Abstract
Fansidar (pyrimethamine-sulfadoxine) has been used extensively worldwide for the treatment of chloroquine resistant Plasmodium falciparum malaria, toxoplasmosis and Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome. Because of the wide usage of pyrimethamine-sulfadoxine in developing countries and the lake of information from open literature and reports from manufacturers about the genotoxicity of such antimalarial drug, the present work was suggested. The possible genetic toxicity of fansidar has been evaluated in human peripheral blood lymphocyte cultures. The frequencies of sister-chromatid exchanges (SCE) and micronuclei (MN) were scored as genetic endpoints. Both tests covering a wide range of induced genetic damage as primary DNA damage, clastogenicity and aneugenicity. Cultures were set up by using blood samples from two healthy donors and the treatment was done using different fansidar concentrations ranging from 1:20 to 10:200 μg/ml. From our results, it appears that this drug is able to induce moderate genotoxic effects, as revealed by the increases found in SCE and MN frequencies in cultures from the two donors at the two highest concentrations tested (5:100 and 10:200 μg/ml). In addition, cyotoxic/cytostatic effects of fansidar were revealed by a decrease in the proliferative rate index (PRI) and in the cytokinesis block proliferation index (CBPI). Our findings suggest that the use of this drug should be restricted to situations where other antimalarial drugs cannot be used. The drug should never be given to pregnant women.
Similar content being viewed by others
References
Abou-Eisha A, Creus A, Marcos R. Genotoxic evaluation of the antimicrobial, trimethoprim, in cultured human lymphocytes. Mutat Res. 1999;440:157–62.
Adier I-D, Kliesch U, Van Hummelen P, Kirsch-Volders M. Mouse micronucleus tests with known and suspects spindle poisons: results from two laboratories. Mutagenesis. 1991;6: 47–53.
Almond DS, Szwandt ISF, Edwards G, Lee MG, Winstanley PA. Disposition of intravenous pyrimethamine in healthy volunteers. Antimicrob Agents Chemother. 2000;44:1691–3.
Bishop JB, Witt KL, Gulati DK, MacGregor JT. Evaluation of the mutagenicity of the anti-inflammatory drug salicylazo-sulfapyridine (SASP). Mutagenesis. 1990;5:549–54.
Bygbjerg IC, Odum N, Theander TG. Effect of pyrimethamine and sulphadoxine on human lymphocyte proliferation. Trans R Soc Trop Med Hyg. 1986;80(2):295–300.
Calva-Mercado MP, Maunoury C, Rethore MO, Lejeune J. Fragility fo the X chromosome and inhibition of dihydrofolate reductase. Comparison of the effects of 2 antibiotics: trimethoprime and pyrimethamine. Ann Genet. 1983;26(3): 147–9.
Chaicumpa W, Roca RV, Atthasishtha N, Chongsuphajalisiddhi T. Effects of antimalarial drugs on human natural killer cell activity. Southeast Asian J Trop Med Public Health. 1983; 14(3):413–19.
Chowdary PS, Rao MS. Effect of sulphasalazine on bone marrow erythrocytes of mice. IRCS Med Sci. 1985;13:1176.
Deen JL, von Seidlein L, Pinder M, Walraven GE, Greenwood BM. The safety of the combination artesunate and pyrimethamine and sulfadoxine given during pregnancy. Trans R Soc Trop Med Hyg. 2001;95(4):424–8.
Egel C, Bilaloglu R, Aydemir N. Inhibitory effects of ascorbic acid and folinic acid on chromosome aberrations induced by pyrimethamine in vitro. Teratog Carcinog Mutagen. 2002;22(5):353–62.
Egeli U. Induction of sister chromatid exchanges by pyrimethamine in human lymphocyte cultures. Teratog Carcinog Mutagen. 1998;18:163–9.
Egeli U, Erdogan G. The elastogenic effect of pyrimethamine (Daraprim) on human chromosomes in lymphocyte cultures. Cell Biol Toxicol. 1991;7:347–56.
Fasunon OD, Uwaifo AO. Prophage induction by 4 antimalaria drugs (daraprim, fansidar, nivaquine and camoquine) and in combination with affatoxin B1. Mutat Res. 1989;222(4): 311–16.
Fenech M, Morley AA. Measurements of micronuclei in lymphocytes. Mutat Res. 1985;147:29–36.
Fenech M. The cytokinesis micronucleus technique: a detailed description of the method and its application to genotoxicity studies in human populations. Mutat Res. 1993;285:35–44.
Fenech M. The advantages and disadvantages of the cytokinesis-block micronucleus method. Mutat Res. 1997;392:11–18.
Fox DP, MacKay JM, Brunt PW, Hawskworth GM, Brown J. Abnormal chromosomes and sulfasalazine therapy. In: 5-ASA. The state of the art. The Medicine Publishing Foundation Symposium Series 21, MES Medical Education Services, Toronto. 1987:15–28.
Galloway SM, Miller JE, Armstrong MJ, Bean CL, Skopek TR, Nichols WW. DNA synthesis inhibition as an indirect mechanism of chromosome aberrations: comparison of DNA-reactive and non-DNA-reactive clastogens. Mutat Res. 1998;400:169–86.
Gibson DP, Aardema MJ, Kerckaert GA, Carr GJ, Brauninger RM, LeBoeuf RA. Detection of aneuploidy-inducing carcinogens in the Syrian hamster embryo (SHE) cell transformation assay. Mutat Res. 1995;343:7–24.
Gudi R, Xu J, Thilagar A. Assessment of the in vivo aneuploidy/micronucleus assay in mouse bone marrow cells with 16 chemicals. Environ Mol Mutagen. 1992;20:106–16.
Kirsh-Volders M, Elhajouji A, Cundari E, Van Hummelen P. The in vitro micronucleus test: a multi-endpoint assay to detect simultaneously mitotic delay, apoptosis, chromosome breakage, chromosome loss and non-disjunction. Mutat Res. 1997;392:19–30.
Klinker H, Langmann P, Richter E. Plasma pyrimethamine concentrations during long-term treatment for cerebral toxoplasmosis in patients with AIDS. Antimicrob Agents Chemother. 1996;40:1623–7.
Kunz BA, Genetic effects deoxyribonucleotide pool imbalances. Environ Mutagen. 1982;4:695–725.
Kunz BA. Mutagenesis and deoxyribonucleotide pool imbalances. Mutat Res. 1988;200:133–47.
Lamberti L, Bigatti Ponzetto P, Ardito G. Cell kinetics and sister chromatid exchange frequency in human lymphocytes. Mutat Res. 1983;120:193–9.
Laurence DR, Bennett PN, Brown MJ. Clinical pharmacology, 8th edn. New York: Churchill and Livingstone. 1997:231–48.
Li XZ, Reidy JA, Wheeler VA, Chen ATL. Folic acid and chromosome breakage. III. Types and frequencies of spontaneous chromosome aberrations in proliferating lymphocytes. Mutat Res. 1986;173:131–4.
Mackay JM, Fox DP, Brunt PW, Johnston AW. Increased sister-chromatid exchange frequency in patients receiving sulphasalazine therapy for ulcerative colitis. Mutat Res. 1983;118:205–12.
Mailhes JB, Aardema MJ, Marchetti E. Investigation of aneuploidy induction in mouse oocytes following exposure to vinblastin-sulfate, pyrimethamine, diethylstilbestrol diphosphate or chloral hydrate. Environ Mol Mutagen. 1993;22: 107–14.
National Toxicology Program. Bioassay of Pyrimethamine for possible carcinogenicity. Natl Toxicol Program Tech Rep Ser. 1978;77:1–107.
Ono T, Norimatsu M, Yoshimura H. Induction of chromosome aberrations by pyrimethamine in cultured Chinese hamster (CHL) cells. Mutat Res. 1994;323:197–201.
Ono T, Yoshimura H. Analysis of micronucleus induction of pyrimethamine in in vitro CHL cells and in in vivo mouse bone marrow cells. Mutagenesis. 1996;11:85–8.
Ono-Ogata T, Ogino T, Nishikawa M, Ohta T, Yamagata H. Mutagenic activity and mutational specificity of antiprotozoal drugs with and without nitrite treatment. Environ Mol Mutagen. 2002;39:43–8.
Ouellette M. Biochemical and molecular mechanisms of drug resistance in parasites. Trop Med Int Health. 2001;6:874–82.
Perry P, Henderson L, Krikland D. Sister-chromatid exchange in cultured cells. In: Dean BJ, editor. UKEMS Sub-committe on Guidelines for Mutagenicity Testing. Part II, UKEMS. 1984:89–109.
Perry P, Wolff S. New Giemsa method for the differential staining of sister chromatids. Nature. 1974;251:156–8.
Phillips-Howard PA, West LJ. Serious adverse drug reactions to pyrimethamine-sulfadoxine, pyrimethamine-dapsone and to amodiaquine in Britain. J Roy Soc Med. 1990;83:82–5.
Rosenthal PJ, Goldsmith RS. Antiprotozoal drugs. In: Basic and clinical pharmacology, 8th edn. New York: McGraw-Hill Companies Inc; 2001.
Reynolds JEF. Martindale. The extra pharmacopoeia, 30th edn. London. The Pharmaceutical Press; 1993:393–411.
Ropper C, Pearce R, Bredenkamp B et al. Antifolate antimalirial resistance in sourheast Africa: a population-based analysis. Lancet. 2003;361:1174–81.
Sanfilippo S, Ragusa RM, Scillato F, Ruggeri M, Neri G. Fragile X expression in normally and mentally retarded subjects: effect of treatment with an antifolic agent. Am J Med Genet. 1988;30:369–76.
Sims P, Wang P, Hyde JE. On “The efficacy of antifolate antimalarial combinations in Africa”, Parasitol Today. 1998;14:136–7.
Staedke SG, Kamya MR, Dorsey G et al. Amodiaquine, sulfadoxine/pyrimethamine, and combinationtherapy for treatment or uncomplicated falciparum malaria in Kampala, Uganda: a randomised trial. Lancet. 2001;358:368–74.
Sulo J, Chimpeni P, Hatcher J et al. Chlorproguanil-dapsone versus sulfadoxine-pyrimethamine for sequential episodes of uncomplicated falciparum malaria in Kenya and Malawi: a randomised clinical trial. Lancet. 2002;360:1136–43.
Surrallés J, Carbonell E, Marcos R, Degrassi F, Antoccia A, Tanzarella C. A collaborative study on the improvement of the micronucleus test in cultured human lymphocytes. Mutagenesis. 1992;7:407–10.
Surrallés J, Antoccia A, Creus A et al. The effects of cytochalasin-B concentration on the frequency of micronuclei induced by four standard mutagens. Results from two laboratories. Mutagenesis. 1994;9:347–53.
Surrallés J, Xamena N, Creus A, Catalán J, Norppa H, Marcos R. Induction of micronuclei by five pyrethroid insecticide in whole-blood lymphocyte cultures. Mutat Res. 1995;341: 169–84.
Tsuda S, Kosaka Y, Matsusaka N, Sasaki YF. Detection of pyrimethamine-induced DNA damage in mouse embryo and maternal organs by the modified alkaline single cell gel electrophoresis assay. Mutat Res. 1998;415:69–77.
Tunca B, Egeli U, Aydemir N, Cecener G, Bilaloglu R. Investigation of genotoxic effect in bone marrow of Swiss albino mice exposed long-term to pyrimethamine. Teratog Carcinog Mutagen. 2002;22:393–402.
Uche-Nwachi EO. Effect of Intramuscular sulfadoxine-pyrimethamine on pregnant Wister rats. Ant Rec. 1998;250: 426–9.
van der Werff Ten Bosch JE, Demanet C, Balduck N et al. The use of anti-malaria drug fansidar (pyrimethamine and sulfadoxine) in the treatment of a patient with autoimmune lymphoproliferative syndrome and Fas deficiency. Br J Hacinatol. 1998;102:578–81.
van der Werff Ten Bosch JE, Schotte P, Ferester A et al. Reversion of autoimmune lymphoproliferative syndrome with an antimalarial drug: preliminary results of a clinical cohort study and molecular observations. Br J Haematol. 2002;117:176–88.
Veigl ML, Schneiter S, Mollis S, Sedwick WD. Specificities mediated by neighbouring nucleotides appear to underlie mutation induced by antifolates in E. coli. Mutat Res. 1991; 246:75–91.
Vijayalaxini KK, Vishalakshi M. Evaluation of the genotoxic effects of pyrimethamine, an antimalarial drug, in the in vivo mouse. Teratog Carcinog Mutagen. 2000;20:65–71.
Watkins WM, Mberu EK, Winstanley PA, Plowe C, The efficacy of antifolate combinations in Africa: a predictive model based on pharmacodynamic and pharmacokinetic analyses. Parasitol Today. 1997;13:459–64.
Witt KL, Gudi R, Bishop JB. Induction of kinetochore positive and negative micronuclei in mouse bone marrow cells by salicylazosulfapyridine and sulfapyridine. Mutat Res. 1992; 283:53–7.
Zeiger E, Anderson B, Hawort S, Lawlor T, Mortelmans K. Salmonella mutagenicity tests: IV. Results from the testing of 300 chemicals. Environ Mol Mutagen. 1988;11(Suppl. 12):1–158.
Zitelli BJ, Alexander J, Taylor S et al. Fatal hepatic necrosis due to pyrimethamine-sulfadoxine (Fansidar). Ann Intern Med. 1987;106(3):393–5.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Abou-Eisha, A., Afifi, M. Genotoxic evaluation of the antimalarial drug, fansidar, in cultured human lymphocytes. Cell Biol Toxicol 20, 303–311 (2004). https://doi.org/10.1007/s10565-004-5352-4
Issue Date:
DOI: https://doi.org/10.1007/s10565-004-5352-4