Skip to main content
SpringerLink
Log in

Antifolate Resistance Mechanisms from Bacteria to Cancer Cells with Emphasis on Parasites

  • Chapter
Resolving the Antibiotic Paradox

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 456))

Abstract

Reduced folates serve as co-factors in a variety of one-carbon transfer reactions including the biosynthesis of thymidylate, of purine nucleotides, and of the amino acids serine and methionine. Dihydrofolate reductase (DHFR) and thymidylate synthase (TS) catalyze consecutive reactions in the de novo synthesis of dTMR In protozoa and plants, these two enzymes are fused resulting in a DHFR-TS protein (Ferone and Roland, 1980). The enzyme DHFR is the target for the action of antifolates, which are widely used during chemotherapeutic interventions. Commonly used antifolates are shown in Figure 1. The folate antagonist trimethoprim (TMP) is used to treat bacterial infections caused by urinary tract or enteric pathogens (Huovinen et al., 1995). The antifolate pyrimethamine (PYR) is used against the protozoan parasites Plasmodium and Toxoplasma (Borst and Ouellette, 1995) whereas trimetrexate with leucovirin is used in fungal infections caused by Pneumocystis carinii (Hitchings, 1989). The antifolate methotrexate (MTX) is widely used for the treatment of various forms of cancer as well as for the treatment of rheumatoid arthritis, psoriasis and some autoimmune diseases (Gorlick et al., 1996). The primary structures of DHFR from a variety of organisms share very little homology, hence explaining, in part, the specificity and activity of different antifolates against targeted organisms. The basis for this selectivity was studied further by using comparative enzymology and structural analyses. Differences in the kinetic properties of the various DHFRs are likely to contribute to the selectivity of antifolates (Schweitzer et al., 1990).

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 39.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 54.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Similar content being viewed by others

References

  • Alt, F.W., Kellems, R.E., Bertino, J.R., and Schimke, R.T. 1978. Selective multiplication of dihydrofolate reductase genes in methotrexate-resistant variant of cultured murine cells. J. Biol. Chem 253:1357.

    PubMed  CAS  Google Scholar 

  • Antony AC. 1996. Folate receptors. Annu. Rev. Nutr 16:501–521.

    Article  PubMed  CAS  Google Scholar 

  • Arrebola, R., Olmo, A., Reche, P., Garvey, E.P., Santi, D.V., Ruiz-Perez, L.M., and Gonzales-Pacanowska, D. 1994. Isolation and characterization of a mutant dihydrofolate reductase-thymidylate synthase from methotrexate-resistant Leishmania cells. J. Biol. Chem 269:10590.

    PubMed  CAS  Google Scholar 

  • Assaraf Y.G., and Goldman I.D. 1997. Loss of folic acid exporter function with markedly augmented folate accumulation in lipophilic antifolate-resistant mammalian cells. J. Biol. Chem 272:17460.

    Article  PubMed  CAS  Google Scholar 

  • Assaraf Y.G., Molina A., and Schimke R.T. 1989. Sequential amplification of dihydrofolate reductase and multidrug resistance genes in Chinese hamster ovary cells selected for stepwise resistance to the lipid-soluble antifolate trimetrexate. J. Biol. Chem 264:18326.

    PubMed  CAS  Google Scholar 

  • Beck, J.T., and Ullman, B. 1990. Nutritional requirements of wild-type and folate transport-deficient Leishmania donovani for pterins and folates. Mol. Biochem. Parasitol 43:221.

    Article  PubMed  CAS  Google Scholar 

  • Beck, J.T., and Ullman, B. 1991. Biopterin conversion to reduced folates by Leishmania donovani promastigotes. Mol. Biochem. Parasitol 49:21.

    Article  PubMed  CAS  Google Scholar 

  • Bello, A.R., Nare, B., Freedman, D., Hardy, L., and Beverley, S.M. 1994. PTR1: a reductase mediating salvage of oxidized pteridines and methotrexate resistance in the protozoan parasite Leishmania major. Proc. Natl. Acad. Sci. USA 91:11442

    Article  PubMed  CAS  Google Scholar 

  • Ben-Yaacov, R., Knoller, S., Caldwell, G.A., Becher, J.M., and Koltin, Y. 1994. Candida albicans gene encoding resistance to benomyl and methotrexate is a multidrug resistance gene. Antimicrob. Agents Chemother 38:648–652.

    Article  PubMed  CAS  Google Scholar 

  • Bertino J.R. 1993. Ode to methotrexate. J. Clin. Oncol 11:5.

    PubMed  CAS  Google Scholar 

  • Beverley, S.M. 1991. Gene amplification in Leishmania. Annu. Rev. Microbiol 45:417.

    Article  PubMed  CAS  Google Scholar 

  • Borst, P., and Ouellette, M. 1995. New mechanisms of drug resistance in parasitic protozoa. Annu. Rev. Microbiol 49:427.

    Article  PubMed  CAS  Google Scholar 

  • Brooks, D., Wang, P., Read, M., Watkins, W., Sims, P., and Hyde, J. 1994. Correlation of sulfadoxine resistance with point mutations located within the bifunctional hydroxymethyldihydrobiopterin pyrophosphokinase-dihydropteroate synthase gene of the human malaria parasite Plasmodium falciparum. Eur. J. Biochem 224:397.

    Article  PubMed  CAS  Google Scholar 

  • Brumfitt W., and Hamilton-Miller J.M. 1995. Combinations of sulphonamides with diaminopyrimidines: how, when and why? J. Chemother 7:136.

    PubMed  CAS  Google Scholar 

  • Callahan, H.L. and Beverley, S.M. 1991. Heavy metal resistance: a new role for P-glycoproteins in Leishmania. J. Biol. Chem 266:18427.

    PubMed  CAS  Google Scholar 

  • Callahan, H.L. and Beverley, S.M. 1992. A member of the aldoketo reductase family confers methotrexate resistance in Leishmania. J. Biol. Chem 267:24165.

    PubMed  CAS  Google Scholar 

  • Chabner B.A., Allegra C.J., Curt G.A., Clendeninn N.J., Baram J., Koizumi S., Drake J.C., Jolivet J. 1985. Poly-glutamation of methotrexate. Is methotrexate a prodrug? J. Clin. Invest 76:907.

    Article  PubMed  CAS  Google Scholar 

  • Charpentier E., Courvalin P. 1997. Emergence of the trimethoprim resistance gene dfrD in Listeria monocytogenes BM4293. Antimicrob. Agents Chemother 41:1134.

    PubMed  CAS  Google Scholar 

  • Coderre, J. A., Beverley, S.M., Schimke, R.T., and Santi, D.V. 1983. Overproduction of a bifunctional thymidylate synthetase-dihydrofolate reductase and DNA amplification in methotrexate-resistant Leishmania tropica. Proc. Natl. Acad. Sci. USA 80:2132.

    Article  PubMed  CAS  Google Scholar 

  • Cowman, A.F. and Lew, A.M. 1989. Antifolate drug selection results in duplication and rearrangement of chromosome 7 in Plasmodium chabaudi. Mol. Cell Biol 9: 5182.

    PubMed  CAS  Google Scholar 

  • Cowman, A.F., Morry, M.J., Biggs, B.A., Cross, G.A.M. and Foote, S.J. 1988. Amino acid changes linked to pyrimethamine resistance in the dihydrofolate reductase-thymidylate synthase gene of Plasmodium falciparum. Proc. Natl. Acad. Sci. USA 25: 9109.

    Article  Google Scholar 

  • Dale G.E., Broger C., D’Arcy A., Hartman P.G., DeHoogt R., Jolidon S., Kompis I., Labhardt A.M., Langen H., Locher H., Page M.G., Stuber D., Then R.L., Wipf B., Oefner C. 1997. A single amino acid substitution in Staphylococcus aureus dihydrofolate reductase determines trimethoprim resistance. J. Mol. Biol 266:23.

    Article  PubMed  CAS  Google Scholar 

  • Dale G.E., Langen H., Page M.G., Then R.L., Stuber D. 1995. Cloning and characterization of a novel, plasmid-encoded trimethoprim-resistant dihydrofolate reductase from Staphylococcus haemolyticus MUR313. Antimicrob. Agents Chemother 39:1920.

    Article  PubMed  CAS  Google Scholar 

  • De Graaf, D., Sharma, R.C., Mechetner, E.B., Schimke, R.T., and Roninson, I.B. 1996. P-glycoprotein confers methotrexate resistance in 3T6 cells with deficient carrier-mediated methotrexate uptake. Proc. Natl. Acad. Sci. USA 93:1238.

    Article  PubMed  Google Scholar 

  • De Groot R., Sluijter M., de Bruyn A., Campos J., Goessens W.H., Smith A.L., and Hermans P.W. 1996. Genetic characterization of trimethoprim resistance in Haemophilus influenzae. Antimicrob. Agents Chemother 40:2131.

    PubMed  Google Scholar 

  • Dewes, H., Ostergaard, H.L., and Simpson, L. 1986. Impaired drug uptake in methotrexate resistant Crithidia fas-ciculata without changes in dihydrofolate reductase activity or gene amplification. Mol. Biochem. Parasitol 19:149.

    Article  PubMed  CAS  Google Scholar 

  • Donald, R.G.K., and Roos, D.S. 1993. Stable molecular transformation of Toxoplasma gondii: a selectable dihydrofolate reductase-thymidylate synthase marker based on drug-resistance mutations in malaria. Proc. Natl. Acad. Sci. USA 90:11703.

    Article  PubMed  CAS  Google Scholar 

  • Ellenberger, T.E., and Beverley, S.M. 1987a. Biochemistry and regulation of folate and methotrexate transport in Leishmania major. J. Biol. Chem 262:10053.

    PubMed  CAS  Google Scholar 

  • Ellenberger, T.E., and Beverley, S.M. 1987b. Reductions in methotrexate and folate influx in methotrexate-resis-tant lines of Leishmania major are independent of R and H region amplification. J. Biol. Chem 262:13501.

    PubMed  CAS  Google Scholar 

  • Ellenberger, T.E., Wright J.E., Rosowsky, A. and Beverley, S.M. 1989. Wild type and drug-resistant Leishmania major hydrolyze methotrexate to N-10-methyl-4-deoxy-4-aminopteroate without accumulation of methotrexate polyglutamates. J. Biol. Chem 264:15960.

    PubMed  CAS  Google Scholar 

  • Fermer C., Kristiansen B.E., Skold O., and Swedberg G. 1995. Sulfonamide resistance in Neisseria meningitidis as defined by site-directed mutagenesis could have its origin in other species. J. Bacteriol 177:4669–4675.

    PubMed  CAS  Google Scholar 

  • Ferone, R., and Roland, S. 1980. Dihydrofolate reductase-thymidylate synthetase a bifunctionnal polypeptide from Crithidiafasciculata. Proc. Natl. Acad. Sci. USA 77:5802.

    Article  PubMed  CAS  Google Scholar 

  • Foote, S.J., Galatis, D. and Cowman, A.F. 1990. Amino acids in the dihydrofolate reductase-thymidylate synthase gene of Plasmodium falciparum involved in cycloguanil resistance differ from those involved in pyrimethamine resistance. Proc. Natl. Acad. Sci. USA 87: 3014.

    Article  PubMed  CAS  Google Scholar 

  • Gamarro, F., Amador, M.V., Chiquero, M.J., Légaré, D., Ouellette, M. and Castanys, S. 1994. Multidrug resistance phenotype and P-glycoprotein overexpression in a methotrexate-resistant Leishmania infantum. Bio-chem. Pharmacol 47: 1939.

    Article  CAS  Google Scholar 

  • Garrow T.A., Admon A., and Shane B. 1992. Expression cloning of a human cDNA encoding folylpoly(gamma-glutamate) synthetase and determination of its primary structure. Proc. Natl. Acad. Sci. USA 89:9151.

    Article  PubMed  CAS  Google Scholar 

  • Goker E., Waltham M., Kheradpour A., Trippett T., Mazumdar M., Elisseyeff Y., Schnieders B., Steinherz P., Tan C., Berman E., et al. 1995. Amplification of the dihydrofolate reductase gene is a mechanism of acquired resistance to methotrexate in patients with acute lymphoblastic leukemia and is correlated with p53 gene mutations. Blood 86:677.

    PubMed  CAS  Google Scholar 

  • Gorlick R., Goker E., Trippett T., Steinherz P., Elisseyeff Y., Mazumdar M., Flintoff W.F., and Bertino J.R. 1997. Defective transport is a common mechanism of acquired methotrexate resistance in acute lymphocytic leukemia and is associated with decreased reduced folate carrier expression. Blood, 89:1013.

    PubMed  CAS  Google Scholar 

  • Gorlick R., Goker E., Trippett T., Waltham M., Banerjee D., and Bertino J.R. 1996. Intrinsic and acquired resistance to methotrexate in acute leukemia. New Engl. J. Med 315:1041.

    Google Scholar 

  • Grondin, K., Haimeur, A., Mukhopadhyay, R., Rosen, B.R., and Ouellette, M. 1997. Co-amplification of the γ-glu-tamylcysteine synthetase gene gshl and of the ABC transporter gene pgpA in arsenite-resistant Leishmania tarentolae. EMBO J 16: 3057

    Article  PubMed  CAS  Google Scholar 

  • Hamlin J.L., and Ma C. 1990. The mammalian dihydrofolate reductase locus. Biochim. Biophys. Acta 1087:107.

    Article  PubMed  CAS  Google Scholar 

  • Hampele I.C. D’Arcy A., Dale G.E., Kostreva D., Nielson J., Oefner C., Page M.G., Schonfeld H.J., Stuber D., Then R.L. 1997. Structure and function of the dihydropteroate synthase from Staphylococcus aureus. J. Mol. Biol 268:21.

    Article  PubMed  CAS  Google Scholar 

  • Henderson G.B., Hughes T.R., and Saxena M. 1994. Functional implications from the effects of l-cholro-2,4-dini-trobenzene and ethacrynic acid on efflux routes for methotrexate and cholate in L1210 cells. J. Biol. Chem 269:13382.

    PubMed  CAS  Google Scholar 

  • Hitchings H.G. 1989. Selective inhibitors of dihydrofolate reductase. In Vitro Cell. Dev. Biol 25:303.

    Article  PubMed  CAS  Google Scholar 

  • Huennekens FM. 1996. In search of dihydrofolate reductase. Protein Sci 5:1201.

    Article  PubMed  CAS  Google Scholar 

  • Huovinen P., Sundström L, Swedberg, G, and Sköld O. 1995. Trimethoprim and sulfanamide resistance. Antimi-crob. Agents Chemother 39:279.

    Article  CAS  Google Scholar 

  • Inselburg, J., Bzik, D.J. and Horii, T. 1987. Pyrimethamine resistant Plasmodium falciparum: overproduction of dihydrofolate reductase by a gene duplication. Mol Biochem. Parasitol 26: 121.

    Article  PubMed  CAS  Google Scholar 

  • Jörnvall, H., Persson, B., Krook, M., Atrian, S., Gonzàles-Duarte, R., Jeffery, J., and Ghosh, D. 1995. Short-chain dehydrogenases/reductases (SDR). Biochemistry 34:6004.

    Google Scholar 

  • Jukes, TH. 1987. Searching for magic bullets: early approaches to chemotherapy-antifolates, methotrexate. Cancer Res 47:5528.

    PubMed  CAS  Google Scholar 

  • Kaur K., Coons, T., Emmet, K., and Ullman, B. 1988. Methotrexate-resistant Leishmania donovani genetically deficient in the folate-methotrexate transporter. J. Biol. Chem 263:7020.

    PubMed  CAS  Google Scholar 

  • Kohler T., Kok M., Michea-Hamzehpour M., Plesiat P., Gotoh N., Nishino T., Curty L.K., Pechere J.C. 1996. Multidrug efflux in intrinsic resistance to trimethoprim and sulfamethoxazole in Pseudomonas aeruginosa. An-timicrob. Agents Chemother 40:2288.

    CAS  Google Scholar 

  • Kündig C, Grondin K, Leblanc É, Haimeur A, Papadopoulou B, and Ouellette M. 1996. Amplification of ptr 1 and dhfr-ts in L. tarentolae selected for methotrexate resistance. Molecular Parasitology meeting VII. Marine Biologicals Laboratories, Woods Hole, U.S.A Abstract 95

    Google Scholar 

  • Kündig C, Haimeur A, Leblanc É, Grondin K, Papadopoulou B, and Ouellette M. 1997. Overexpression of btl, a novel mechanisms of methotrexate resistance in Leishmania. Molecular Parasitology meeting VIII. Marine Biologicals Laboratories, Woods Hole, U.S.A. Abstract

    Google Scholar 

  • Leblanc É., Papadopoulou B., Bernatchez C., Ouellette M. 1998. Residues involved in co-factor and substrate binding of the short chain dehydrogenase/reductase PTR1 producing methotrexate resistance in Leishmania. Eur. J. Biochem in press

    Google Scholar 

  • Légaré D., Papadopoulou B., Roy G., Mukhopadhyay R., Haimeur A., Dey S., Grondin K., Brochu C., Rosen B.P., and Ouellette M. 1997. Efflux systems and increased trypanothione levels in arsenite resistant Leishmania species. Exp. Parasitol In press

    Google Scholar 

  • Lewis, K., Hooper, D. and Ouellette, M. 1997. Multidrug resistance pumps provide broad defense. ASM News, 63:605.

    Google Scholar 

  • Longo G.S., Gorlick R., Tong W.P., Lin S., Steinherz P., and Beitino J.R. 1997. Gamma-glutamyl hydrolase and folylpolyglutamate synthetase activities predict polyglutamylation of methotrexate in acute leukemias. Oncol. Res 9:259.

    PubMed  CAS  Google Scholar 

  • Melera P.W. 1991. Acquired versus intrinsic resistance to methotrexate: diversity of the drug-resistant phenotype in mammalian cells. Semin. Cancer Biol 2:245.

    PubMed  CAS  Google Scholar 

  • Moore J.B., Beverley S.M. 1996. Pteridine transport and recurrent amplification of extrachromosomal DNAs in Leishmania. Molecular Parasitology meeting VIII. Marine Biologicals Laboratories, Woods Hole, U.S.A Abstract 107.

    Google Scholar 

  • Moscow J.A., Connolly T., Myers T.G., Cheng C.C., Pauli K., and Cowan K.H. 1997. Reduced folate carrier gene (RFC1) expression and anti-folate resistance in transfected and non-selected cell lines. Int. J. Cancer 72:184.

    Article  PubMed  CAS  Google Scholar 

  • Myler P.J., Lodes M.J., Merlin G. de Vos T., and Stuart K.D. 1994. An amplified DNA element in Leishmania encodes potential integral membrane and nucleotide-binding proteins. Mol. Biochem. Parasitol 66:11.

    Article  PubMed  CAS  Google Scholar 

  • Nare B., Luba J., Hardy L.W., and Beverley S.. 1997a. New approaches to Leishmania chemotherapy: pteridine reductase 1 (PTR1) as a target and modulator of antifolate sensitivity. Parasitology 114:S101.

    PubMed  Google Scholar 

  • Nare, B., Hardy, L.W., and Beverley, S.M. 1997b. The roles of pterine reductase 1 and dihydrofolate reductase-thymidylate synthase in pteridine metabolism in the protozoan parasite Leishmania major. J. Biol. Chem 272:13883.

    Article  PubMed  CAS  Google Scholar 

  • Ouellette, M. and Kündig C. 1997. Microbial multidrug resistance. Int. J. Antimicrob. Agents 8: 179.

    Article  PubMed  CAS  Google Scholar 

  • Ouellette, M. and Papadopoulou, B. 1993. Mechanisms of drug resistance in Leishmania. Parasitol. Today 9:150.

    Article  PubMed  CAS  Google Scholar 

  • Ouellette, M., Fase-Fowler, F., and Borst, P. 1990. The amplified H circle of methotrexate-resistant Leishmania tarentolae contains a novel P-glycoprotein gene. EMBO J 9:1027.

    PubMed  CAS  Google Scholar 

  • Ouellette, M., Papadopoulou, B., Haimeur, A, Grondin, K. Leblanc, E., Légaré, D., and Roy, G. 1995. Transport of antimonials and antifolates in drug resistant Leishmania. In “Drug transport in antimicrobial and anticancer chemotherapy” in Georgopapadakou, N.H. ed. pp. 377–402 Marcel Dekker, New York, NY.

    Google Scholar 

  • Papadopoulou, B., Roy, G., and Ouellette M., 1992. A novel antifolate resistance gene on the amplified H circle of Leishmania. EMBO J, 11:3601.

    PubMed  CAS  Google Scholar 

  • Papadopoulou, B., Roy, G., and Ouellette M., 1993. Frequent amplification of a short chain dehydrogenase gene as part of circular and linear amplicons in methotrexate resistant Leishmania. Nucleic Acids Res 21:4305.

    Article  PubMed  CAS  Google Scholar 

  • Papadopoulou, B., Roy, G., Dey, S., Rosen, B.P. and Ouellette, M. 1994a. Contribution of the Leishmania P-glycoprotein related gene ItpgpA to oxyanion resistance. J. Biol. Chem 269:11980.

    PubMed  CAS  Google Scholar 

  • Papadopoulou, B., Roy, G., Mourad, W., Leblanc, E. and Ouellette, M. 1994b. Changes in folate and pterin metabolism after disruption of the Leishmania H locus short-chain dehydrogenase gene. J. Biol. Chem 269:7310.

    PubMed  CAS  Google Scholar 

  • Pashley T.V., Volpe F., Pudney M., Hyde J.E., Sims P.F., and Delves C.J. 1997. Isolation and molecular characterization of the bifunctional hydroxymethyldihydropterin pyrophosphokinase-dihydropteroate synthase gene from Toxoplasma gondii. Mol. Biochem. Parasitol 86:37.

    PubMed  CAS  Google Scholar 

  • Peterson, D.S. Milhous, W.K. and Wellems, T.E. 1990. Molecular basis of differential resistance to cycloguanil and pyrimethamine in Plasmodium falciparum. Proc. Natl. Acad. Sci. USA 87: 3018.

    Article  PubMed  CAS  Google Scholar 

  • Peterson, D.S., Walliker, D. and Wellems, T.E. 1988. Evidence that a point mutation in dihydrofolate reductase-thymidylate synthase confers resistance to pyrimethamine in falciparum malaria. Proc. Natl Acad. Sci. USA 85,9114.

    Article  PubMed  CAS  Google Scholar 

  • Petrillo-Peixoto, M.L., and Beverley, S.M. 1987. In vito activity of sulfonamides and sulfones against Leishmania major promastigotes. Antimicrob. Agents Chemother 31:1575.

    Article  Google Scholar 

  • Rhee, M.S., Wang, Y., Nair, M.G., and Galivan, J. 1993. Acquisition of resistance to antifolates caused by enhanced g-glutamyl hydrolase activity. Cancer Res 53:2227.

    PubMed  CAS  Google Scholar 

  • Robello C., Navarro P., Castanys S., and Gamarro F. 1998. A pteridine reductase gene ptrl contiguous to a P-glycoprotein confers resistance to antifolates in Trypanosoma cruzi. Mol. Biochem Parasitol in press

    Google Scholar 

  • Rouch D.A., Messerotti L.J., Loo L.S.L., Jackson C.A., and Skurray R.A. 1989. Trimethoprim resistance transposon Tn4003 from Staphylococcus aureus encodes genes for a dihydrofolate reductase and thymidy-late synthetase flnaked by three copies of IS257. Mol. Microbiol 3:161.

    Article  PubMed  CAS  Google Scholar 

  • Roy K., Egan M.G., Sirlin S., and Sirotnak, F.M. 1997. Posttranscriptionally mediated decreases in folylpolygluta-mate synthetase gene expression in some folate analogue-resistant variants of the L210 cell. Evidence for an altered cognate mRNA in the variants affecting the rate of de novo synthesis of the enzyme. J. Biol. Chem 272:6903.

    Article  PubMed  CAS  Google Scholar 

  • Ryan, K.A., Garraway, L.A., Descoteaux, A., Turco, S.J., and Beverley, S.M. 1993. Isolation of virulence genes directing surface glycosyl-phosphatidylinositol synthesis by functional complementation of Leishmania. Proc. Natl. Acad. Sci. USA 90:8609.

    Article  PubMed  CAS  Google Scholar 

  • Saikawa Y., Knight C.B., Saikawa T., Page S.T., Chabner B.A., and Elwood P.C. 1993. Decreased expression of the human folate receptor mediates transport-defective methotrexate resistance in KB cells. J. Biol. Chem 268:5293.

    PubMed  CAS  Google Scholar 

  • Santi, D.V., Nolan, P., and Shane, B. 1987. Folylpolyglutamates in Leishmania major. Biochem. Biophys. Res. Comm 146:1089.

    Article  PubMed  CAS  Google Scholar 

  • Schlemmer S.R., and Sirotnak F.M. 1992. Energy-dependent efflux of methotrexate in L1210 leukemia cells. Evidence for the role of an ATPase obtained with inside-out plasma membrane vesicles. J. Biol. Chem 267:14746.

    PubMed  CAS  Google Scholar 

  • Schweitzer, B.I., Dicker, A.P., and Bertino, J.R. 1990. Dihydrofolate reductase as a therapeutic target. FASEB J 4:2441

    PubMed  CAS  Google Scholar 

  • Segovia M., and Ortiz G. 1997. LD1 amplification in Leishmania. Parasitol Today 13:342.

    Article  PubMed  CAS  Google Scholar 

  • Sirawaraporn W., Sathitkul T., Sirawaraporn R., Yuthavong Y., Santi D.V. 1997. Antifolate-resistant mutants of Plasmodium falciparum dihydrofolate reductase. Proc. Natl. Acad. Sci. USA 94:1124.

    Article  PubMed  CAS  Google Scholar 

  • Spencer H.T., Sorrentino B.P., Pui C.H., Chunduru S.K., Sleep S.E., Blakley R.L. 1996. Mutations in the gene for human dihydrofolate reductase: an unlikely cause of clinical relapse in pediatric leukemia after therapy with methotrexate. Leukemia 10:439.

    PubMed  CAS  Google Scholar 

  • Tamura T., Baggott J.E., Johnston K.E., Li Q.J., and Antony AC. 1997. The form of folate affects the mechanisms of methotrexate resistance in Enterococcus faecium. Microbiology 143:2639.

    Article  PubMed  CAS  Google Scholar 

  • Triglia, T., and Cowman, A.F. 1994. Primary structure and expression of the dihydropteroate synthetase gene of Plasmodium falciparum. Proc. Natl. Acad. Sci. USA 91:7149.

    Article  PubMed  CAS  Google Scholar 

  • Van Dijk M.R., Waters A.P., Janse C.J. 1995. Stable transfection of malaria parasite blood stages. Science 268:1358.

    Article  PubMed  Google Scholar 

  • Vasquez J.R., Gooze L., Kim K., Gut J., Peterson C., Nelson R.G. 1996. Potential antifolate resistance determinants and genotypic variation in the bifunctional dihydrofolate reductase-thymidylate synthase gene from human and bovine isolates of Cryptosporidium parvum. Mol. Biochem. Parasitol 79:153.

    Article  PubMed  CAS  Google Scholar 

  • Volpe F., Ballantine S.P., Delves C.J. 1993. The multifunctional folic acid synthesis fas gene of Pneumocystis carinii encodes dihydroneopterin aldolase, hydroxymethyldihydropterin pyrophosphokinase and dihydropteroate synthase. Eur. J. Biochem 216:449

    Article  PubMed  CAS  Google Scholar 

  • Wang P., Lee C.-S., Bayoumi R., Djimde A., Doumbo O., Swedberg G., Dao L., Mshinda H., Tanner M., Watkins W.M., Sims P.F.G., and Hyde J.E. 1997a. Resistance to antifolates in Plasmodium falciparum monitored by sequence analysis of dihydropteroate synthetase and dihydrofolate reductase alleles in a large number of field samples of diverse origins. Mol. Biochem. Parasitol 89:161.

    Article  PubMed  CAS  Google Scholar 

  • Wang P., Read M., Sims P.F., and Hyde J.E. 1997b. Sulfadoxine resistance in the human malaria parasite Plasmodium falciparum is determined by mutations in dihydropteroate synthetase and an additional factor associated with folate utilization. Mol. Microbiol 23:979

    Article  PubMed  CAS  Google Scholar 

  • Wang, J., Leblanc, E. Chang C.-F., Papadopoulou, B., Bray, T. Whiteley, J.S.X. Lin and Ouellette, M. 1997c. Folate and pterin reduction by the Leishmania tarentolae H locus short-chain dehydrogenase/ reductase PTR1. Arch. Biochem. Biophys 342:197.

    Article  PubMed  CAS  Google Scholar 

  • Williams F.M., and Flintoff W.F. 1995. Isolation of a human cDNA that complements a mutant hamster cell defective in methotrexate uptake. J. Biol. Chem 270:2987.

    Article  PubMed  CAS  Google Scholar 

  • Wu Y., Kirkman L.A., and Wellems T.E. 1996. Transformation of Plasmodium falciparum malaria parasites by homologous integration of plasmids that confer resistance to pyrimethamine. Proc. Natl. Acad. Sci. USA 93:1130.

    Article  PubMed  CAS  Google Scholar 

  • Yao R., Schneider E., Ryan T.J., Galivan J. 1996. Human gamma-glutamylhydrolasexloning and characterization of the enzyme expressed in vitro. Proc. Natl. Acad. Sci. USA 93:10134.

    Article  PubMed  CAS  Google Scholar 

  • Zhao R., Seither R, Brigle KE, Sharina IG, Wang PJ, Goldman ID. 1997. Impact of overexpression of the reduced folate carrier (RFC1), an anion exchanger, on concentrative transport in murine L1210 leukemia cells. J. Biol. Chem 272:21207.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Centre de Recherche en Infectiologie du CHUL, Département de Microbiologie, Université Laval, Québec, G1V 4G2, Canada

    Marc Ouellette, Éric Leblanc, Christoph Kündig & Barbara Papadopoulou

Authors
  1. Marc Ouellette
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Éric Leblanc
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christoph Kündig
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Barbara Papadopoulou
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Wayne State University, Detroit, Michigan, USA

    Barry P. Rosen  & Shahriar Mobashery  & 

Rights and permissions

Reprints and permissions

Copyright information

© 1998 Springer Science+Business Media New York

About this chapter

Cite this chapter

Ouellette, M., Leblanc, É., Kündig, C., Papadopoulou, B. (1998). Antifolate Resistance Mechanisms from Bacteria to Cancer Cells with Emphasis on Parasites. In: Rosen, B.P., Mobashery, S. (eds) Resolving the Antibiotic Paradox. Advances in Experimental Medicine and Biology, vol 456. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-4897-3_6

Download citation

  • DOI: https://doi.org/10.1007/978-1-4615-4897-3_6

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4613-7220-2

  • Online ISBN: 978-1-4615-4897-3

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation