Abstract
Flucytosine (5-FC)-resistant strains were isolated from the haploid opportunistic pathogen Candida glabrata by UV-induced mutation and fluoropyrimidine selection. These strains were characterized biochemically, and the metabolism of fluorinated pyrimidines was studied by 19F nuclear magnetic resonance spectroscopy. No evidence was obtained from these studies for degradative metabolism of the fluorinated derivatives. In the parental susceptible strain of C. glabrata, 5-fluorouracil but not 5-FC was detected within the cells. 5-Fluorouracil was also present in the culture supernatant after incubation of the cells with 5-FC. The distribution of fluorinated derivatives within the 5-FC-resistant strains was consistent with their genotype. Two strains of C. glabrata which had only a partial loss of cytosine deaminase and UMP pyrophosphorylase activity had high levels of resistance to 5-FC. Both C. glabrata and Candida albicans were susceptible to 5-fluorouridine. This compound but not the anticancer drug 5-fluoro-2-deoxyuridine was shown to be transported into susceptible cells by a specific uridine permease.
Full text
PDFSelected References
These references are in PubMed. This may not be the complete list of references from this article.
- Bachelard H. S., Cox D. W., Morris P. G. Nuclear magnetic resonance as a tool to study brain metabolism. Gerontology. 1987;33(3-4):235–246. doi: 10.1159/000212884. [DOI] [PubMed] [Google Scholar]
- Chouini-Lalanne N., Malet-Martino M. C., Martino R., Michel G. Study of the metabolism of flucytosine in Aspergillus species by 19F nuclear magnetic resonance spectroscopy. Antimicrob Agents Chemother. 1989 Nov;33(11):1939–1945. doi: 10.1128/aac.33.11.1939. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Di Vito M., Podo F., Torosantucci A., Carpinelli G., Whelan W. L., Kerridge D., Cassone A. A 19F nuclear magnetic resonance study of uptake and metabolism of 5-fluorocytosine in susceptible and resistant strains of Candida albicans. Antimicrob Agents Chemother. 1986 Feb;29(2):303–308. doi: 10.1128/aac.29.2.303. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fasoli M., Kerridge D. Isolation and characterization of fluoropyrimidine-resistant mutants in two Candida species. Ann N Y Acad Sci. 1988;544:260–263. doi: 10.1111/j.1749-6632.1988.tb40411.x. [DOI] [PubMed] [Google Scholar]
- Gochin M., James T. L., Shafer R. H. In vivo 19F-NMR of 5-fluorouracil incorporation into RNA and metabolites in Escherichia coli cells. Biochim Biophys Acta. 1984 May 22;804(1):118–124. doi: 10.1016/0167-4889(84)90105-8. [DOI] [PubMed] [Google Scholar]
- Harris B. E., Manning B. W., Federle T. W., Diasio R. B. Conversion of 5-fluorocytosine to 5-fluorouracil by human intestinal microflora. Antimicrob Agents Chemother. 1986 Jan;29(1):44–48. doi: 10.1128/aac.29.1.44. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hull W. E., Port R. E., Herrmann R., Britsch B., Kunz W. Metabolites of 5-fluorouracil in plasma and urine, as monitored by 19F nuclear magnetic resonance spectroscopy, for patients receiving chemotherapy with or without methotrexate pretreatment. Cancer Res. 1988 Mar 15;48(6):1680–1688. [PubMed] [Google Scholar]
- Ipata P. L., Cercignani G. Cytosine and cytidine deaminase from yeast. Methods Enzymol. 1978;51:394–400. doi: 10.1016/s0076-6879(78)51053-7. [DOI] [PubMed] [Google Scholar]
- Jund R., Chevallier M. R., Lacroute F. Uracil transport in Saccharomyces cerevisiae. J Membr Biol. 1977 Sep 14;36(2-3):233–251. doi: 10.1007/BF01868153. [DOI] [PubMed] [Google Scholar]
- Keniry M., Benz C., Shafer R. H., James T. L. Noninvasive spectroscopic analysis of fluoropyrimidine metabolism in cultured tumor cells. Cancer Res. 1986 Apr;46(4 Pt 1):1754–1758. [PubMed] [Google Scholar]
- Kirschenlohr H. L., Metcalfe J. C., Morris P. G., Rodrigo G. C., Smith G. A. Ca2+ transient, Mg2+, and pH measurements in the cardiac cycle by 19F NMR. Proc Natl Acad Sci U S A. 1988 Dec;85(23):9017–9021. doi: 10.1073/pnas.85.23.9017. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lee K. R., Sheu S. Y. Evidence of a new metabolic pathway of 5-fluorouracil in Escherichia coli from in vivo 19F-NMR spectroscopy. Biochim Biophys Acta. 1989 Mar 28;1011(1):12–17. doi: 10.1016/0167-4889(89)90071-2. [DOI] [PubMed] [Google Scholar]
- Loomis R. E., Alderfer J. L. Halogenated nucleic acids: effects of 5-fluorouracil on the conformation and properties of a polyribonucleotide and its constituents. Biopolymers. 1986 Apr;25(4):571–600. doi: 10.1002/bip.360250405. [DOI] [PubMed] [Google Scholar]
- Markwell M. A., Haas S. M., Bieber L. L., Tolbert N. E. A modification of the Lowry procedure to simplify protein determination in membrane and lipoprotein samples. Anal Biochem. 1978 Jun 15;87(1):206–210. doi: 10.1016/0003-2697(78)90586-9. [DOI] [PubMed] [Google Scholar]
- Parisot D., Malet-Martino M. C., Crasnier P., Martino R. 19F nuclear magnetic resonance analysis of 5-fluorouracil metabolism in wild-type and 5-fluorouracil-resistant Nectria haematococca. Appl Environ Microbiol. 1989 Oct;55(10):2474–2479. doi: 10.1128/aem.55.10.2474-2479.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Semmler W., Bachert-Baumann P., Gückel F., Ermark F., Schlag P., Lorenz W. J., van Kaick G. Real-time follow-up of 5-fluorouracil metabolism in the liver of tumor patients by means of F-19 MR spectroscopy. Radiology. 1990 Jan;174(1):141–145. doi: 10.1148/radiology.174.1.2104675. [DOI] [PubMed] [Google Scholar]
- Stevens A. N., Morris P. G., Iles R. A., Sheldon P. W., Griffiths J. R. 5-fluorouracil metabolism monitored in vivo by 19F NMR. Br J Cancer. 1984 Jul;50(1):113–117. doi: 10.1038/bjc.1984.146. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Stewart E., Gow N. A., Bowen D. V. Cytoplasmic alkalinization during germ tube formation in Candida albicans. J Gen Microbiol. 1988 May;134(5):1079–1087. doi: 10.1099/00221287-134-5-1079. [DOI] [PubMed] [Google Scholar]
- Vialaneix J. P., Chouini N., Malet-Martino M. C., Martino R., Michel G., Lepargneur J. P. Noninvasive and quantitative 19F nuclear magnetic resonance study of flucytosine metabolism in Candida strains. Antimicrob Agents Chemother. 1986 Nov;30(5):756–762. doi: 10.1128/aac.30.5.756. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wain W. H., Staatz W. D. Rates of synthesis of ribosomal protein and total ribonucleic acid through the cell cycle of the fission yeast Schizosaccharomyces pombe. Exp Cell Res. 1973 Oct;81(2):269–278. doi: 10.1016/0014-4827(73)90515-6. [DOI] [PubMed] [Google Scholar]
- Waldorf A. R., Polak A. Mechanisms of action of 5-fluorocytosine. Antimicrob Agents Chemother. 1983 Jan;23(1):79–85. doi: 10.1128/aac.23.1.79. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Whelan W. L., Kerridge D. Decreased activity of UMP pyrophosphorylase associated with resistance to 5-fluorocytosine in Candida albicans. Antimicrob Agents Chemother. 1984 Oct;26(4):570–574. doi: 10.1128/aac.26.4.570. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wolf W., Albright M. J., Silver M. S., Weber H., Reichardt U., Sauer R. Fluorine-19 NMR spectroscopic studies of the metabolism of 5-fluorouracil in the liver of patients undergoing chemotherapy. Magn Reson Imaging. 1987;5(3):165–169. doi: 10.1016/0730-725x(87)90016-6. [DOI] [PubMed] [Google Scholar]
- Wolf W., Presant C. A., Servis K. L., el-Tahtawy A., Albright M. J., Barker P. B., Ring R., 3rd, Atkinson D., Ong R., King M. Tumor trapping of 5-fluorouracil: in vivo 19F NMR spectroscopic pharmacokinetics in tumor-bearing humans and rabbits. Proc Natl Acad Sci U S A. 1990 Jan;87(1):492–496. doi: 10.1073/pnas.87.1.492. [DOI] [PMC free article] [PubMed] [Google Scholar]