Because thymidine metabolism is a potential target for therapy of Pneumocystis pneumonia, it was investigated whether Pneumocystis organisms have a salvage pathway for thymidine by administering 5-bromo-2′-deoxyuridine (BrdU) to mice and rats with Pneumocystis pneumonia. Although BrdU incorporation was detected in host cells, no incorporation was seen in Pneumocystis organisms infecting either rats or mice. This suggests that Pneumocystis organisms do not have a salvage pathway for thymidine, and that inhibitors of de novo synthesis, such as thymidylate synthase inhibitors, may be effective drugs for treating Pneumocystis pneumonia.
AndersonA. C., PerryK. M., FreymannD. M., StroudR. M.2000; The crystal structure of thymidylate synthase from Pneumocystis carinii reveals a fungal insert important for drug design. J Mol Biol 297:645–657[CrossRef]
AngusC. W., TuA., VogelP., QinM., KovacsJ. A.1996; Expression of variants of the major surface glycoprotein of Pneumocystis carinii. J Exp Med 183:1229–1234[CrossRef]
DolbeareF.1995a; Bromodeoxyuridine: a diagnostic tool in biology and medicine, part II: oncology, chemotherapy and carcinogenesis. Histochem J 27:923–964[CrossRef]
DolbeareF.1995b; Bromodeoxyuridine: a diagnostic tool in biology and medicine, part I: historical perspectives, histochemical methods and cell kinetics. Histochem J 27:339–369[CrossRef]
DolbeareF.1996; Bromodeoxyuridine: a diagnostic tool in biology and medicine, part III. Proliferation in normal, injured and diseased tissue, growth factors, differentiation, DNA replication sites and in situ hybridization. Histochem J 28:531–575[CrossRef]
EdmanJ. C., KovacsJ. A., MasurH., SantiD. V., ElwoodH. J., SoginM. L.1988; Ribosomal RNA sequence shows Pneumocystis carinii to be a member of the fungi. Nature 334:519–522[CrossRef]
EdmanU., EdmanJ. C., LundgrenB., SantiD. V.1989; Isolation and expression of the Pneumocystis carinii thymidylate synthase gene. Proc Natl Acad Sci U S A 86:6503–6507[CrossRef]
FlynnK. J., RiberdyJ. M., ChristensenJ. P., AltmanJ. D., DohertyP. C.1999; In vivo proliferation of naive and memory influenza-specific CD8+ T cells. Proc Natl Acad Sci U S A 96:8597–8602[CrossRef]
GutierrezJ. C., CallejasS., BorniquelS., Martin-GonzalezA.2000; DNA methylation in ciliates: implications in differentiation processes. Int Microbiol 3:139–146
Helweg-LarsenJ., BenfieldT. L., Eugen-OlsenJ., LundgrenJ. D., LundgrenB.1999; Effects of mutations in Pneumocystis carinii dihydropteroate synthase gene on outcome of AIDS-associatedP. carinii pneumonia. Lancet 354:1347–1351[CrossRef]
HodsonJ. A., BailisJ. M., ForsburgS. L.2003; Efficient labeling of fission yeast Schizosaccharomyces pombe with thymidine and BUdR. Nucleic Acids Res 31:e134[CrossRef]
HughesW., LeoungG., KramerF.14 other authors1993; Comparison of atovaquone (566C80) with trimethoprim-sulfamethoxazole to treat Pneumocystis carinii pneumonia in patients with AIDS. N Engl J Med 328:1521–1527[CrossRef]
JiangL., LeeP. C., WhiteJ., RathodP. K.2000; Potent and selective activity of a combination of thymidine and 1843U89, a folate-based thymidylate synthase inhibitor, against Plasmodium falciparum. Antimicrob Agents Chemother 44:1047–1050[CrossRef]
KazanjianP., ArmstrongW., HosslerP. A., BurmanW., RichardsonJ., LeeC. H., CraneL., KatzJ., MeshnickS. R.2000; Pneumocystis carinii mutations are associated with duration of sulfa or sulfone prophylaxis exposure in AIDS patients. J Infect Dis 182:551–557[CrossRef]
KellettM., PottenC. S., RewD. A.1992; A comparison of in vivo cell proliferation measurements in the intestine of mouse and man. Epithelial Cell Biol 1:147–155
KovacsJ. A., MasurH.2000; Prophylaxis against opportunistic infections in patients with human immunodeficiency virus infection. N Engl J Med 342:1416–1429[CrossRef]
KovacsJ. A., HalpernJ. L., SwanJ. C., MossJ., ParrilloJ. E., MasurH.1988; Identification of antigens and antibodies specific for Pneumocystis carinii. J Immunol 140:2023–2031
KovacsJ. A., AllegraC. J., MasurH.1990; Characterization of dihydrofolate reductase of Pneumocystis carinii and Toxoplasma gondii. Exp Parasitol 71:60–68[CrossRef]
KovacsJ. A., GillV. J., MeshnickS., MasurH.2001a; New insights into transmission, diagnosis, and drug treatment of Pneumocystis carinii pneumonia. JAMA (J Am Med Assoc) 286:2450–2460[CrossRef]
KovacsJ. A., LempickiR. A., SidorovI. A.17 other authors2001b; Identification of dynamically distinct subpopulations of T lymphocytes that are differentially affected by HIV. J Exp Med 194:1731–1741[CrossRef]
MartinezA., KovacsJ. A.1993; Development and characterization of a rapid screening assay for identifying antipneumocystis agents. Antimicrob Agents Chemother 37:1674–1678[CrossRef]
MeiQ., WangQ., ChenY., LiuY., FanW., LiP.1995; Experimental and clinical study on pneumocystosis. IV. Use of a 4D7 monoclonal antibody to detect Pneumocystis carinii by immunoperoxidase staining. Zhongguo Ji Sheng Chong Xue Yu Ji Sheng Chong Bing Za Zhi 13:130–133 in Chinese
NavinT. R., BeardC. B., HuangL.7 other authors2001; Effect of mutations in Pneumocystis carinii dihydropteroate synthase gene on outcome of P. carinii pneumonia in patients with HIV-1: a prospective study. Lancet 358:545–549[CrossRef]
PhairJ., MunozA., DetelsR., KaslowR., RinaldoC., SaahA.1990; The risk of Pneumocystis carinii pneumonia among men infected with human immunodeficiency virus type 1. Multicenter AIDS Cohort Study Group. N Engl J Med 322:161–165[CrossRef]
RoblotF., GodetC., Le MoalG.9 other authors2002; Analysis of underlying diseases and prognosis factors associated with Pneumocystis carinii pneumonia in immunocompromised HIV-negative patients. Eur J Clin Microbiol Infect Dis 21:523–531[CrossRef]
SattlerF. R., CowanR., NielsenD. M., RuskinJ.1988; Trimethoprim-sulfamethoxazole compared with pentamidine for treatment of Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. A prospective, noncrossover study. Ann Intern Med 109:280–287[CrossRef]
VasconcellesM. J., BernardoM. V., KingC., WellerE. A., AntinJ. H.2000; Aerosolized pentamidine as pneumocystis prophylaxis after bone marrow transplantation is inferior to other regimens and is associated with decreased survival and an increased risk of other infections. Biol Blood Marrow Transplant 6:35–43[CrossRef]
VernisL., PiskurJ., DiffleyJ. F.2003; Reconstitution of an efficient thymidine salvage pathway in Saccharomyces cerevisiae. Nucleic Acids Res 31:e120[CrossRef]
WalzerP. D., RunckJ., SteeleP., WhiteM., LinkeM. J., SidmanC. L.1997; Immunodeficient and immunosuppressed mice as models to test anti-Pneumocystis carinii drugs. Antimicrob Agents Chemother 41:251–258