Mode of action of 5-fluorocytosine and mechanisms of resistance
Abstract
Mode of action of 5-fluorocytosine (5-FC) and mechanisms of resistance to the drug are discussed on the basis of experiments performed with Candida albicans ATCC 26790 and with 50 selected clinical isolates of C. albicans belonging to serological type A or B and representing various degrees and models of 5-FC resistance (sensitivity). Incorporation of 5-fluorouridylic acid into RNA appeared as a prerequisite to antifungal activity, although at a given incorporation rate, growth inhibition varied considerably from one strain to the other. The amino acid pool was unbalanced, and there was evidence for disturbance of protein synthesis. These dysfunctions of RNA probably account for growth inhibition and cell death, whereas up to the present, there was no proof of formation of 5-fluorodeoxyuridylic acid nor of subsequent inhibition of thymidylate synthetase. Incorporation of fluorinated pyrimidine into RNA was lower in normally sensitive type B strains than in normally sensitive ones of type A, whereas the frequency of 5-FC-resistant mutants was the same. The two serological types did not differ in the activity of cytosine permease nor in that of cytosine deaminase. Among 29 clinical isolates with 5-FC resistance (or impaired sensitivity) no instance of cytosine permease deficiency was found. Two isolates (belonging to the serological type A) were deficient in cytosine deaminase, whereas the majority was probably deficient in uridine monophosphate pyrophosphorylase or had a surplus of de novo synthesis of pyrimidines. Relative 5-FC resistance was more common than complete resistance.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Cited by
Sorted by citations
Ghannoum, M. A., & Rice, L. B. (1999) · Clinical Microbiology Reviews · doi:10.1128/cmr.12.4.501 · Cited by 1,788 · see citing works
“albicans and Cryptococcus neoformans is attributable to mutational loss of one of the pyrimidine salvage enzymes (99, 108, 150).”
BackgroundVermes, A. (2000) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/46.2.171 · Cited by 803 · see citing works
“The occurrence of resistance with the use of 5-FC has been widely described and precludes use of 5-FC as a single agent.(5,11,17) Two basic mechanisms of resistance can be distinguished: (i) certain mutations can result in a deficiency in the enzymes necessary for cellular transport and uptake of 5-FC or for its metab…”
BackgroundAntifungal Resistance and New Strategies to Control Fungal Infections
Vandeputte, P., Ferrari, S., & Coste, A. T. (2011) · International Journal of Microbiology · doi:10.1155/2012/713687 · Cited by 507 · see citing works
“Numerous enzymes of the pyrimidine salvage pathway are involved in 5FC mode of action and thus numerous molecular mechanisms could lead to resistance to this drug [16, 204].”
BackgroundInfluentialMullen, C. A., Kilstrup, M., & Blaese, R. M. (1992) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.89.1.33 · Cited by 495 · see citing works
Antifungal therapeutic drug monitoring: established and emerging indications
Andes, D., Pascual, A., & Marchetti, O. (2009) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00705-08 · Cited by 490 · see citing works
“Use in other situations has been limited due to clinician concerns regarding drug toxicity and resistance development with monotherapy administration (35, 67, 73).”
BackgroundAntifungal Therapy: New Advances in the Understanding and Treatment of Mycosis
Scorzoni, L., de Paula e Silva, A. C. A., Marcos, C. M., Assato, P. A., de Melo, W. C. M. A., de Oliveira, H. C., Costa-Orlandi, C. B., Mendes-Giannini, M. J. S., & Fusco-Almeida, A. M. (2017) · Frontiers in Microbiology · doi:10.3389/fmicb.2017.00036 · Cited by 418 · see citing works
“This acid can be incorporated into RNA, resulting in premature chain termination, thereby inhibiting DNA synthesis through effects on the enzyme thymidylate synthase (Polak and Scholer, 1975; Odds et al., 2003; Kathiravan et al., 2012).”
BackgroundHigh-Frequency Switching of Colony Morphology in Candida albicans
Slutsky, B., Buffo, J., & Soll, D. R. (1985) · Science · doi:10.1126/science.3901258 · Cited by 400 · see citing works
Strategies in the Treatment of Systemic Fungal Infections
Medoff, G., & Kobayashi, G. S. (1980) · New England Journal of Medicine · doi:10.1056/nejm198001173020304 · Cited by 342 · see citing works
Fluorinated Pyrimidines and Their Nucleosides
Heidelberger, C. (1975) · Springer eBooks · doi:10.1007/978-3-642-65806-8_12 · Cited by 337 · see citing works
Liu, T. T., Lee, R. E. B., Barker, K. S., Lee, R. E., Wei, L., Homayouni, R., & Rogers, P. D. (2005) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.49.6.2226-2236.2005 · Cited by 313 · see citing works
“5FU also undergoes conversion to 5-fluorodeoxyuridine monophosphate, which inhibits thymidylate synthetase, encoded by CDC21, by disrupting DNA synthesis (11, 18, 25, 26).”
BackgroundPharmacology of Systemic Antifungal Agents
Ashley, E. S. D., Lewis, R. E., Lewis, J. S., Martin, C. A., & Andes, D. R. (2006) · Clinical Infectious Diseases · doi:10.1086/504492 · Cited by 311 · see citing works
“Unfortunately, the toxicity of this agent and the rapid development of resistance when used as monotherapy have precluded its routine use for the treatment of other invasive infections [5, 32, 33].”
Sanglard, D., Coste, A., & Ferrari, S. (2009) · FEMS Yeast Research · doi:10.1111/j.1567-1364.2009.00578.x · Cited by 285 · see citing works
“Susceptible fungi have a cytosine deaminase that converts 5-FC into 5-fluorouracil, which is then incorporated into DNA and RNA, therefore inhibiting cellular function and division (Polak & Scholer, 1975).”
BackgroundLoeffler, J., & Stevens, D. A. (2003) · Clinical Infectious Diseases · doi:10.1086/344658 · Cited by 252 · see citing works
Antifungal Agents Useful in Therapy of Systemic Fungal Infections
Medoff, G., Brajtburg, J., Kobayashi, G. S., & Bolard, J. (1983) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pa.23.040183.001511 · Cited by 236 · see citing works
Francis, P., & Walsh, T. J. (1992) · Clinical Infectious Diseases · doi:10.1093/clind/15.6.1003 · Cited by 232 · see citing works
“5-fluorouridine triphosphate and incorporation into fungal RNA with resultant inhibition of protein synthesis [15]; and (2) conversion by uridine monophosphate pyrophosphorylase into 5-fluorodeoxyuridine monophosphate (F-dUMP), which inhibits thymidylate synthetase and, consequently, DNA synthesis [19].”
BackgroundCryptococcus neoformans, a global threat to human health
Zhao, Y., Ye, L., Zhao, F., Zhang, L., Lu, Z., Chu, T., Wang, S., Liu, Z., Sun, Y., Chen, M., et al. (2023) · Infectious Diseases of Poverty · doi:10.1186/s40249-023-01073-4 · Cited by 206 · see citing works
“The converted metabolites then inhibit thymidylate synthase activity and consequently inhibits DNA and RNA synthesis [92, 93].”
BackgroundHay, R. J. (1995) · Journal of the European Academy of Dermatology and Venereology · doi:10.1016/0926-9959(95)95776-w · Cited by 181 · see citing works
In vitro and in vivo evaluation of antifungal agents
Espinel-Ingroff, A. V., & Shadomy, S. (1989) · European Journal of Clinical Microbiology & Infectious Diseases · doi:10.1007/bf01963469 · Cited by 179 · see citing works
“Because of this, 5-fluorocytosine is subject to antagonistic effects, and its in vitro evaluation should be performed in a medium free of cytosine, uridine, and other pyrimidines and purines which are antagonistic to the drug (42).”
BackgroundMolecular Mechanisms of Primary Resistance to Flucytosine in <i>Candida albicans</i>
Hope, W. W., Tabernero, L., Denning, D. W., & Anderson, M. J. (2004) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.48.11.4377-4386.2004 · Cited by 160 · see citing works
“The prospect of more than one resistance mechanism is also supported by the early observation that there was a large degree of variability in the incorporation of fluorinated pyrimidine nucleotides into RNA for a group of isolates with otherwise similar levels of susceptibility to 5-FC (17).”
BackgroundLoyse, A., Dromer, F., Day, J., Lortholary, O., & Harrison, T. S. (2013) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dkt221 · Cited by 159 · see citing works
Mode of Action of Clinically Important Antifungal Drugs
Kerridge, D. (1986) · Advances in microbial physiology/Advances in Microbial Physiology · doi:10.1016/s0065-2911(08)60303-3 · Cited by 142 · see citing works
Mechanisms of action of 5-fluorocytosine
Waldorf, A. R., & Polak, A. (1983) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.23.1.79 · Cited by 141 · see citing works
“Eleven isolates of known 5-FC resistance (10) were kindly supplied by S.”
BackgroundMethodSelf-citationThompson, G. R., Cadena, J., & Patterson, T. F. (2009) · Clinics in Chest Medicine · doi:10.1016/j.ccm.2009.02.001 · Cited by 141 · see citing works
“1).(92) This agent may be either fungistatic or fungicidal depending on fungal species and strain.”
BackgroundMode of action of 5-fluorocytosine
Diasio, R. B., Bennett, J. E., & Myers, C. E. (1978) · Biochemical Pharmacology · doi:10.1016/0006-2952(78)90507-5 · Cited by 139 · see citing works
Combatting the evolution of antifungal resistance in Cryptococcus neoformans
Bermas, A., & Geddes‐McAlister, J. (2020) · Molecular Microbiology · doi:10.1111/mmi.14565 · Cited by 138 · see citing works
“5FUTP is incorporated into fungal RNA in place of uridylic acid, altering the aminoacylation of tRNA, disturbing RNA synthesis (Polak and Scholer, 1975; Longley et al., 2003).”
BackgroundAntifungal susceptibility tests
Galgiani, J. N. (1987) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.31.12.1867 · Cited by 138 · see citing works
“Medium components may antagonize drug activity (2, 5, 8, 14, 16-19, 25-29, 36).”
BackgroundDodgson, A. R., Dodgson, K. J., Pujol, C., Pfaller, M. A., & Soll, D. R. (2004) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.48.6.2223-2227.2004 · Cited by 133 · see citing works
“5-Fluorouridine monophosphate is then converted to 5-fluorouridine triphosphate, which, when incorporated into RNA in place of UTP, disrupts protein synthesis (7, 16).”
BackgroundInfluentialHistone acetyltransferase Rtt109 is required for <i>Candida albicans</i> pathogenesis
Lopes da Rosa, J., Boyartchuk, V. L., Zhu, L. J., & Kaufman, P. D. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0912427107 · Cited by 132 · see citing works
“As a nucleotide analog, it impedes DNA synthesis (47), suggesting that mutants defective for replication fork stability may be more sensitive to this compound.”
BackgroundConversion of 5-fluorocytosine to 5-fluorouracil by human intestinal microflora
Harris, B., Manning, B. W., Federle, T. W., & Diasio, R. B. (1986) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.29.1.44 · Cited by 128 · see citing works
Cryptococcosis: epidemiology, fungal resistance, and new alternatives for treatment
Gullo, F. P., Rossi, S. A., Sardi, J. D. C. O., Teodoro, V. L. I., Mendes‐Giannini, M. J. S., & Fusco‐Almeida, A. M. (2013) · European Journal of Clinical Microbiology & Infectious Diseases · doi:10.1007/s10096-013-1915-8 · Cited by 122 · see citing works
“The yeast cell division is inhibited by acting on cytosine deaminase, responsible for converting 5-FC into 5-fluorouracil, which binds to DNA and yeast RNA, and blocks cell functions [47, 51].”
BackgroundAntifungal Resistance Trends Towards the Year 2000: Implications for Therapy and New Approaches
Alexander, B. D., & Perfect, J. R. (1997) · Drugs · doi:10.2165/00003495-199754050-00002 · Cited by 153 · see citing works
Stott, K. E., & Hope, W. W. (2017) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dkx029 · Cited by 115 · see citing works
Degradation of pyrimidines and pyrimidine analogs—Pathways and mutual influences
Wasternack, C. H. (1980) · Pharmacology & Therapeutics · doi:10.1016/0163-7258(80)90079-0 · Cited by 114 · see citing works
Espinel‐Ingroff, A., Pfaller, M. A., Erwin, M. E., & Jones, R. N. (1996) · Journal of Clinical Microbiology · doi:10.1128/jcm.34.4.848-852.1996 · Cited by 112 · see citing works
John, J., Loo, A. S., Mazur, S., & Walsh, T. J. (2019) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1080/17425255.2019.1671971 · Cited by 107 · see citing works
Mechanisms of Fungal Resistance
Balkis, M. M., Leidich, S. D., Mukherjee, P. K., & Ghannoum, M. A. (2002) · Drugs · doi:10.2165/00003495-200262070-00004 · Cited by 106 · see citing works
“(FdUMP), a potent inhibitor of thymidylate synthase, an enzyme involved in DNA synthesis and nuclear division.[86,87] The initial promise of this agent has been diminished by the high prevalence of primary resistance in many fungal species.”
Antifungal Agents. Part I. Amphotericin B Preparations and Flucytosine
Patel, R. (1998) · Mayo Clinic Proceedings · doi:10.4065/73.12.1205 · Cited by 106 · see citing works
Antifungal Agents Used in Systemic Mycoses Activity and Therapeutic Use
Graybill, J. R., & Craven, P. C. (1983) · Drugs · doi:10.2165/00003495-198325010-00003 · Cited by 105 · see citing works
Vanreppelen, G., Wuyts, J., Dijck, P. V., & Vandecruys, P. (2023) · Journal of Fungi · doi:10.3390/jof9020171 · Cited by 112 · see citing works
“These pyridine analogs are compounds that mimic the structure of pyrimidine [13].”
BackgroundPharmacologic management of keratomycoses
Johns, K. J., & O’Day, D. M. (1988) · Survey of Ophthalmology · doi:10.1016/0039-6257(88)90086-0 · Cited by 103 · see citing works
Cardenas, M. E., Cruz, M. C., Poeta, M. D., Chung, N., Perfect, J. R., & Heitman, J. (1999) · Clinical Microbiology Reviews · doi:10.1128/cmr.12.4.583 · Cited by 103 · see citing works
Fungal Drug Response and Antimicrobial Resistance
Osset-Trénor, P., Pascual‐Ahuir, A., & Proft, M. (2023) · Journal of Fungi · doi:10.3390/jof9050565 · Cited by 103 · see citing works
Transplantation of prodrug-converting neural progenitor cells for brain tumor therapy
Barresi, V., Belluardo, N., Sipione, S., Mudò, G., Cattaneo, E. F., & Condorelli, D. F. (2003) · Cancer Gene Therapy · doi:10.1038/sj.cgt.7700580 · Cited by 99 · see citing works
New investigational antifungal agents for treating invasive fungal infections
Hossain, M. A., & Ghannoum, M. A. (2000) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.9.8.1797 · Cited by 95 · see citing works
“resulting in the disruption of protein synthesis [26].”
BackgroundNakamura, H., Mullen, J. T., Chandrasekhar, S., Pawlik, T. M., Yoon, S. S., & Tanabe, K. K. (2001) · PubMed · Cited by 93 · see citing works
Fluorinated Pyrimidines and Their Nucleosides
Heidelberger, C., Danenberg, P. V., & Moran, R. G. (1983) · Advances in enzymology and related areas of molecular biology/Advances in enzymology and related subjects · doi:10.1002/9780470122990.ch2 · Cited by 93 · see citing works
Khil, M. S., Kim, J. H., Mullen, C. A., Kim, S. H., & Freytag, S. O. (1996) · PubMed · Cited by 92 · see citing works
The Genetic Basis of Resistance to 5-Fluorocytosine in Candida Species and Cryptococcus Neoformans
Whelan, W. L. (1987) · CRC Critical Reviews in Microbiology · doi:10.3109/10408418709104447 · Cited by 88 · see citing works
Use of suicide genes in gene therapy
Tiberghien, P. (1994) · Journal of Leukocyte Biology · doi:10.1002/jlb.56.2.203 · Cited by 85 · see citing works
“Microorganisms that express the CD gene convert 5-fluorocytosine (5-FC) to 5-fluoruracil (5-FU), a highly toxic metabolite that is lethal to the cell [28, 29].”
BackgroundPharmacologic therapy of mycotic keratitis
Sahay, P., Singhal, D., Nagpal, R., Maharana, P. K., Farid, M., Gelman, R. A., Sinha, R., Agarwal, T., Titiyal, J. S., & Sharma, N. (2019) · Survey of Ophthalmology · doi:10.1016/j.survophthal.2019.02.007 · Cited by 83 · see citing works
Pharmacokinetics and Pharmacodynamics of Antifungals in Children: Clinical Implications
Autmizguine, J., Guptill, J. T., Cohen‐Wolkowiez, M., Benjamin, D. K., & Capparelli, E. V. (2014) · Drugs · doi:10.1007/s40265-014-0227-3 · Cited by 75 · see citing works
“5-Flucytosine (5-FC) is an antimetabolite drug that causes RNA miscoding and inhibits DNA synthesis [174].”
BackgroundAntifungal Pharmacodynamics: Concentration‐Effect Relationships in Vitro and in Vivo
Groll, A. H., Piscitelli, S. C., & Walsh, T. J. (2001) · Pharmacotherapy The Journal of Human Pharmacology and Drug Therapy · doi:10.1592/phco.21.12.133s.34507 · Cited by 73 · see citing works
“It is taken up into the fungal cell by the fungus-specific enzyme cytosine permease and converted in the cytoplasm by cytosine deaminase to 5-fluorouracil, a potent antimetabolite that causes RNA miscoding and inhibits DNA synthesis.(40) Flucytosine has broad-spectrum antifungal activity against Candida sp, C.”
BackgroundNew Approaches for Cryptococcosis Treatment
Spadari, C. D. C., Wirth, F., Lopes, L. B., & Ishida, K. (2020) · Microorganisms · doi:10.3390/microorganisms8040613 · Cited by 73 · see citing works
Groll, A. H., & Kolve, H. (2004) · European Journal of Clinical Microbiology & Infectious Diseases · doi:10.1007/s10096-004-1108-6 · Cited by 72 · see citing works
“Following uptake by the fungus-specific enzyme cytosine permease, it is converted to 5-fluorouracil, a potent anticancer agent that causes RNA miscoding and inhibits DNA synthesis [54].”
BackgroundGlucan synthase inhibitors as antifungal agents
Kurtz, M. B., & Rex, J. H. (2001) · Advances in protein chemistry · doi:10.1016/s0065-3233(01)56011-8 · Cited by 72 · see citing works
Overview of treatment options for invasive fungal infections
Pound, M. W., Townsend, M. L., DiMondi, V. P., Wilson, D. T., & Drew, R. H. (2011) · Medical Mycology · doi:10.3109/13693786.2011.560197 · Cited by 69 · see citing works
Overview: Treatment of Cryptococcal Meningitis
Sugar, A. M., Stem, J. J., & Dupont, B. (1990) · Clinical Infectious Diseases · doi:10.1093/clinids/12.supplement_3.s338 · Cited by 70 · see citing works
“neoformans [16-18].”
Antifungal resistance in dermatology
Pai, V. V., Ganavalli, A., & Kikkeri, N. (2018) · Indian Journal of Dermatology · doi:10.4103/ijd.ijd_131_17 · Cited by 69 · see citing works
“The antifungal drug 5FC competes with the regular pyrimidine intermediate metabolites for incorporation into nucleic acids.[14,22] De Novo increase in pyrimidine synthesis leads to 5FC resistance as seen in Candida glabrata.”
Canadian Clinical Practice Guidelines for Invasive Candidiasis in Adults
Bow, E. J., Evans, G. A., Fuller, J., Laverdière, M., Rotstein, C., Rennie, R. P., Shafran, S. D., Sheppard, D. C., Carle, S., Phillips, P., et al. (2010) · Canadian Journal of Infectious Diseases and Medical Microbiology · doi:10.1155/2010/357076 · Cited by 68 · see citing works
Auger, P., Dumas, C., & Joly, J. (1979) · The Journal of Infectious Diseases · doi:10.1093/infdis/139.5.590 · Cited by 66 · see citing works
“albicans [5], although many mechanisms of resistance to 5-FC have been demonstrated [6-11].”
BackgroundThe Genetics of Medically Important Fungi
Whelan, W. L. (1987) · CRC Critical Reviews in Microbiology · doi:10.3109/10408418709104437 · Cited by 65 · see citing works
New antifungal strategies: Drug combination and co-delivery
Zhu, P., Li, Y., Guo, T., Liu, S., Tancer, R. J., Hu, C., Zhao, C., Xue, C., & Liao, G. (2023) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2023.114874 · Cited by 63 · see citing works
Use of Salmonella Bacteria in Cancer Therapy: Direct, Drug Delivery and Combination Approaches
Badie, F., Ghandali, M., Tabatabaei, S. A., Safari, M., Khorshidi, A., Shayestehpour, M., Mahjoubin‐Tehran, M., Morshedi, K., Jalili, A., Tajiknia, V., et al. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.624759 · Cited by 62 · see citing works
“5-FUTP and 5-FdUTP can be produced by the insertion of enzymes into RNA and DNA (71) thus leading to cell death (72, 73).”
BackgroundGalgiani, J. N., & Stevens, D. A. (1978) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.13.2.249 · Cited by 62 · see citing works
“rent understanding of the mechanism of action of these three drugs (7, 8, 10).”
BackgroundSystemic Antifungal Agents: Current Status and Projected Future Developments
Seyedmousavi, S., Rafati, H., İlkit, M., Tolooe, A., Hedayati, M. T., & Verweij, P. E. (2016) · Methods in molecular biology · doi:10.1007/978-1-4939-6515-1_5 · Cited by 61 · see citing works
Antifungal Resistance Among Candida Species
Klepser, M. E. (2001) · Pharmacotherapy The Journal of Human Pharmacology and Drug Therapy · doi:10.1592/phco.21.12.124s.34511 · Cited by 60 · see citing works
“73 On internalization, it is rapidly deaminated to 5-fluorouracil by cytosine deaminase.(74) 5-Fluorouracil can then be converted to either 5-fluorouridine triphosphate (FUTP) or 5-fluorodeoxyuridine monophosphate (FdUMP), which inhibit RNAmediated protein synthesis and DNA synthesis, respectively.”
BackgroundVibrational spectroscopy investigation using ab initio and density functional theory on flucytosine
Seshadri, S., Gunasekaran, S., Muthu, S., Kumaresan, S., & Arunbalaji, R. (2007) · Journal of Raman Spectroscopy · doi:10.1002/jrs.1808 · Cited by 57 · see citing works
Antifungal Susceptibility Testing of Yeasts: A Brief Overview
Sheehan, D. J., Espinel-Ingroff, A. V., Moore, L. S., & Webb, C. D. (1993) · Clinical Infectious Diseases · doi:10.1093/clinids/17.supplement_2.s494 · Cited by 57 · see citing works
“Susceptibility testing with flucytosine is clinically significant since de novo resistance as well as the emergence of resistant strains of yeasts and fungi after treatment with flucytosine used alone is well documented [9-11].”
BackgroundYang, F., Gritsenko, V., Lu, H., Zhen, C., Gao, L., Berman, J., & Jiang, Y.-Y. (2021) · Microbiology Spectrum · doi:10.1128/spectrum.00723-21 · Cited by 49 · see citing works
Whelan, W. L., & Kerridge, D. (1984) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.26.4.570 · Cited by 53 · see citing works
“In agreement with a study by other workers (7), our results suggest that it is unlikely that defective 5-FC uptake accounts for a significant number of resistant strains.”
BackgroundMethodResultDefever, K. S., Whelan, W. L., Rogers, A. L., Beneke, E. S., Veselenak, J. M., & Soll, D. R. (1982) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.22.5.810 · Cited by 53 · see citing works
“Although partially resistant isolates have been described by other workers with a variety of methods to assess resistance (5, 7-9), our studies (10; present study) are the first to show that such isolates give rise to highly resistant varieties.”
BackgroundResultPharmacokinetics and Pharmacodynamics of Antifungals in Children and their Clinical Implications
Stockmann, C. R., Constance, J. E., Roberts, J. K., Olson, J. A., Doby, E. H., Ampofo, K., Stiers, J., Spigarelli, M. G., & Sherwin, C. M. T. (2014) · Clinical Pharmacokinetics · doi:10.1007/s40262-014-0139-0 · Cited by 50 · see citing works
CandidaInfections and Their Prevention
Kabir, M. A., & Ahmad, Z. (2012) · ISRN Preventive Medicine · doi:10.5402/2013/763628 · Cited by 50 · see citing works
“5-FC is taken up by Candida species through cytosine permease and once inside the cell, it is rapidly converted into 5-FU [28, 29].”
BackgroundPolak, A. (1990) · Handbook of experimental pharmacology · doi:10.1007/978-3-642-75458-6_8 · Cited by 50 · see citing works
Self-citationDrug resistance in human pathogenic fungi
Iwata, K. (1992) · European Journal of Epidemiology · doi:10.1007/bf00158576 · Cited by 48 · see citing works
Past, Present, and Future of Antifungal Drug Development
Shukla, P. K., Singh, P., Yadav, R. K., Pandey, S., & Bhunia, S. S. (2016) · Topics in medicinal chemistry · doi:10.1007/7355_2016_4 · Cited by 46 · see citing works
Baddley, J. W., & Moser, S. A. (2004) · Clinics in Laboratory Medicine · doi:10.1016/j.cll.2004.05.003 · Cited by 46 · see citing works
“Resistance also can be caused by loss of activity of uracil phosphoribosyltransferase [54,55] and by increased synthesis of pyrimidines that compete with the fluorinated antimetabolites of 5-FC [53].”
BackgroundAntifungal Drug Development: Targeting the Fungal Sphingolipid Pathway
McEvoy, K., Normile, T. G., & Poeta, M. D. (2020) · Journal of Fungi · doi:10.3390/jof6030142 · Cited by 44 · see citing works
“The fluorinated cytosine (5-FC) is a prodrug that is converted into the active antifungal form inside the cell (5-fluorouracil (5-FU)) by fungal cytosine deaminase (Fcy1) [10,11].”
BackgroundDrutz, D. J. (1987) · Clinical Infectious Diseases · doi:10.1093/clinids/9.2.392 · Cited by 41 · see citing works
“for intrinsic or acquired drug resistance is high [16].”
BackgroundTHERAPY OF OCULAR FUNGAL INFECTIONS
OBRIEN, T. (1999) · Ophthalmology Clinics of North America · doi:10.1016/s0896-1549(05)70147-4 · Cited by 39 · see citing works
Fimua Cryptococcosis Network (2002) · Medical Mycology · doi:10.1080/714031142 · Cited by 39 · see citing works
Calhoun, D. L., & Galgiani, J. N. (1984) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.26.3.364 · Cited by 39 · see citing works
Antimicrobial Susceptibility Testing of Six Clinical Isolates of Aspergillus
Kitahara, M., Seth, V. K., Medoff, G., & Kobayashi, G. S. (1976) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.9.6.908 · Cited by 39 · see citing works
Antifungal drugs: An updated review of central nervous system pharmacokinetics
Wirth, F., & Ishida, K. (2020) · Mycoses · doi:10.1111/myc.13157 · Cited by 37 · see citing works
Fungal Infections: Their Diagnosis and Treatment in Transplant Recipients
Thiel, D. H. V., George, M., & Moore, C. M. (2012) · International Journal of Hepatology · doi:10.1155/2012/106923 · Cited by 36 · see citing works
“The development of rapid drug resistance and its toxicity pattern (see Table 3(b)) limits its usefulness in other fungal infections [41].”
Small-molecule inhibitors for the Prp8 intein as antifungal agents
Li, Z., Tharappel, A. M., Xu, J., Lang, Y., Green, C. M., Zhang, J., Lin, Q., Chaturvedi, S., Zhou, J., Belfort, M., et al. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2008815118 · Cited by 32 · see citing works
“These drugs kill fungi through various mechanisms, including interfering with membrane permeabilization (AmB) (65, 66), inhibition of 14α-demethylase (triazoles) (67), inhibition of DNA/RNA synthesis (5-FC) (68), and inhibition of (1→3)-β-D-glucan synthase (CAS) (69).”
BackgroundThangarasu, S., Kumar, S. S., Athimoolam, S., Sridhar, B., Bahadur, S. A., Shanmugam, R., & Thamaraichelvan, A. (2014) · Journal of Molecular Structure · doi:10.1016/j.molstruc.2014.05.054 · Cited by 32 · see citing works
Baracaldo-Santamaría, D., Cala-García, J., Medina-Rincón, G. J., Rojas-Rodríguez, L. C., & Calderón‐Ospina, C. (2022) · Antibiotics · doi:10.3390/antibiotics11050645 · Cited by 32 · see citing works
“It should be noted that 5-fluorouracil is highly toxic to human and non-human mammalian cells and is not readily taken up by fungal cells, thus leaving it ineffective as an antifungal agent; instead, its main current use concerns the treatment of certain types of cancer, mainly colorectal carcinoma [152,153].”
BackgroundSynthesis andin vivodiuretic activity of some novel pyrimidine derivatives
Majeed, J., & Yar, M. S. (2011) · Journal of Enzyme Inhibition and Medicinal Chemistry · doi:10.3109/14756366.2011.557022 · Cited by 30 · see citing works
Chemotherapy of Systemic Fungal Diseases
Hoeprich, P. D. (1978) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pa.18.040178.001225 · Cited by 30 · see citing works
Resistance to Systemic Antifungal Agents
Scholer, H. J., & Polak, A. (1984) · Elsevier eBooks · doi:10.1016/b978-0-12-138120-2.50019-8 · Cited by 30 · see citing works
Self-citationTreatment of severe chromoblastomycosis with itraconazole and 5-flucytosine association
Antonello, V. S., da Silva, M. C. A., Cambruzzi, E., Kliemann, D. A., Santos, B. R., & Queiroz‐Telles, F. (2010) · Revista do Instituto de Medicina Tropical de São Paulo · doi:10.1590/s0036-46652010000600008 · Cited by 29 · see citing works
Gubbins, P. O., & Anaissie, E. J. (2009) · Elsevier eBooks · doi:10.1016/b978-1-4160-5680-5.00007-4 · Cited by 29 · see citing works
Chavan, P. N., Bangale, S., Pansare, D. N., Shelke, R. N., Jadhav, S., Tupare, S., Kamble, D. P., & Rai, M. (2020) · Journal of Heterocyclic Chemistry · doi:10.1002/jhet.4048 · Cited by 28 · see citing works
Topical and systemic antifungals in dermatology practice
Durdu, M., İlkit, M., Tamaddon, Y., Tolooe, A., Rafati, H., & Seyedmousavi, S. (2016) · Expert Review of Clinical Pharmacology · doi:10.1080/17512433.2017.1263564 · Cited by 28 · see citing works
Antifungal Susceptibility Testing of Yeasts
Espinel‐Ingroff, A., & Cantón, E. (2007) · CRC Press eBooks · doi:10.1201/9781420014495.ch9 · Cited by 28 · see citing works
El‐Sayed, A. S. A., Mohamed, N. Z., Yassin, M. A., Amer, M. M., El-Sharkawy, R. M., Elsayed, N., & Ali, M. G. (2022) · Heliyon · doi:10.1016/j.heliyon.2022.e10660 · Cited by 27 · see citing works
Candida: A Causative Agent of an Emerging Infection
Ghannoum, M. A. (2001) · Journal of Investigative Dermatology Symposium Proceedings · doi:10.1046/j.0022-202x.2001.00047.x · Cited by 27 · see citing works
“Subsequently, 5-FU is converted by UMP pyrophosphorylase into 5-fluorouridylic acid, which is further phosphorylated and incorporated into RNA, resulting in disruption of protein synthesis”
BackgroundSaundane, A. R., Manjunatha, Y., & Rayappa, K. (2011) · Medicinal Chemistry Research · doi:10.1007/s00044-011-9915-7 · Cited by 25 · see citing works
“Some of the pyrimidine analogues (2) (Agarwal et al., 2002), and (3) (Polak and Scholer, 1975) have been reported as potential antimicrobial agents.”
BackgroundMcManus, B. A., Moran, G. P., Higgins, J., Sullivan, D. J., & Coleman, D. C. (2009) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00607-09 · Cited by 24 · see citing works
“1), leading to the depletion of dTTP and the misincorporation of dUTP into newly synthesized DNA, causing irreversible DNA damage and cell cycle arrest (14, 31, 41).”
BackgroundInfluential
- Authors
- Polak, A., & Scholer, H. J.
- Affiliations
- F. Hoffmann-La Roche AG (CH)
- ORCID
- Polak, Annemarie
- Venue
- Chemotherapy
- Publisher
- S. Karger AG
- Published
- 2009-05-25
- Volume
- 21
- Issue
- 3-4
- Pages
- 113-130
- ISSN
- 0009-3157 (ISSN-L)
- 1421-9794
- OpenAlex
- W2072785474
- Cited by
- 250
- References
- 0
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 10 · 2023: 12 · 2022: 7 · 2021: 6 · 2020: 10 · 2019: 7 · 2018: 7 · 2017: 4 · 2016: 5 · 2015: 2 · 2014: 8 · 2013: 4 · 2012: 6
- FWCI
- 7.57
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Chemotherapy (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Keywords
- 5-fluorocytosine, Candida albicans, antifungal resistance, mechanism of action, cytosine deaminase, protein synthesis inhibition, clinical isolates
- MeSH terms
- Candida albicans, Cell Division, Cytidine Deaminase, Cytosine, Drug Resistance, Microbial, Flucytosine, RNA, Serotyping, Uracil Nucleotides, Membrane Transport Proteins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
