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. 1981 Sep;20(3):286–290. doi: 10.1128/aac.20.3.286

Activity of trifluorothymidine against cytomegalovirus.

J R Wingard, R K Stuart, R Saral, W H Burns
PMCID: PMC181689  PMID: 6272627

Abstract

Trifluorothymidine (TFT) was tested for antiviral activity against mouse cytomegalovirus (MCMV) and human cytomegalovirus (HCMV) in one-step replication assays. The TFT concentration required to reduce virus yield by 50% (ID50) was 0.22 microM for MCMV and 0.012 microM for HCMV. The antiviral activity of TFT against MCMV was reversed by addition of equimolar thymidine, and no antiviral activity was demonstrable in a host cell line lacking thymidine kinase. Thus, TFT's anti-MCMV activity is dependent on a host cell TK since this herpesvirus lacks thymidine kinase. A continuous subcutaneous infusion of TFT achieving a serum concentration of 1 microM failed to protect mice from lethal MCMV infection, perhaps because serum levels of thymidine were comparable to the drug level. Comparison of the ID50 against HCMV and the ID50 against human bone marrow progenitor cells resulted in an in vitro therapeutic ratio of 108, suggesting that TFT might offer some promise as a clinically useful anti-HCMV agent.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Allen L. B., Sidwell R. W. Target-organ treatment of neurotropic virus diseases: efficacy as a chemotherapy tool and comparison of activity of adenine arabinoside, cytosine arabinoside, idoxuridine, and trifluorothymidine. Antimicrob Agents Chemother. 1972 Sep;2(3):229–233. doi: 10.1128/aac.2.3.229. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Ansfield F. J., Ramirez G. Phase I and II studies of 2'-deoxy-5-(trifluoromethyl)-uridine (NSC-75520). Cancer Chemother Rep. 1971 Apr;55(2):205–208. [PubMed] [Google Scholar]
  3. Bresnick E., Williams S. S. Effects of 5-trifluoromethyldeoxyuridine upon deoxythymidine kinase. Biochem Pharmacol. 1967 Mar;16(3):503–507. doi: 10.1016/0006-2952(67)90097-4. [DOI] [PubMed] [Google Scholar]
  4. Burns W. H., Wingard J. R., Bender W. J., Saral R. Thymidine kinase not required for antiviral activity of acyclovir against mouse cytomegalovirus. J Virol. 1981 Sep;39(3):889–893. doi: 10.1128/jvi.39.3.889-893.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Ch'ien L. T., Cannon N. J., Whitley R. J., Diethelm A. G., Dismukes W. E., Scott C. W., Buchanan R. A., Alford C. A., Jr Effect of adenine arabinoside on cytomegalovirus infections. J Infect Dis. 1974 Jul;130(1):32–39. doi: 10.1093/infdis/130.1.32. [DOI] [PubMed] [Google Scholar]
  6. Clough D. W., Parkhurst J. R. Experimental herpes simplex virus type 1 encephalitis: treatment with 5-trifluoromethyl-2'-deoxyuridine. Antimicrob Agents Chemother. 1977 Feb;11(2):307–311. doi: 10.1128/aac.11.2.307. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Coen D. M., Schaffer P. A. Two distinct loci confer resistance to acycloguanosine in herpes simplex virus type 1. Proc Natl Acad Sci U S A. 1980 Apr;77(4):2265–2269. doi: 10.1073/pnas.77.4.2265. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Collins P., Bauer D. J. Relative potencies of anti-herpes compounds. Ann N Y Acad Sci. 1977 Mar 4;284:49–59. doi: 10.1111/j.1749-6632.1977.tb21936.x. [DOI] [PubMed] [Google Scholar]
  9. De Clercq E., Krajewska E., Descamps J., Torrence P. F. Anti-herpes activity of deoxythymidine analogues: specific dependence on virus-induced deoxythymidine kinase. Mol Pharmacol. 1977 Sep;13(5):980–984. [PubMed] [Google Scholar]
  10. Dexter D. L., Wolberg W. H., Ansfield F. J., Helson L., Heidelberger C. The clinical pharmacology of 5-trifluoromethyl-2'-deoxyuridine. Cancer Res. 1972 Feb;32(2):247–253. [PubMed] [Google Scholar]
  11. Eizuru Y., Minamishima Y., Hirano A., Kurimura T. Replication of mouse cytomegalovirus in thymidine kinase-deficient mouse cells. Microbiol Immunol. 1978;22(12):755–764. doi: 10.1111/j.1348-0421.1978.tb00429.x. [DOI] [PubMed] [Google Scholar]
  12. Estes J. E., Huang E. S. Stimulation of cellular thymidine kinases by human cytomegalovirus. J Virol. 1977 Oct;24(1):13–21. doi: 10.1128/jvi.24.1.13-21.1977. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Fujiwara Y., Heidelberger C. Fluorinated pyrimidines. 38. The incorporation of 5-trifluoromethyl-2'-deoxyuridine into the deoxyribonucleic acid of vaccinia virus. Mol Pharmacol. 1970 May;6(3):281–291. [PubMed] [Google Scholar]
  14. GOTTSCHLING H., HEIDELBERGER C. FLUORINATED PYRIMIDINES. XIX. SOME BIOLOGICAL EFFECTS OF 5-TRIFLUOROMETHYLURACIL AND 5-TRIFLUOROMETHYL-2'-DEOXYURIDINE ON ESCHERICHIA COLI AND BACTERIOPHAGE T4B. J Mol Biol. 1963 Nov;7:541–560. doi: 10.1016/s0022-2836(63)80101-1. [DOI] [PubMed] [Google Scholar]
  15. HARTMANN K. U., HEIDELBERGER C. Studies on fluorinated pyrimidines. XIII. Inhibition of thymidylate synthetase. J Biol Chem. 1961 Nov;236:3006–3013. [PubMed] [Google Scholar]
  16. HEIDELBERGER C., ANDERSON S. W. FLUORINATED PYRIMIDINES. XXI. THE TUMOR-INHIBITORY ACTIVITY OF 5-TRIFLUOROMETHYL-2'-DEOXYURIDINE. Cancer Res. 1964 Dec;24:1979–1985. [PubMed] [Google Scholar]
  17. Heidelberger C. On the molecular mechanism of the antiviral activity of trifluorothymidine. Ann N Y Acad Sci. 1975 Aug 8;255:317–325. doi: 10.1111/j.1749-6632.1975.tb29239.x. [DOI] [PubMed] [Google Scholar]
  18. Hughes W. L., Christine M., Stollar D. A radioimmunoassay for measurement of serum thymidine. Anal Biochem. 1973 Oct;55(2):468–478. doi: 10.1016/0003-2697(73)90137-1. [DOI] [PubMed] [Google Scholar]
  19. KAUFMAN H. E., HEIDELBERGER C. THERAPEUTIC ANTIVIRAL ACTION OF 5-TRIFLUOROMETHYL-2'-DEOXYURIDINE IN HERPES SIMPLEX KERATITIS. Science. 1964 Aug 7;145(3632):585–586. doi: 10.1126/science.145.3632.585. [DOI] [PubMed] [Google Scholar]
  20. Kaufmann H. E. In vivo studies with antiviral agents. Ann N Y Acad Sci. 1965 Jul 30;130(1):168–180. doi: 10.1111/j.1749-6632.1965.tb12550.x. [DOI] [PubMed] [Google Scholar]
  21. Kelsey D. K., Kern E. R., Overall J. C., Jr, Glasgow L. A. Effect of cytosine arabinoside and 5-iodo-2'-deoxyuridine on a cytomegalovirus infection in newborn mice. Antimicrob Agents Chemother. 1976 Mar;9(3):458–464. doi: 10.1128/aac.9.3.458. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Muller M. T., Hudson J. B. Thymidine kinase activity in mouse 3T3 cells infected by murine cytomegalovirus (MCV). Virology. 1977 Jul 15;80(2):430–433. doi: 10.1016/s0042-6822(77)80019-6. [DOI] [PubMed] [Google Scholar]
  23. Nottebrock H., Then R. Thymidine concentrations in serum and urine of different animal species and man. Biochem Pharmacol. 1977 Nov 15;26(22):2175–2179. doi: 10.1016/0006-2952(77)90271-4. [DOI] [PubMed] [Google Scholar]
  24. Pike B. L., Robinson W. A. Human bone marrow colony growth in agar-gel. J Cell Physiol. 1970 Aug;76(1):77–84. doi: 10.1002/jcp.1040760111. [DOI] [PubMed] [Google Scholar]
  25. Pollard R. B., Egbert P. R., Gallagher J. G., Merigan T. C. Cytomegalovirus retinitis in immunosuppressed hosts. I. Natural history and effects of treatment with adenine arabinoside. Ann Intern Med. 1980 Nov;93(5):655–664. doi: 10.7326/0003-4819-93-5-655. [DOI] [PubMed] [Google Scholar]
  26. Reyes P., Heidelberger C. Fluorinated pyrimidines. XXVI. Mammalian thymidylate synthetase: its mechanism of action and inhibition by fluorinated nucleotides. Mol Pharmacol. 1965 Jul;1(1):14–30. [PubMed] [Google Scholar]
  27. Tone H., Heidelberger C. Fluorinated pyrimidines. XLIV. Interaction of 5-trifluoromethyl-2'-deoxyuridine 5'-triphosphate with deoxyribonucleic acid polymerases. Mol Pharmacol. 1973 Nov;9(6):783–791. [PubMed] [Google Scholar]
  28. Umeda M., Heidelberger C. Fluorinated pyrimidines. XXXI. Mechanisms of inhibition of vaccinia virus replication in HeLa cells by pyrimidine nucleosides. Proc Soc Exp Biol Med. 1969 Jan;130(1):24–29. doi: 10.3181/00379727-130-33480. [DOI] [PubMed] [Google Scholar]
  29. Závada V., Erban V., Rezácová D., Vonka V. Thymidine-kinase in cytomegalovirus infected cells. Arch Virol. 1976;52(4):333–339. doi: 10.1007/BF01315622. [DOI] [PubMed] [Google Scholar]

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