In vitro and in vivo activity of 5-fluorocytosine on Acanthamoeba.
The results of our studies indicated that the avirulent Neff strain of Acanthamoeba was more susceptible to the activity of the anti-metabolite 5-fluorocytosine (5-FC) than was the virulent A-1 strain or a mouse brain reisolate of this strain, designated A-3. Results of competition experiments in which cultures were exposed simultaneously to 5-FC and either uracil, thymidine, or both uracil and thymidine demonstrated that the drug was directed against both deoxyribonucleic acid and ribonucleic acid in the avirulent strain, whereas ribonucleic acid was mainly affected in the virulent amebas. Concentrations >10 mug of 5-FC per ml were amebicidal to the avirulent strain; lower concentrations of the drug, which only affected growth slightly, significantly impaired the capacity of the cells to spontaneously encyst in stationary-phase cultures. On the other hand, the virulent strains were capable of growing in the presence of 5-FC (40 mug/ml) after an initial period of susceptibility. After a few transfers in growth medium lacking the drug, 5-FC-treated virulent amebas exhibited growth parameters typical of untreated cells. However, after successive subcultures in drug-free medium, 5-FC-treated cells lost their resistance and were again susceptible to the drug. This result suggested that the capacity of the cells to develop resistance resulted from a drug-induced mechanism. Spontaneous encystment, which was normally minimal in stationary-phase A-1 or A-3 cultures, was enhanced in A-3 but not A-1 cultures treated with 5-FC (>30 mug/ml). Results obtained from experiments to determine the effectiveness of 5-FC in protecting mice experimentally infected with either A-1 or A-3 amebas indicated that the clinical usefulness of 5-FC may be limited by the capacity of the amebas to develop resistance.
Stevens
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O'Dell
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D000048:Acanthamoeba / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D000562:Amebiasis / Q000188:drug therapy; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D005437:Flucytosine / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008813:Mice, Inbred ICR
D005437:Flucytosine