Prevention of 5-Fluorouracil-Caused Growth Inhibition in Sordaria fimicola
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Abstract:
Growth (dry weight accumulation) of Sordaria fimicola in standing liquid culture (sucrose-nitrate-salts-vitamins) is inhibited by the presence of 5 μM 5-fluorouracil in the medium. This inhibition is completely prevented by uracil, deoxyuridine, and 5-bromouracil, partly prevented (40 to 90% of growth observed without 5-fluorouracil) by uridine, thymidine, and 5-bromodeoxyuridine, and slightly prevented by trifluorothymine, cytosine, cytidine, deoxycytidine, and 5-methylcytosine (all at 0.5 to 1 mM). Thymidine and thymine riboside were without any apparent effect. Growth is also inhibited by 0.2 mM 6-azauracil, and this inhibition was completely prevented by uracil and uridine, partly prevented by deoxyuridine, 5-bromouracil, cytidine, and 5-methylcytosine, and slightly prevented by thymine, thymidine, 5-bromodeoxyuridine, cytosine, and deoxycytidine. The data suggest that the observed inhibition of growth by 5-fluorouracil is due to inhibition of both ribonucleic acid and deoxyribonucleic acid synthesis. The data also allow inferences concerning pyrimidine interconversions in S. fimicola; i.e., thymine can be anabolized to thymidylic acid without first being demethylated, although demethylation appears to occur also.Keywords:
Uracil
Cytidine
Thymine
Cytosine
Thymidine
Deoxyuridine
Bromodeoxyuridine
This study was conducted to determine the mode(s) of uptake of selected pyrimidine bases and nucleosides by axenically grown Entamoeba histolytica. Two-minute uptake studies with 3H-labeled compounds showed the following: 1) uridine and cytidine are taken up, in part, by a carrier mediated system; 2) uracil, cytosine, thymine and thymidine enter amebae via passive diffusion; both cytidine and uridine are taken up by passive diffusion when present at exogenous concentration greater than 500 muM; 3) specific carrier sites are used for transport of uridine-cytidine and uridine-adenosine; 4) cytidine and uridine uptake is markedly inhibited by iodoacetate and N-ethylmalemide; 5) hypoxanthine (10mM) stimulates uptake of uridine; 6) ribose fails to inhibit uptake of cytidine and uridine; 7) cytidine uptake exceeds that of uridine (i.e., apparent Vmax for: a) cytidine = 10.0 nmoles/2 min/10(6) amebae; b) uridine = 3.0 nmoles/2 min/10(6) amebae); 8) Kt for: cytidine = 0.30 mM; uridine = 0.21 mM; 9) Q 10's at 35.5 C vs 25.5 C for: a) cytidine = 3.9; b) uridine = 2.6.
Cytidine
Uracil
Thymidine
Hypoxanthine
Cytosine
Thymine
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The mode of antiproliferative action of two 5-fluorocytosine nucleosides, 5-fluoro-cytidine (FCR) and 5-fluoro-2'-deoxycytidine (FCdR), was examined using mouse leukemia L5178Y cells in vitro. FCR and FCdR were markedly active against L5178Y cells, though the cells were deficient in cytidine deaminase activity. Both compounds increased the incorporation of 14C-labeled thymidine into the acid-insoluble fraction of L5178Y cells and decreased labeled deoxycytidine incorporation. In reversal studies, the antiproliferative effects of both compounds were almost abolished by simultaneous addition of thymidine or deoxyuridine. Deoxycytidine completely reversed the growth inhibition caused by FCdR, but not that caused by FCR. These results demonstrate that the cytotoxicity of both compounds is due to inhibition of thymidylate synthetase, presumably through formation of 5-fluoro-2'-deoxyuridine monophosphate (FdUMP) after deamination by deoxycytidylate deaminase in the pyrimidine de novo pathway.
Cytidine
Deoxyuridine
Thymidine
Deamination
Deoxyribonucleosides
Deoxycytidine kinase
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Uridine-cytidine kinase isolated from murine L1210 leukemia cells exist in several isozymic forms, as indicted by isoelectric focusing and by column chromatography on Sepharose 6B. Of 39 compounds thus far examined as potential inhibitors of the phosphorylation of uridine by ATP, four were of significant activity: 5'-azido-5'-deoxycytidine, 5'-O-nitro-5-fluorouridine, 5'-O-nitrouridine, and 5'-azido-5'-deoxyuridine. 5'-Azido-5'-deoxycytidine was the most active (competitive with uridine) and exhibited a Ki of 37 x 10(-5) M. Other properties of uridine-cytidine kinase were examined, and the apparent Michaelis constants for uridine, cytidine, and adenosine 5'-triphosphate were 23 x 10(-5) M, 15 x 10(-5) M, and 34.9 x 10(-5) M, respectively.
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Deoxyuridine
Deoxycytidine kinase
Thymidine
Nucleotide salvage
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Nucleotide salvage
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Investigation of certain nutritional requirements of neoplastic cells of a C3H mouse strain, when cultured in chemically defined medium, showed that thymidine, deoxycytidine, or 5-methyldeoxycytidine would support their growth as continuously growing long-term cultures. None of these nucleosides would substitute for vitamin 812. With vitamin 812 present, cytidine, uridine, deoxyuridine, or orotic acid did not support growth but were not toxic at 0.04 mM/liter. The find1ngs suggest that these cells are able to convert deoxycytidine, but not cytidine or uridine, to thymidylate.
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Deoxyuridine
Orotic acid
Floxuridine
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Deoxyuridine
Thymidine
Deoxyribonucleosides
Floxuridine
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Transformation of 2'-deoxyuridine and uridine analogs to protected 2'-deoxycytidine and cytidine analogs has been investigated by two different methods. First, traditional triazolation protocol and second p-nitrophenoxylation method. Our studies conclude that the triazolation method is better and suitable for commercial scale-up.
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Deoxyuridine
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Cytidine
Phosphorolysis
Deoxyuridine
Nucleotide salvage
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