050. 
  81. ^ Lewenhaupt A, Ekman P, Eneroth P, Nilsson B (August 1990). "Tumour markers as prognostic aids in prostatic carcinoma". Br J Urol 66 (2): 182–7. doi:10.1111/j.1464-410X.1990.tb14900.x. PMID 1697204. 
  82. ^ Ekman P, Lewenhaupt A (1991). "Serum tumour markers in human prostatic carcinoma. The value of a marker panel for prognostic information". Acta Oncol 30 (2): 173–5. doi:10.3109/02841869109092345. PMID 2029401. 
  83. ^ Gronowitz JS, Bergström R, Nôu E, et al. (August 1990). "Clinical and serologic markers of stage and prognosis in small cell lung cancer. A multivariate analysis". Cancer 66 (4): 722–32. doi:10.1002/1097-0142(19900815)66:4<722::AID-CNCR2820660421>3.0.CO;2-J. PMID 2167141. 
  84. ^ Gronowitz JS, Steinholtz L, Källander CF, Hagberg H, Bergh J (July 1986). "Serum deoxythymidine kinase in small cell carcinoma of the lung. Relation to clinical features, prognosis, and other biochemical markers". Cancer 58 (1): 111–8. doi:10.1002/1097-0142(19860701)58:1<111::AID-CNCR2820580120>3.0.CO;2-K. PMID 3011236. 
  85. ^ Nisman, B.; Allweis, T.; Kaduri, L.; Maly, B.; Gronowitz, S.; Hamburger, T.; Peretz, T. (2010). "Serum thymidine kinase 1 activity in breast cancer". Cancer biomarkers : section a of Disease markers 7 (2): 65–72. doi:10.3233/CBM-2010-0148 (inactive 2014-06-04). PMID 21178264.  edit
  86. ^ Nisman, B.; Yutkin, V.; Nechushtan, H.; Gofrit, O. N.; Peretz, T.; Gronowitz, S.; Pode, D. (2010). "Circulating Tumor M2 Pyruvate Kinase and Thymidine Kinase 1 Are Potential Predictors for Disease Recurrence in Renal Cell Carcinoma After Nephrectomy". Urology 76 (2): 513.5e1–513.5e1. doi:10.1016/j.urology.2010.04.034. PMID 20573390.  edit
  87. ^ Ellims, P. H.; Hayman, R. J.; Van Der Weyden, M. B. (1979). "Expression of fetal thymidine kinase in human cobalamin or folate deficient lymphocytes". Biochemical and Biophysical Research Communications 89 (1): 103–107. doi:10.1016/0006-291X(79)90949-5. PMID 475797.  edit
  88. ^ a b Neumuller, M.; Källander, C. F.; Gronowitz, J. S. (1989). "Detection and characteristics of DNA polymerase activity in serum from patients with malignant, viral, or B12-deficiency disease". Enzyme 41 (1): 6–16. PMID 2543552.  edit
  89. ^ Tufveson, G.; Tötterman, T. H.; Källander, C. F.; Hagström, A.; Gronowitz, J. S. (1988). "Serum thymidine-kinase and cytomegalovirus-specific antibodies after renal transplantation". Transplantation proceedings 20 (3): 405–407. PMID 2837850.  edit
  90. ^ Källander, C. F.; Gronowitz, J. S.; Olding-Stenkvist, E. (1983). "Rapid diagnosis of varicella-zoster virus infection by detection of viral deoxythymidine kinase in serum and vesicle fluid". Journal of clinical microbiology 17 (2): 280–287. PMC 272623. PMID 6339548.  edit
  91. ^ Lin TS, Neenan JP, Cheng YC, Prusoff WH (April 1976). "Synthesis and antiviral activity of 5- and 5'-substituted thymidine analogs". Journal of Medicinal Chemistry 19 (4): 495–8. doi:10.1021/jm00226a009. PMID 177781. 
  92. ^ Helgstrand E, Oberg B (1980). "Enzymatic targets in virus chemotherapy". Antibiot Chemother 27: 22–69. PMID 6996606. 
  93. ^ Shannon WM, Schabel FM (1980). "Antiviral agents as adjuncts in cancer chemotherapy". Pharmacol. Ther. 11 (2): 263–390. doi:10.1016/0163-7258(80)90034-0. PMID 7001501. 
  94. ^ Hirsch MS (May 1990). "Chemotherapy of human immunodeficiency virus infections: current practice and future prospects". J. Infect. Dis. 161 (5): 845–57. doi:10.1093/infdis/161.5.845. PMID 1691243. 
  95. ^ Shiau GT, Schinazi RF, Chen MS, Prusoff WH (February 1980). "Synthesis and biological activities of 5-(hydroxymethyl, azidomethyl, or aminomethyl)-2'-deoxyuridine and related 5'-substituted analogues". Journal of Medicinal Chemistry 23 (2): 127–33. doi:10.1021/jm00176a005. PMID 6244411. 
  96. ^ Mitsuya H, Weinhold KJ, Furman PA, et al. (October 1985). "3'-Azido-3'-deoxythymidine (BW A509U): an antiviral agent that inhibits the infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy-associated virus in vitro". Proc. Natl. Acad. Sci. U.S.A. 82 (20): 7096–100. Bibcode:1985PNAS...82.7096M. doi:10.1073/pnas.82.20.7096. PMC 391317. PMID 2413459. 
  97. ^ Baba M, Pauwels R, Herdewijn P, De Clercq E, Desmyter J, Vandeputte M (January 1987). "Both 2',3'-dideoxythymidine and its 2',3'-unsaturated derivative (2',3'-dideoxythymidinene) are potent and selective inhibitors of human immunodeficiency virus replication in vitro". Biochem. Biophys. Res. Commun. 142 (1): 128–34. doi:10.1016/0006-291X(87)90460-8. PMID 3028398. 
  98. ^ Hamamoto Y, Nakashima H, Matsui T, Matsuda A, Ueda T, Yamamoto N (June 1987). "Inhibitory effect of 2',3'-didehydro-2',3'-dideoxynucleosides on infectivity, cytopathic effects, and replication of human immunodeficiency virus". Antimicrob. Agents Chemother. 31 (6): 907–10. doi:10.1128/aac.31.6.907. PMC 284209. PMID 3039911. 
  99. ^ a b Ohrvik A, Lindh M, Einarsson R, Grassi J, Eriksson S (September 2004). "Sensitive nonradiometric method for determining thymidine kinase 1 activity". Clin. Chem. 50 (9): 1597–606. doi:10.1373/clinchem.2003.030379. PMID 15247154. 
  100. ^ Prusoff WH (March 1959). "Synthesis and biological activities of iododeoxyuridine, an analog of thymidine". Biochim. Biophys. Acta 32 (1): 295–6. doi:10.1016/0006-3002(59)90597-9. PMID 13628760. 
  101. ^ Morgenroth A, Deisenhofer S, Glatting G, et al. (November 2008). "Preferential Tumor Targeting and Selective Tumor Cell Cytotoxicity of 5-[131/125I]Iodo-4'-Thio-2'-Deoxyuridine". Clin. Cancer Res. 14 (22): 7311–9. doi:10.1158/1078-0432.CCR-08-0907. PMID 19010846. 
  102. ^ Andrei, G.; Snoeck, R. (2011). "Emerging drugs for varicella-zoster virus infections". Expert Opinion on Emerging Drugs 16 (3): 1–29. doi:10.1517/14728214.2011.591786. PMID 21699441.  edit
  103. ^ Johnson VA, Hirsch MS (1990). "New developments in antiretroviral drug therapy for human immunodeficiency virus infections. Ganciclover is a 5' monophosphate that does not require thymidine kinase activation and thus expresses higher toxicity to host enzymes due to a decrease in selectivity". AIDS Clin Rev: 235–72. PMID 1707295. 
  104. ^ Mar EC, Chiou JF, Cheng YC, Huang ES (March 1985). "Inhibition of cellular DNA polymerase alpha and human cytomegalovirus-induced DNA polymerase by the triphosphates of 9-(2-hydroxyethoxymethyl)guanine and 9-(1,3-dihydroxy-2-propoxymethyl)guanine". J. Virol. 53 (3): 776–80. PMC 254706. PMID 2983088. 
  105. ^ Black ME, Hruby DE (June 1990). "Quaternary structure of vaccinia virus thymidine kinase". Biochem. Biophys. Res. Commun. 169 (3): 1080–6. doi:10.1016/0006-291X(90)92005-K. PMID 2114104. 
  106. ^ Nicholas TW, Read SB, Burrows FJ, Kruse CA (April 2003). "Suicide gene therapy with Herpes simplex virus thymidine kinase and ganciclovir is enhanced with connexins to improve gap junctions and bystander effects". Histol. Histopathol. 18 (2): 495–507. PMID 12647801. 
  107. ^ Preuß, E.; Muik, A.; Weber, K.; Otte, J. R.; Von Laer, D.; Fehse, B. (2011). "Cancer suicide gene therapy with TK.007: Superior killing efficiency and bystander effect". Journal of Molecular Medicine 89 (11): 1113–1124. doi:10.1007/s00109-011-0777-8. PMID 21698427.  edit
  108. ^ Hart IR (February 1996). "Tissue specific promoters in targeting systemically delivered gene therapy". Semin. Oncol. 23 (1): 154–8. PMID 8607025. 
  109. ^ Wills KN, Huang WM, Harris MP, Machemer T, Maneval DC, Gregory RJ (September 1995). "Gene therapy for hepatocellular carcinoma: chemosensitivity conferred by adenovirus-mediated transfer of the HSV-1 thymidine kinase gene". Cancer Gene Ther. 2 (3): 191–7. PMID 8528962. 
  110. ^ Ido A, Nakata K, Kato Y, et al. (July 1995). "Gene therapy for hepatoma cells using a retrovirus vector carrying herpes simplex virus thymidine kinase gene under the control of human alpha-fetoprotein gene promoter". Cancer Res. 55 (14): 3105–9. PMID 7541712. 
  111. ^ Kanai F, Shiratori Y, Yoshida Y, et al. (June 1996). "Gene therapy for alpha-fetoprotein-producing human hepatoma cells by adenovirus-mediated transfer of the herpes simplex virus thymidine kinase gene". Hepatology 23 (6): 1359–68. doi:10.1002/hep.510230611. PMID 8675152. 
  112. ^ Garver RI, Goldsmith KT, Rodu B, Hu PC, Sorscher EJ, Curiel DT (January 1994). "Strategy for achieving selective killing of carcinomas". Gene Ther. 1 (1): 46–50. PMID 7584059. 
  113. ^ Hart IR (1996). "Transcriptionally targeted gene therapy". Curr. Top. Microbiol. Immunol. 213 (3): 19–25. PMID 8815006. 
  114. ^ Byun Y, Thirumamagal BT, Yang W, Eriksson S, Barth RF, Tjarks W (September 2006). "Preparation and biological evaluation of 10B-enriched 3-[5-{2-(2,3-dihydroxyprop-1-yl)-o-carboran-1-yl}pentan-1-yl]thymidine (N5-2OH), a new boron delivery agent for boron neutron capture therapy of brain tumors". Journal of Medicinal Chemistry 49 (18): 5513–23. doi:10.1021/jm060413w. PMID 16942024. 
  115. ^ Thirumamagal BT, Johnsamuel J, Cosquer GY, et al. (2006). "Boronated thymidine analogues for boron neutron capture therapy". Nucleosides Nucleotides Nucleic Acids 25 (8): 861–6. doi:10.1080/15257770600793844. PMID 16901817. 
  116. ^ Narayanasamy S, Thirumamagal BT, Johnsamuel J, et al. (October 2006). "Hydrophilically enhanced 3-carboranyl thymidine analogues (3CTAs) for boron neutron capture therapy (BNCT) of cancer". Bioorg. Med. Chem. 14 (20): 6886–99. doi:10.1016/j.bmc.2006.06.039. PMID 16831554. 
  117. ^ Byun Y, Narayanasamy S, Johnsamuel J, et al. (March 2006). "3-Carboranyl thymidine analogues (3CTAs) and other boronated nucleosides for boron neutron capture therapy". Anticancer Agents Med Chem 6 (2): 127–44. doi:10.2174/187152006776119171. PMID 16529536. 
  118. ^ Byun Y, Yan J, Al-Madhoun AS, et al. (February 2005). "Synthesis and biological evaluation of neutral and zwitterionic 3-carboranyl thymidine analogues for boron neutron capture therapy". Journal of Medicinal Chemistry 48 (4): 1188–98. doi:10.1021/jm0491896. PMID 15715485. 
  119. ^ Barth RF, Yang W, Al-Madhoun AS, et al. (September 2004). "Boron-containing nucleosides as potential delivery agents for neutron capture therapy of brain tumors". Cancer Res. 64 (17): 6287–95. doi:10.1158/0008-5472.CAN-04-0437. PMID 15342417. 
  120. ^ Al-Madhoun AS, Johnsamuel J, Barth RF, Tjarks W, Eriksson S (September 2004). "Evaluation of human thymidine kinase 1 substrates as new candidates for boron neutron capture therapy". Cancer Res. 64 (17): 6280–6. doi:10.1158/0008-5472.CAN-04-0197. PMID 15342416. 
  121. ^ Johnsamuel J, Lakhi N, Al-Madhoun AS, et al. (September 2004). "Synthesis of ethyleneoxide modified 3-carboranyl thymidine analogues and evaluation of their biochemical, physicochemical, and structural properties". Bioorg. Med. Chem. 12 (18): 4769–81. doi:10.1016/j.bmc.2004.07.032. PMID 15336255. 
  122. ^ Byun Y, Yan J, Al-Madhoun AS, et al. (November 2004). "The synthesis and biochemical evaluation of thymidine analogues substituted with nido carborane at the N-3 position". Appl Radiat Isot 61 (5): 1125–30. doi:10.1016/j.apradiso.2004.05.023. PMID 15308203. 
  123. ^ Yan J, Naeslund C, Al-Madhoun AS, et al. (August 2002). "Synthesis and biological evaluation of 3'-carboranyl thymidine analogues". Bioorg. Med. Chem. Lett. 12 (16): 2209–12. doi:10.1016/S0960-894X(02)00357-8. PMID 12127539. 
  124. ^ Barth RF, Yang W, Wu G, et al. (November 2008). "Thymidine kinase 1 as a molecular target for boron neutron capture therapy of brain tumors". Proc. Natl. Acad. Sci. U.S.A. 105 (45): 17493–7. Bibcode:2008PNAS..10517493B. doi:10.1073/pnas.0809569105. PMC 2582264. PMID 18981415. 
  125. ^ Gronowitz JS, Källander CF (August 1980). "Optimized assay for thymidine kinase and its application to the detection of antibodies against herpes simplex virus type 1- and 2-induced thymidine kinase". Infect. Immun. 29 (2): 425–34. PMC 551136. PMID 6260651. 
  126. ^ Gronowitz JS, Källander FR, Diderholm H, Hagberg H, Pettersson U (January 1984). "Application of an in vitro assay for serum thymidine kinase: results on viral disease and malignancies in humans". Int. J. Cancer 33 (1): 5–12. doi:10.1002/ijc.2910330103. PMID 6693195. 
  127. ^ Gronowitz JS, Källander CF (1983). "A sensitive assay for detection of deoxythymidine kinase and its application to herpesvirus diagnosis". Curr. Top. Microbiol. Immunol. 104: 235–45. doi:10.1007/978-3-642-68949-9_14. PMID 6307593. 
  128. ^ Gronowitz, JS (24.2.2006) A method and kit for determination of thymidine kinase activity and use thereof. International patent application PCT/SE2006/000246
  129. ^ He Q, Zou L, Zhang PA, Lui JX, Skog S, Fornander T (2000). "The clinical significance of thymidine kinase 1 measurement in serum of breast cancer patients using anti-TK1 antibody". Int. J. Biol. Markers 15 (2): 139–46. PMID 10883887. 
  130. ^ Kimmel N, Friedman MG, Sarov I (May 1982). "Enzyme-linked immunosorbent assay (ELISA) for detection of herpes simplex virus-specific IgM antibodies". J. Virol. Methods 4 (4–5): 219–27. doi:10.1016/0166-0934(82)90068-4. PMID 6286702. 
  131. ^ Huang, S.; Lin, J.; Guo, N.; Zhang, M.; Yun, X.; Liu, S.; Zhou, J.; He, E.; Skog, S. (2011). "Elevated serum thymidine kinase 1 predicts risk of pre/early cancerous progression". Asian Pacific journal of cancer prevention : APJCP 12 (2): 497–505. PMID 21545220.  edit
  132. ^ Romain S, Spyratos F, Guirou O, Deytieux S, Chinot O, Martin PM (1994). "Technical evaluation of thymidine kinase assay in cytosols from breast cancers. EORTC Receptor Study Group Report". Eur. J. Cancer 30A (14): 2163–5. doi:10.1016/0959-8049(94)00376-G. PMID 7857717. 
  133. ^ Arnér ES, Spasokoukotskaja T, Eriksson S (October 1992). "Selective assays for thymidine kinase 1 and 2 and deoxycytidine kinase and their activities in extracts from human cells and tissues". Biochem. Biophys. Res. Commun. 188 (2): 712–8. doi:10.1016/0006-291X(92)91114-6. PMID 1359886. 
  134. ^ Wang L, Eriksson S (June 2008). "5-Bromovinyl 2'-deoxyuridine phosphorylation by mitochondrial and cytosolic thymidine kinase (TK2 and TK1) and its use in selective measurement of TK2 activity in crude extracts". Nucleosides Nucleotides Nucleic Acids 27 (6): 858–62. doi:10.1080/15257770802146510. PMID 18600552. 
  135. ^ a b Herzfeld A, Greengard O (November 1980). "Enzyme activities in human fetal and neoplastic tissues". Cancer 46 (9): 2047–54. doi:10.1002/1097-0142(19801101)46:9<2047::AID-CNCR2820460924>3.0.CO;2-Q. PMID 6253048. 
  136. ^ Machovich R, Greengard O (December 1972). "Thymidine kinase in rat tissues during growth and differentiation". Biochim. Biophys. Acta 286 (2): 375–81. doi:10.1016/0304-4165(72)90273-5. PMID 4660462. 
  137. ^ Herzfeld A, Raper SM, Gore I (December 1980). "The ontogeny of thymidine kinase in tissues of man and rat". Pediatr. Res. 14 (12): 1304–10. doi:10.1203/00006450-198012000-00006. PMID 7208144. 
  138. ^ Schollenberger S, Taureck D, Wilmanns W (November 1972). "[Enzymes of thymidine and thymidylate metabolism in normal and pathological blood and bone marrow cells]" [Enzymes of thymidine and thymidylate metabolism in normal and pathological blood and bone marrow cells]. Blut (in German) 25 (5): 318–34. doi:10.1007/BF01631814. PMID 4508724. 
  139. ^ Nakao K, Fujioka S (April 1968). "Thymidine kinase activity in the human bone marrow from various blood diseases". Life Sci. 7 (8): 395–9. doi:10.1016/0024-3205(68)90039-8. PMID 5649653. 
  140. ^ Wickramasinghe SN, Olsen I, Saunders JE (September 1975). "Thymidine kinase activity in human bone marrow cells". Scand J Haematol 15 (2): 139–44. doi:10.1111/j.1600-0609.1975.tb01065.x. PMID 1059244. 
  141. ^ Gordon HL, Bardos TJ, Chmielewicz ZF, Ambrus JL (October 1968). "Comparative study of the thymidine kinase and thymidylate kinase activities and of the feedbach inhibition of thymidine kinase in normal and neoplastic human tissue". Cancer Res. 28 (10): 2068–77. PMID 5696936. 
  142. ^ Stafford MA, Jones OW (August 1972). "The presence of "fetal" thymidine kinase in human tumors". Biochim. Biophys. Acta 277 (2): 439–42. PMID 4672678. 
  143. ^ Maehara Y, Nakamura H, Nakane Y, et al. (April 1982). "Activities of various enzymes of pyrimidine nucleotide and DNA syntheses in normal and neoplastic human tissues". Gann 73 (2): 289–98. PMID 6288502. 
  144. ^ Persson L, Gronowitz SJ, Källander CF (1986). "Thymidine kinase in extracts of human brain tumours". Acta Neurochir (Wien) 80 (3–4): 123–7. doi:10.1007/BF01812286. PMID 3012969. 
  145. ^ Filanovskaia LI, Togo AV, Shcherbakova EG, Blinov MN (1994). "[Thymidine kinase activity in leukocytes from patients with chronic myeloid leukemia at various periods in the disease]" [Thymidine kinase activity in leukocytes from patients with chronic myeloid leukemia at various periods in the disease]. Vopr. Med. Khim. (in Russian) 40 (1): 29–32. PMID 8122406. 
  146. ^ Lipkin M (July 1971). "Proliferation and differentiation of normal and neoplastic cells in the colon of man". Cancer 28 (1): 38–40. doi:10.1002/1097-0142(197107)28:1<38::AID-CNCR2820280108>3.0.CO;2-W. PMID 5110642. 
  147. ^ Lipkin M, Deschner E, Troncale F (1970). "Cell differentiation and the development of colonic neoplasms". CA Cancer J Clin 20 (6): 386–90. doi:10.3322/canjclin.20.6.386. PMID 4992499. 
  148. ^ Weber G, Lui MS, Takeda E, Denton JE (September 1980). "Enzymology of human colon tumors". Life Sci. 27 (9): 793–9. doi:10.1016/0024-3205(80)90333-1. PMID 7412505. 
  149. ^ Sagara T, Tsukada K, Iwama T, Mishima Y, Sakamoto S, Okamoto R (August 1985). "[Thymidine kinase isozymes in human colon polyps]" [Thymidine kinase isozymes in human colon polyps]. Nippon Gan Chiryo Gakkai Shi (in Japanese) 20 (7): 1312–6. PMID 4078430. 
  150. ^ Sakamoto S, Sagara T, Iwama T, Kawasaki T, Okamoto R (June 1985). "Increased activities of thymidine kinase isozymes in human colon polyp and carcinoma". Carcinogenesis 6 (6): 917–9. doi:10.1093/carcin/6.6.917. PMID 4006080. 
  151. ^ Sakamoto S, Okamoto R (October 1992). "Thymidine kinase activity in familial adenomatous polyposis". Tohoku J. Exp. Med. 168 (2): 291–301. doi:10.1620/tjem.168.291. PMID 1339104. [dead link]
  152. ^ Galloux H, Javre JL, Guerin D, Sampérez S, Jouan P (1988). "[Prognostic value of fetal thymidine kinase measurements in breast cancer]" [Prognostic value of fetal thymidine kinase measurements in breast cancer]. C. R. Acad. Sci. III, Sci. Vie (in French) 306 (3): 89–92. PMID 3126994. 
  153. ^ O'Neill KL, Hoper M, Odling-Smee GW (December 1992). "Can thymidine kinase levels in breast tumors predict disease recurrence?". J. Natl. Cancer Inst. 84 (23): 1825–8. doi:10.1093/jnci/84.23.1825. PMID 1433372. 
  154. ^ O'Neill KL, McKelvey VJ, Hoper M, et al. (December 1992). "Breast tumour thymidine kinase levels and disease recurrence". Med Lab Sci 49 (4): 244–7. PMID 1339926. 
  155. ^ Romain S, Javre JL, Samperez S, et al. (1990). "[Prognostic value of thymidine kinase in cancer of the breast]" [Prognostic value of thymidine kinase in cancer of the breast]. Bull Cancer (in French) 77 (10): 973–83. PMID 2249017. 
  156. ^ Romain S, Chinot O, Guirou O, Soullière M, Martin PM (October 1994). "Biological heterogeneity of ER-positive breast cancers in the post-menopausal population". Int. J. Cancer 59 (1): 17–9. doi:10.1002/ijc.2910590105. PMID 7927897. 
  157. ^ Sakamoto S, Iwama T, Ebuchi M, et al. (April 1986). "Increased activities of thymidine kinase isozymes in human mammary tumours". Br J Surg 73 (4): 272–3. doi:10.1002/bjs.1800730409. PMID 3697655. 
  158. ^ Greengard O, Head JF, Goldberg SL, Kirschner PA (February 1982). "Enzyme pathology and the histologic categorization of human lung tumors: the continuum of quantitative biochemical indices of neoplasticity". Cancer 49 (3): 460–7. doi:10.1002/1097-0142(19820201)49:3<460::AID-CNCR2820490312>3.0.CO;2-Y. PMID 6277448. 
  159. ^ Greengard O, Head JF, Goldberg SL, Kirschner PA (April 1985). "Biochemical measure of the volume doubling time of human pulmonary neoplasms". Cancer 55 (7): 1530–5. doi:10.1002/1097-0142(19850401)55:7<1530::AID-CNCR2820550720>3.0.CO;2-V. PMID 2983858. 
  160. ^ Yusa T, Tamiya N, Yamaguchi Y, et al. (March 1994). "[A study of thymidine kinase activity in lung cancer tissue]" [A study of thymidine kinase activity in lung cancer tissue]. Nihon Kyobu Shikkan Gakkai Zasshi (in Japanese) 32 (3): 211–5. PMID 8189640. 
  161. ^ Konishi T, Miyama T, Sakamoto S, et al. (June 1992). "Activities of thymidylate synthetase and thymidine kinase in gastric cancer". Surg Oncol 1 (3): 215–21. doi:10.1016/0960-7404(92)90067-U. PMID 1341254. 
  162. ^ Look KY, Moore DH, Sutton GP, Prajda N, Abonyi M, Weber G (1997). "Increased thymidine kinase and thymidylate synthase activities in human epithelial ovarian carcinoma". Anticancer Res. 17 (4A): 2353–6. PMID 9252646. 
  163. ^ Greengard O, Head JF, Chahinian AP, Goldberg SL (April 1987). "Enzyme pathology of human mesotheliomas". J. Natl. Cancer Inst. 78 (4): 617–22. PMID 2882044. 
  164. ^ Borovanský J, Stríbrná J, Elleder M, Netíková I (October 1994). "Thymidine kinase in malignant melanoma". Melanoma Res. 4 (5): 275–9. doi:10.1097/00008390-199410000-00001. PMID 7858409. 
  165. ^ Sakamoto S, Murakami S, Sugawara M, Mishima Y, Okamoto R (1991). "Increased activities of thymidylate synthetase and thymidine kinase in human thyroid tumors". Thyroid 1 (4): 347–51. doi:10.1089/thy.1991.1.347. PMID 1841732. 
  166. ^ Pikner R, Ludvíkova M, Ryska A, et al. (2005). "TPS, thymidine kinase, VEGF and endostatin in cytosol of thyroid tissue samples". Anticancer Res. 25 (3A): 1517–21. PMID 16033053. 
  167. ^ Wilms K, Wilmanns W (September 1972). "[Effects of dauno-rubidomycin and adriamycin on enzymes of DNA synthesis in leukocytes in vivo and in culture]" [Effects of dauno-rubidomycin and adriamycin on enzymes of DNA synthesis in leukocytes in vivo and in culture]. Klin. Wochenschr. (in German) 50 (18): 866–70. doi:10.1007/BF01488943. PMID 4507472. 
  168. ^ Wilmanns W, Wilms K (1972). "DNA synthesis in normal and leucemic cells as related to therapy with cytotoxic drugs". Enzyme 13 (1): 90–109. PMID 4507104. 
  169. ^ Zhang HJ, Kennedy BJ, Kiang DT (1984). "Thymidine kinase as a predictor of response to chemotherapy in advanced breast cancer". Breast Cancer Res. Treat. 4 (3): 221–5. doi:10.1007/BF01806488. PMID 6487823. 
  170. ^ Kuroiwa N, Nakayama M, Fukuda T, et al. (July 2001). "Specific recognition of cytosolic thymidine kinase in the human lung tumor by monoclonal antibodies raised against recombinant human thymidine kinase". Journal of Immunology Methods 253 (1–2): 1–11. doi:10.1016/S0022-1759(01)00368-4. PMID 11384664. 
  171. ^ a b He Q, Mao Y, Wu J, et al. (October 2004). "Cytosolic thymidine kinase is a specific histopathologic tumour marker for breast carcinomas". Int. J. Oncol. 25 (4): 945–53. PMID 15375544. 
  172. ^ Mao Y, Wu J, Wang N, et al. (2002). "A comparative study: immunohistochemical detection of cytosolic thymidine kinase and proliferating cell nuclear antigen in breast cancer". Cancer Invest. 20 (7–8): 922–31. doi:10.1081/CNV-120005905. PMID 12449723. 
  173. ^ Mao Y, Wu J, Skog S, et al. (May 2005). "Expression of cell proliferating genes in patients with non-small cell lung cancer by immunohistochemistry and cDNA profiling". Oncol. Rep. 13 (5): 837–46. doi:10.3892/or.13.5.837. PMID 15809747. 
  174. ^ Wu J, Mao Y, He L, et al. (2000). "A new cell proliferating marker: cytosolic thymidine kinase as compared to proliferating cell nuclear antigen in patients with colorectal carcinoma". Anticancer Res. 20 (6C): 4815–20. PMID 11205225. 
  175. ^ Li HX, Lei DS, Wang XQ, Skog S, He Q (January 2005). "Serum thymidine kinase 1 is a prognostic and monitoring factor in patients with non-small cell lung cancer". Oncol. Rep. 13 (1): 145–9. doi:10.3892/or.13.1.145. PMID 15583816. 
  176. ^ Kruck, S.; Hennenlotter, J.; Vogel, U.; Schilling, D.; Gakis, G.; Hevler, J.; Kuehs, U.; Stenzl, A.; Schwentner, C. (2011). "Exposed proliferation antigen 210 (XPA-210) in renal cell carcinoma (RCC) and oncocytoma: Clinical utility and biological implications". BJU International 109 (4): 634–638. doi:10.1111/j.1464-410X.2011.10392.x. PMID 21711439.  edit

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