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PubMed1977

[Hydrogen-adduct radicals in thymidine and thymidine 5'-monophosphate photosensitized by proflavin. Protection by sulfur compounds (author's transl)].

At pH values 5 and 9, the influence of cysteine, cystine, 3-mercaptopropionic acid and S-methylcysteine on the induction of H-adduct radicals in thymidine and thymidine 5'-monophosphate photosensitized by proflavin is investigated. The results obtained indicate that efficient protection is given when the electrostatic interactions between the charged groups of the molecules present allow the close proximity of a thiol or a disulfide bridge and the proflavin - DNAs complex constituent. The scheme proposed for the mechanism involves the capture by the protector of an electron or a proton, indispensable intermediates in the formation of the H-adduct radicals.

Acridines↗
PubMed1981

Thymidine catabolism and the reutilization of its degradative products in Tetrahymena pyriformis. Metabolism of [2,6-14C2]thymidine and [2-14C]methylmalonic acid.

The operation of reductive pyrimidine catabolic and reutilization pathway in Tetrahymena pyriformis was investigated. Consistent with the proposed catabolic interconversions, radioactivity from [2,6-14C2]thymidine was recovered in respired CO2 30 min after its addition to the culture, whereas, consistent with the proposed anabolic interconversions, over 50% of the incorporated label was recovered in cellular macromolecules other than DNA 12 h after its addition. The chromatographic recovery of 14C radioactivity in monosaccharides from [2,6-14C2]thymidine as well as from [2-14C]methylmalonic acid, a key reutilization intermediate in this proposed pathway, further substantiated the operation of the required anabolic interconversions in this organism.

Animals↗
PubMed1984

The diurnal fluctuations in unincorporated radio-thymidine pool and its relation to the circadian rhythm of thymidine incorporation in mouse pinna skin.

The circadian variation in the labelling indices of epidermal basal and sebaceous gland cells in murine pinna is a well documented phenomenon. This, however, observes only the incorporated label and takes no account of any rhythmic changes in the precursor pool. It is reported here that, using a liquid scintillation counting method, there is a diurnal change in the level of unincorporated radio-labelled thymidine, which is apparently not related to the rhythm of thymidine incorporation. The implications of this phenomenon and its relationship to DNA synthesis are discussed.

Animals↗
PubMed2002

Induction of thymidine phosphorylase by interferon and taxanes occurs only in human cancer cells with low thymidine phosphorylase activity.

Thymidine phosphorylase (TP) regulates intracellular thymidine metabolism. It has been reported to be a prognostic factor for tumor angiogenesis and to activate some prodrugs of 5-fluorouracil (5-FU) to 5-FU. There is also evidence that TP is induced by interferons (IFNs) and xenobiotics, such as cyclophosphamide and taxanes, in experimental human cancer cells and xenografts. We investigated the induction of TP expression by IFNalpha and Paclitaxel in vitro and in vivo in human tumor cells with low and with high TP activity. TP activity in KB, NUGC-3, and KOC2S cells, which had low TP activity, was increased 2 to 4 fold by IFNalpha, but was still lower than in non-treated SHIN-3 and HRA cells, which have high TP activity. IFNalpha did not promote TP activity in SHIN-3 and HRA cells, but expression of TP mRNA increased 2 to 4 fold in response to IFNalpha in all cells tested. These results suggest that the expression of TP protein would be regulated post-transcriptionally by another factor after IFN-induced amplification of TP mRNA. A single dose of Paclitaxel to nude mice xenografted with KB and KM20C tumors, expressing low TP activity, increased TP activity about 4 to 7 fold compared to non-treated tumors. In contrast, TP expression in MX-1 and H-31 tumors was originally high and did not change by the treatment of Paclitaxel. The activities of uridine phosphorylase in all tumors used showed no changes in response to IFNalpha or Paclitaxel. We determined the level of STAT1alpha, an IFN-inducible transcription factor of the TP gene, and found that it was low in low TP expressing tumor cells and markedly increased to about 4 fold by IFN, almost reaching the level in high TP expressing cells whose STAT1alpha level was unchanged by IFN. When TP activity and STAT1alpha expression in clinically resected colorectal cancers were simultaneously measured, almost all tumors had high expression of both TP and STAT1alpha. In conclusion, our results suggest that IFN and Paclitaxel affect human cancer cells with low TP activity but not those with high TP activity and that the STAT1alpha expression may reflect TP activity, at least in experimental human cancer cells.

Animals↗
PubMed2003

Thymidine and thymidine-5'-O-monophosphate analogues as inhibitors of Mycobacterium tuberculosis thymidylate kinase.

The affinity of a series of 2', 3'- and 5-modified thymidine analogues for Mycobacterium tuberculosis thymidine monophosphate kinase (TMPKmt) was evaluated. The affinities of several non-phosphorylated analogues are in the same order of magnitude as those of their phosphorylated congeners. In view of drug delivery problems associated with phosphorylated compounds, these 'free' nucleosides seem more promising leads in the search of TMPKmt inhibitors as novel anti-tuberculosis agents.

Antitubercular Agents↗
PubMed2001

Preparation of 4'-substituted thymidines by substitution of the thymidine 5'-esters.

tert-Butyl thymidylate 3 was prepared from thymidine 1 in six steps and 67% overall yield. When the lithium trianion of 3 (prepared by treatment of 3 with excess LDA and then excess tert-butyllithum) is reacted with electrophiles, trapping occurs stereoselectively from either the alpha- or beta-face depending on the electrophile (Scheme 1). Deuterioacetic acid in deuteriomethanol affords mainly the alpha-deuterated product (4a/4b = 2.4:1) while all other electrophiles, e.g., phenylselenenyl chloride, allyl bromide, and N-fluorobenzenesulfonimide (NFSI), give predominately (or completely) the products of attack from the beta-face (5bcd/4bcd = 3.7:1 to 100:0). The structures of the products were determined by coupling constant analysis of both the initial compounds and the diols 6bcd prepared by ester reduction and by formation of the acetonides 7bc. The methyl ester of the 3'-epimer of thymidylic acid 9 was also prepared from thymidine 1 in nine steps and 74% overall yield. When the lithium trianion of 9 (prepared by treatment of 9 with excess LDA and then excess tert-butyllithum) is reacted with electrophiles, trapping also occurs stereoselectively with attack on either the alpha- or beta-face depending on the electrophile (Scheme 2). Again, deuterioacetic acid in deuteriomethanol affords mainly the beta-deuterated product (11a/10a = 1.6:1) while all other electrophiles, e.g., phenylselenenyl chloride, methyl iodide, allyl bromide, and NFSI, gave predominately (or completely) the product of attack from the alpha-face (8.7:1 to 100: 0). Again, the structures of the products were determined by coupling constant analysis of both the initial compounds, and the diols 12b-e were prepared by reduction of the ester and by formation of the acetonides 13bcd. A rationale has been developed using molecular mechanics calculations to explain the diastereoselectivity that involves staggered axial attack on the sp(2) carbon opposite to the pseudoaxial alkoxy group in the most stable half-chair conformation of the enolates, as shown in Schemes 3-5.

Anti-HIV Agents↗
PubMed1999

The equine herpes virus 4 thymidine kinase is a better suicide gene than the human herpes virus 1 thymidine kinase.

The herpes simplex virus type 1 thymidine kinase suicide gene (HSV1tk) together with ganciclovir (GCV) have been successfully used for in vivo treatment of various experimental tumors, and many clinical trials using this system have been launched. With the aim to improve this therapeutic system, we compared the potential efficacy of different herpes virus derived thymidine kinases (HSV1, varicella-zoster virus, equine herpes virus type-4 and Epstein-Barr virus) as suicide genes in association with the nucleoside analogs acyclovir, ganciclovir and bromovinyldeoxyur- idine. Using various murine and human cell lines expressing these viral tk, we show that HSV1- and EHV4tk are the more efficient suicide genes for the different nucleoside analogs tested. Moreover, EHV4tk expressing murine and human cells were three- to 12-fold more sensitive to GCV than HSV1tk expressing cells. This was correlated with the presence of five-fold higher amounts of the toxic triphosphated-GCV in EHV4- versus HSV1tk expressing cells. Altogether, these experiments underline the potential advantages of the EHV4tk as a suicide gene.

Animals↗
PubMed1989

Mouse thymidine kinase: the promoter sequence and the gene and pseudogene structures in normal cells and in thymidine kinase deficient mutants.

The mouse genome carries one gene and two pseudogenes for cytoplasmic thymidine kinase. The overall structure of these genes was determined with the help of cosmids and lambda phage clones and the upstream sequence containing the promoter was determined. The data allow an allocation of bands seen in the complex patterns of genomic Southern blots obtained from the DNA of wild type cells and of thymidine kinase deficient mutants to the gene as well as to the two pseudogenes. The much used LTK cell line was found to lack the entire gene but to retain the pseudogenes. Two other TK cell lines had DNA patterns indistinguishable from the wild type. Whereas the LTK line did not produce any TKmRNA, the two other mutants had normal amounts of TKmRNA but no cytoplasmic TK activity.

Animals↗
PubMed2000

Phage display of ScFv peptides recognizing the thymidine(6-4)thymidine photoproduct.

Solar ultraviolet (UV) radiation induces DNA photoproducts in skin cells and is the predominant cause of human skin cancers. To understand human susceptibility to skin cancer and to facilitate the development of prevention measures, highly specific reagents to detect and quantitate UV-induced DNA adducts in human skin will be needed. One approach towards this end is the use of monoclonal antibody-based molecular dosimetry methods. To facilitate the development of photoproduct-specific antibody reagents we have: (i) cloned and sequenced a single chain variable fragment (ScFv) gene coding for one such high affinity monoclonal antibody, [alpha]UVssDNA-1 (mAb C3B6), recognizing the thymidine(6-4)thymidine photoproduct; (ii) expressed and displayed the cloned ScFv gene on the surface of phage; (iii) selected functional recombinant phage by panning; (iv) purified the ScFv peptide; (v) shown that the purified ScFv peptide binds to UV-irradiated polythymidylic acid but not unirradiated polythymidylic acid. This is the first demonstration of the use of phage display to select a ScFv recognizing DNA damage. In addition, this is the initial step towards immortalizing the antibody gene for genetic manipulation, structure-function studies and application to human investigations.

Amino Acid Sequence↗
PubMed1975

Regulation by thymidine monophosphate and other nucleotides of thymidine kinase activity in extracts from primary rabbit kidney cells infected by HSV types 1 and 2.

In an attempt to differentiate between thymidine kinase (EC.2.4.1.21) induced by herpesvirus hominis type I (TK I) and type 2 (TK2), the different susceptibilities to the modifying effects of some thymidine analogues proved to be useful criteria: (I)2'-deoxythymidine-5'-triphosphate (dThd-5'-PPP) inhibits TK 2 at a concentration of 0-125 mM by 90%, whereas TK I is inhibited at 4-03 mM by 50%. (2) 2'-deoxythymidine-5'-monophosphate (dThd-5'-P) competitively inhibits TK 2 at all concentrations tested. On the other hand, the direction of its effect on TK I is concentration dependent: at 500 mum it stimulates and at 8 mM inhibits TK I activity. During enzyme kinetic studies, TK I displays substrate inhibition which is reversed by dThd-5'-P. This result explains the stimulating effect of dThd-5'-P at 500 muM. This phenomenon suggests the existence on the enzyme molecule of a second binding site for dThd which mediates substrate inhibition and which can be occupied also by dThd-5'-P. After polyacrylamide gel electrophoresis of TK I, the stimulation by dThd-5'-P disappears, suggesting the separation of the second binding site from the catalytic centre.

Cell-Free System↗
PubMed1995

Analysis of the relationship between cellular thymidine kinase activity and virulence of thymidine kinase-negative herpes simplex virus types 1 and 2.

The virulence of thymidine kinase-negative herpes simplex virus type 1 (HSV-1; VRTK- strain) and type 2 (HSV-2; UWTK- strain) was studied in comparison with that of their parental strains (VR-3 and UW-268, respectively) in an encephalitis model of adult (4-week-old) and newborn (3-day-old) mice. Viral thymidine kinase (TK) activity was essential for the maximum expression of virulence of HSV-1, because the 50% lethal dose (LD50) of VRTK- was 60 times higher than that of VR-3 in the brains of newborn mice expressing high levels of cellular TK activity. However, the UWTK- strain showed that replication of the UWTK- strain was completely supported by cellular TK activity. This difference in the role of viral and cellular TKs for virus growth between HSV-1 and HSV-2 was¿ confirmed with the one-step growth of virus strains in L-M and L-M(TK-) cells.

Amino Acid Sequence↗
PubMed1979

Effects of intestinally absorbed thymidine on tritiated thymidine utilization.

Experimental evidence presented suggests that [3H]TdR can be rapidly and efficiently transported from the intestine to the systemic circulation. This pathway for thymidine transport may be physiologically important since administration of cold thymidine in the drinking water enhances the utilization of a parenterally injected dose of [3H]TdR in several body tissues of the mouse.

Animals↗
PubMedDate not supplied

Uptake of tritiated thymidine, deoxyglucose and methionine in three lung cancer cell lines: deoxyglucose uptake mirrors tritiated thymidine uptake.

[(18)F]-fluorodeoxyglucose and [(11)C]-methionine are tracers which are widely used in oncological positron emission tomography. This study has been designed to assess the deoxyglucose and methionine uptake behaviour in three cell lines from different lung cancer histotypes. Tracer uptake was compared with proliferative activity as determined by growth curves and tritiated thymidine uptake. Deoxyglucose paralleled thymidine in all cell lines, peaking in the lag phase, decreasing throughout the exponential phase, and reaching its minimum in the plateau phase. The correlation was statistically verified and Spearman's rho ranged from 0.79 to 0.99. The absolute methionine uptake was always highest and always peaked on day 2, followed by a quite rapid decrease. However, besides the delay in maximum uptake, methionine incorporation was also related to proliferation, although the statistical correlations were weaker. These results show for the first time a clear correlation between deoxyglucose uptake and cell proliferation in a model comparing tracer uptake in different growth phases. Although delayed, methionine uptake was also related to cell growth and its greater intensity could be of interest for clinical use.

Carcinoma, Non-Small-Cell Lung↗
PubMed1991

Inhibition of poly(adenosine diphosphate-ribose) polymerase by thymidine and thymidine analogues in L1210 cells and its relationship to the potentiation of the antitumor activity of 1,3-bis(2-chloroethyl)-1-nitrosourea but not of 3'-[3-(2-chloroethyl)-3-nitrosoureido]-3'-deoxythymidine.

The coadministration of thymidine (dThd) with either 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) or 3'-[3-(2-chloroethyl)-3-nitrosoureido]-3'-deoxythymidine (3'-CTNU) to L1210-bearing mice significantly enhanced the antitumor activity of both nitrosoureas (T-S. Lin and W. H. Prusoff, Cancer Res., 47:394-397, 1987, and T-S. Lin, P.H. Fischer, J. C. Marsh, and W. H. Prusoff, Cancer Res., 42:1624-1629, 1982). As a possible mechanism for this observed enhancement, we have investigated the role of dThd as an inhibitor of poly(ADP-ribose) polymerase (ADPRP), an enzyme which is activated in response to DNA damage. Exposure of L1210 cells in culture to 50 microM BCNU resulted in a greater than 10-fold increase in ADPRP activity within 3-4 h. The polymerase activity increased with increasing BCNU concentration after a 4-h exposure, reaching apparent saturation at 50 microM BCNU. However, this activation was abolished by 2 mM dThd. Median inhibition of the ADPRP activity elicited by 30 and 75 microM BCNU occurred at 38 and 135 microM dThd, respectively. When BCNU was replaced by 3'-CTNU, no activation of ADPRP was observed, even at or above concentration of 3'-CTNU previously shown to cause DNA damage. 3'-Amino-3'-deoxythymidine, the principal hydrolysis product of 3'-CTNU, was found to be an inhibitor of BCNU-stimulated ADPRP activity with potency similar to dThd. Furthermore, intact 3'-CTNU was found to inhibit BCNU-stimulated ADPRP activity. Although 3'-CTNU should be capable of activating ADPRP by causing DNA damage, our results suggest that no net activation is observed due to inhibition by the various thymidine species present. Thus, inhibition of ADPRP by dThd following DNA damage by BCNU is consistent with the potentiation of antitumor activity previously reported. However, the observed potentiation of 3'-CTNU activity by dThd does not appear to result from such a mechanism.

Animals↗
PubMed1987

[Comparative study of the transformation of various thymidine kinase-deficient human and animal cell lines with the thymidine kinase gene of the Herpes simplex virus].

The comparative study of transformation of four thymidine kinase deficient cell lines (mouse mammary carcinoma cell line FS tk-; rat cell line Rat-2tk-; mouse cell line Ltk-, clone D1; human cell line 143tk-) with the thymidine kinase cloned gene of Herpes simplex virus 1 was undertaken. The differences in efficiency and optimal conditions of transformation were shown for these cell lines. The advantages and disadvantages of the cell systems examined for the use in experiments for transformation and cotransformation of cultured cells with isolated genes are discussed.

Animals↗
PubMed1986

Inhibition of thymidine kinase by P1-(adenosine-5')-P5-(thymidine-5')-pentaphosphate.

Potential bisubstrate analogs, with adenosine and thymidine joined at their 5' positions by polyphosphoryl linkages of varying lengths (ApndT, where n = the number of phosphoryl groups), were examined as inhibitors of cytosolic thymidine kinase from blast cells of patients with acute myelocytic leukemia. Ki values were 1.2 microM for Ap3dT, 0.31 microM for Ap4dT, 0.12 microM for Ap5dT, and 0.19 microM for Ap6dT. The best inhibitor of the cytosolic enzyme, Ap5dT, was somewhat less effective as an inhibitor of the mitochondrial enzyme (Ki = 0.50 microM). In addition to their inhibitory modes of binding by the cytosolic enzyme, these compounds were bound at considerably lower concentrations (Kd = 0.029 microM for Ap4dT, 0.0025 microM for Ap5dT, and 0.0027 microM for Ap4dT), in such a way as to protect the cytosolic enzyme from thermal inactivation at 37 degrees C in the absence of substrates.

Adenine Nucleotides↗
PubMed1991

On the conversion of thymidine phosphate bromohydrins to thymidine phosphates: a model reaction for the repair of oxidized nucleotides.

Bromohydrins (12, 13, and 14), which were oxidatively damaged products of thymidine nucleotides, were repaired by the action of sunlight (2700 lux) or heat via a radical mechanism to regenerate the original nucleotides (8,9, and 10). A significant effect of 3',5'-phosphate linkage on the repair reactions to natural type of thymidine nucleotide was proposed.

Alcohols↗