Ethyl methanesulfonate toxicity in Viracept-A comprehensive human risk assessment based on threshold data for genotoxicity

Toxicology Letters

Volumn 190, Issue 3, 2009, Pages 317-329

  Müller, Lutz ^a   Gocke, Elmar ^a   Lavé, Thierry ^a   Pfister, Thomas ^a  

^a F HOFFMANN LA ROCHE LTD   (Switzerland)

Author keywords

AUC; Birth defects; Cmax; Cancer; Contamination; DNA adducts; DNA repair; Ethyl methanesulfonate; Ethyl valine adducts; MGMT; Mutation threshold; Patient exposure risk; Viracept

Indexed keywords

COTRIMOXAZOLE; LAMIVUDINE; MESYLIC ACID ETHYL ESTER; NELFINAVIR; RNA DIRECTED DNA POLYMERASE INHIBITOR; ZALCITABINE; ZIDOVUDINE;

ARTICLE; CHROMOSOME ABERRATION; DOSE RESPONSE; DRUG CONTAMINATION; DRUG EXPOSURE; GENE MUTATION; GENOTOXICITY; HALF LIFE TIME; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; MAXIMUM PLASMA CONCENTRATION; NONHUMAN; PRIORITY JOURNAL; RISK ASSESSMENT; STATISTICAL ANALYSIS; TOXICITY TESTING; TOXICOKINETICS;

ALKYLATING AGENTS; ANIMALS; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG CONTAMINATION; ENVIRONMENTAL EXPOSURE; ETHYL METHANESULFONATE; HIV PROTEASE INHIBITORS; HUMANS; MICE; MUTAGENS; MUTATION; NELFINAVIR; NEOPLASMS; NO-OBSERVED-ADVERSE-EFFECT LEVEL; RATS; REPRODUCTION; RISK ASSESSMENT; TOXICITY TESTS;

ANIMALIA; MUS; RATTUS;

EID: 69549149576     PISSN: 03784274     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.toxlet.2009.04.003     Document Type: Article

References (71)

1. Amara K., Trimeche M., Ziadi S., Laatiri A., Hachana M., Sriha B., Mokni M., and Korbi S. Presence of simian virus 40 DNA sequences in diffuse large B-cell lymphomas in Tunisia correlates with aberrant promoter hypermethylation of multiple tumor suppressor genes. Int. J. Cancer 121 12 (2007) 2693-2702
2. Barrington de Gonzales A., and Darby S. Risk of cancer from diagnostic X-rays: estimates for the UK and 14 other countries. Lancet 363 (2004) 345-351
3. Barvaux V.A., Lorigan P., Ranson M., Gillum A.M., McElhinney R.S., McMurry T.B., and Margison G.P. Sensitization of a human ovarian cancer cell line to temozolomide by simultaneous attenuation of the Bcl-2 antiapoptotic protein and DNA-repair by O6-alkylguanine-DNA alkyltransferase. Cancer Ther. 3 (2004) 1215-1220
4. Beranek D.T. Distribution of methyl and ethyl adducts following alkylation with monofunctional alkylating agents. Mutat. Res. 231 1 (1990) 11-30
5. Carmella S.G., Chen M., Villalta P.W., Gurney J.G., Hatsukami D.K., and Hecht S.S. Ethylation and methylation of hemoglobin in smokers and non-smokers. Carcinogenesis 23 11 (2002) 1903-1910
6. Chen L., Wang M., Villalta P.W., and Hecht S.S. Liquid chromatography-electrospray ionization tandem mass spectrometry analysis of 7-ethylguanine in human liver DNA. Chem. Res. Toxicol. 20 (2007) 1498-1502
7. Chinnasamy D., Fairbairn L.J., Neuenfeldt J., Treisman J.S., Hanson Jr. J.P., Margison G.P., and Chinnasamy N. Lentivirus-mediated expression of mutant MGMTp140K protects human CD34+ cells against the combined toxicity of O6-benzylguanine and 1,3-bis(2-chloroethyl)-nitrourea or temozolomide. Hum. Gene Ther. 15 (2004) 758-769
8. Clemann, N., 2008. Results of the embryonic stem cell (EST) test, a non-GLP in vitro test for embryotoxicity, with ethylmethanesulfonate (EMS) and methylmethanesulfonate (MMS). Roche internal report No. 1028027.
9. Cohen S.M. Thresholds in genotoxicity and carcinogenicity: urinary bladder carcinogenesis. Genes Environ. 30 (2008) 132-138
10. Davis B.M. In vivo selection for human and murine hematopoietic cells transduced with a therapeutic MGMT lentiviral vector that inhibits HIV replication. Mol. Ther. 9 (2004) 160-172
11. De Bont R., and van Larebeke N. Endogenous DNA damage in humans: a review of quantitative data. Mutagenesis 19 3 (2004) 169-185
12. Doak S.H., Brüsehafer K., Dudley K., Quick E., Johnson G., Newton R.P., and Jenkins G.J. No-observed effects levels are associated with up-regulation of MGMT following MMS exposure. Mutat. Res. 648 (2008) 9-14
13. Doak S.H., Jenkins G.J., Johnson G.E., Quick E., Parry E.M., and Parry J.M. Mechanistic influences for mutation induction curves after exposure to DNA-reactive carcinogens. Cancer Res. 15 (2007) 3904-3911
14. Escobar P.A., Olivero O.A., Wade N.A., Abrams E.J., Nesel C.J., Ness R.B., Day R.D., Day B.W., Meng Q., O'Neill J.P., Walker D.M., Poirier M.C., Walker V.E., and Bigbee W.L. Genotoxicity assessed by the Comet and GPA assays following in vitro exposure of human lymphoblastoid cells (H9) or perinatal exposure of mother-child pairs to AZT or AZT-3TC. Environ. Mol. Mutagen. 48 (2007) 330-343
15. Esteller M., and Herman J.G. Cancer as an epigenetic disease: DNA methylation and chromatin alterations in human tumours. J. Pathol. 196 1 (2002) 1-7
16. Everly M.J., Bloom R.D., Tsai D.E., and Trofe J. Posttransplant lymphoproliferative disorder. Ann. Pharmacother. 41 11 (2007) 1850-1858
17. Fang J.-L., and Vaca C.E. Detection of DNA adducts of acetaldehyde in peripheral white blood cells of alcohol abusers. Carcinogenesis 18 (1997) 627-632
18. Fang J.Y., Mikovits J.A., Bagni R., Petrow-Sadowski C.L., and Ruscetti F.W. Infection of lymphoid cells by integration-defective human immunodeficiency virus type 1 increases de novo methylation. J. Virol. 75 20 (2001) 9753-9761
19. Gerber C., and Toelle H.-G. What happened-the chemistry side of the incident with EMS contamination in Viracept tablets. Toxicol. Lett. 190 (2009) 248-253
20. Gerson S.L., Miller K., and Berger N.A. O6 alkylguanine-DNA alkyltransferase in human myeloid cells. J. Clin. Invest. 76 (1985) 2106-2114
21. Gerson S.L., Trey J.E., Miller K., and Berger N.A. Comparison of O6a-alkylguanine-DNA alkyltransferase activity based on cellular DNA content in human, rat and mouse tissue. Carcinogenesis 7 (1986) 745-749
22. Gerson S.L., Phillips W., Kastan M., Dumenco L.L., and Donovan C. Human CD34+ hematopoietic progenitors have low, cytokine-unresponsive O6-alkylguanine-DNA alkyltransferase and are sensitive to O6-benzylguanine plus BCNU. Blood 88 (1996) 1649-1655
23. Gocke E., Buergin H., Müller L., and Pfister T. Literature review on the genotoxicity, reproductive toxicity, and carcinogenicity of ethyl methanesulfonate. Toxicol. Lett. 190 (2009) 254-265
24. Gocke E., Müller L., and Pfister T. EMS in Viracept-initial ('traditional') assessment of risk to patients based on linear dose response relations. Toxicol. Lett. 190 (2009) 266-270
25. Gocke E., Ballantyne M., Whitwell J., and Müller L. MNT and MutaMouse studies to define the in vivo dose response relations of the genotoxicity of EMS and ENU. Toxicol. Lett. 190 (2009) 286-297
26. Gocke E., and Wall M. In vivo genotoxicity of EMS: Statistical assessment of the dose response curves. Toxicol. Lett. 190 (2009) 298-302
27. Grafstrom R.C., Pegg A.E., Trump B.F., and Harris C.C. O6-alkylguanine-DNA alkyltransferase activity in normal human tissues and cells. Cancer Res. 44 (1984) 2855-2857
28. Greenfield R.E., Ellwein L.B., and Cohen S.M. A general probabilistic model of carcinogenesis: analysis of experimental urinary bladder cancer. Carcinogenesis 5 (1984) 437-445
29. Gutekunst K.A., Kashanchi F., Brady J.N., and Bednarik D.P. Transcription of the HIV-1 LTR is regulated by the density of DNA CpG methylation. J. Acquir. Immune Defic. Syndr. 6 6 (1993) 541-549
30. Hong H.-H.L. Genetic alterations in K-ras and p53 cancer genes in lung neoplasms from Swiss (Cd-1) male mice exposed transplacentally to AZT. Environ. Mol. Mutagen. 48 (2007) 299-306
31. Jansen J.G., Vrieling H., van Teijlingen C.M., Mohn G.R., Tates A.D., and van Zeeland A.A. Marked differences in the role of O6-alkylguanine in hprt mutagenesis in T-lymphocytes of rats exposed in vivo to ethylmethanesulfonate, N-(2-hydroxyethyl)-N-nitrosourea, or N-ethyl-N-nitrosourea. Cancer Res. 55 9 (1995) 1875-1882
32. Jiao L., Chang P., Firozi P.F., Lai D., Abbruzzese J.L., and Li D. Polymorphisms of Phase II xenobiotic-metabolizing and DNA repair genes and in vitro N-ethyl-N-nitrosourea-induced O6 ethylguanine levels in human lymphocytes. Mutat. Res. 627 (2007) 146-157
33. Johnson, G., Doak, S.H., Griffiths, S.M., Quick, E.L., Skibinski, D.O.F., Zaïr, Z.M., Jenkins, G.J., in press. Non-linear dose-response of DNA-reactive genotoxins: recommendations for analysis. Mutat. Res.
34. Jun G.J., Ro J.Y., Kim M.H., Park G.H., Paik W.K., Magee P.N., and Kim S. Studies on the distribution of O6-methylguanine-DNA methyltransferase in rat. Biochem. Pharmacol. 35 (1986) 377-384
35. Kaina B., Christmann M., Naumann S., and Roos W.P. MGMT: key node in the battle against genotoxicity, carcinogenicity and apoptosis induced by alkylating agents. DNA Repair 6 (2007) 1079-1099
36. Kaneto H., Sasaki S., Yamamoto H., Itoh F., Toyota M., Suzuki H., Ozeki I., Iwata N., Ohmura T., Satoh T., Karino Y., Satoh T., Toyota J., Satoh M., Endo T., Omata M., and Imai K. Detection of hypermethylation of the p16(INK4A) gene promoter in chronic hepatitis and cirrhosis associated with hepatitis B or C virus. Gut 48 3 (2001) 372-377
37. Lave T., Birnböck H., Götschi A., Ramp T., and Pähler A. In vivo and in vitro characterization of ethyl methanesulfonate pharmacokinetics in animals and in human. Toxicol. Lett. 190 (2009) 303-309
38. Lave T., Päehler A., and Grimm H.P. Modelling of patient EMS exposure: translating pharmacokinetics of EMS in vitro and in animals into patients. Toxicol. Lett. 190 (2009) 310-316
39. Lutz W.K. Inducible repair of DNA methylated by carcinogens. Trends Pharmacol. Sci. (1982) 398-399
40. Lutz, R.W., Lutz, W.K., in press. Statistical model to estimate a threshold dose and its confidence limits for the analysis of a sublinear dose response relationship, exemplified for mutagenicity data. Mutat. Res.
41. Matsukura S., Soejima H., Nakagawachi T., Yakushiji H., Ogawa A., Fukuhara M., Miyazaki K., Nakabeppu Y., Sekiguchi M., and Mukai T. CpG methylation of MGMT and hMLH1 promoter in hepatocellular carcinoma associated with hepatitis viral infection. Br. J. Cancer 88 4 (2003) 521-529
42. Mientjes E.J., Luiten-Schuite A., van der Wolf E., Borsboom Y., Bergmans A., Berends F., Lohman P.H., Baan R.A., and van Delft J.H. DNA adducts, mutant frequencies, and mutation spectra in various organs of lambda lacZ mice exposed to ethylating agents. Environ. Mol. Mutagen. 31 1 (1998) 18-31
43. Mita S., Monnat Jr. R.J., and Loeb L.A. Resistance of HeLa cell mitochondrial DNA to mutagenesis by chemical carcinogens. Cancer Res. 48 16 (1988) 4578-4583
44. Müller L., and Gocke E. Considerations regarding a Permitted daily exposure calculation for ethyl methansulfonate. Toxicol. Lett. 190 (2009) 330-332
45. Müller L., and Singer S. EMS in Viracept - The course of events in 2007 and 2008 from the non-clinical safety point of view. Toxicol. Lett. 190 (2009) 243-247
46. Murthy M.S., Calleman C.J., Osterman-Golkar S., Segerbäck D., and Svensson K. Relationships between ethylation of hemoglobin, ethylation of DNA and administered amount of ethyl methanesulfonate in the mouse. Mutat. Res. 127 (1984) 1-8
47. Op het Veld C.W., van Hees-Stuivenberg S., van Zeeland A.A., and Jansen J.G. Effect of nucleotide excision repair on hprt gene mutations in rodent cells exposed to DNA ethylating agents. Mutagenesis 12 6 (1997) 417-424
48. Platzek T., Bochert G., and Rahm U. Embryotoxicity induced by alkylating agents 8. DNA adduct formation induced by ethylmethanesulfonate in mouse embryos. Teratogen. Carcinogen. Mutagen. 14 (1994) 65-73
49. Platzek T., Bochert G., and Meister R. Embryotoxicity induced by alkylating agents: 9. Low dose prenatal-toxic risk estimation of ethylmethanesulfonate based on no-observed-adverse-effect-level risk factor approach, dose-response relationships, and molecular dosimetry. Teratogen. Carcinogen. Mutagen. 15 2 (1995) 81-92
50. Pfister T., and Eichinger-Chapelon A. General toxicity studies with ethyl methanesulfonate. Toxicol. Lett. 190 (2009) 271-285
51. Robbiano L., Parodi A., Venturelli S., and Brambilla S. Comparison of DNA alkylation, fragmentation, and repair in maternal and fetal tissue of pregnant rats treated with ethyl methanesulfonate, ethyl-N-nitrosourea, diethylnitrosamine, and methyl-N-nitrosourea. Teratogen. Carcinogen. Mutagen. 9 (1989) 157-166
52. Roberts J.J., and Warwick G.P. Studies on the mode of action of tumour-growth-inhibiting alkylating agents. I-The fate of ethyl methanesulphonate ("half myleran") in the rat. Biochem. Pharmacol. 1 (1958) 60-75
53. Roos W.P., Christmann M., Fraser S.T., and Kaina B. Mouse embryonic stem cells are hypersensitive to apoptosis triggered by the DNA damage O6-methylguanine due to high E2F1 regulated mismatch repair. Cell Death Different. 14 (2007) 1422-1432
54. Rossi D., Gaidano G., Gloghini A., Deambrogi C., Franceschetti S., Berra E., Cerri M., Vendramin C., Conconi A., Viglio A., Muti G., Oreste P., Morra E., Paulli M., Capello D., and Carbone A. Frequent aberrant promoter hypermethylation of O6-methylguanine-DNA methyltransferase and death-associated protein kinase genes in immunodeficiency-related lymphomas. Br. J. Haematol. 123 3 (2003) 475-478
55. Schneider J., Warzok R., Schreiber D., and Heiderstaedt R. Zur postnatalen und transplazentaren kanzerogenen Wirkung von Methylmethansulfat (MMS) und Äthylmethansulfonat (ÄMS) bei der Haubenratte. Exp. Pathol. Jena 16 (1978) 157-167
56. Singh R., Kaur B., and Farmer P.B. Detection of DNA damage derived from a direct acting ethylating agent present in cigarette smoke by use of liquid chromatography-tandem mass spectrometry. Chem. Res. Toxicol. 18 2 (2005) 249-256
57. Slupphaug G., Lettrem I., Myrnes B., and Krokan H.E. Expression of O6-methylguanine-DNA methyltransferase and uracil-DNA glycosylase in human placentae from smokers and non-smokers. Carcinogenesis 13 (1992) 1769-1773
58. Su P.F., Lee T.C., Lin P.J., Lee P.H., Jeng Y.M., Chen C.H., Liang J.D., Chiou L.L., Huang G.T., and Lee H.S. Differential DNA methylation associated with hepatitis B virus infection in hepatocellular carcinoma. Int. J. Cancer 121 6 (2007) 1257-1264
59. Sun Y.I., Yue-Chen H., Qin-Zhi X., Hui-Ping W., Bei B., Jian-Li S., and Ping-Kun Z. HIV-1 Tat depresses DNA-PKCS expression and DNA repair and sensitizes cells to ionizing radiation. Int. J. Radiat. Oncol. Biol. Phys. 65 3 (2006) 842-850
60. Swenberg J.A., Fryar-Tita E., Jeong Y.C., Boysen G., Starr T., Walker V.E., and Albertini R.J. Biomarkers in toxicology and risk assessment: informing critical dose-response relationships. Chem. Res. Toxicol. 21 (2008) 253-265
61. Törnqvist M., Osterman-Golkar S., Kautiainen A., Näslund M., Calleman C.J., and Ehrenberg L. Methylations in human hemoglobin. Mutat. Res. 204 (1988) 521-529
62. Törnqvist M., Fred C., Haglund J., Helleberg H., Paulsson B., and Rydberg P. Protein adducts: quantitative and qualitative aspects of their formation, analysis and applications. J. Chromatogr. B: Anal. Technol. Biomed. Life Sci. 778 1-2 (2002) 279-308
63. Uren A.G., Kool J., Berns A., and van Lohuizen M. Retroviral insertional mutagenesis: past, present and future. Oncogene 24 52 (2005) 7656-7672
64. van der Ven A.J., Koopmans P.P., Vree T.B., and van derMeer J.W. Drug intolerance in HIV disease. J. Antimicrob. Chemother. 34 (1994) 1-5
65. Walker D.M., Malarkey D.E., Seilkop S.K., Ruecker F.A., Funk K.A., Wolfe M.J., Treanor C.P., Foley J.F., Hahn F.F., Hardisty J.F., and Walker V.E. Transplacental carcinogenicity of 3′-azido-3′deoxythymidine in B6C3F1 mice and F344 rats. Environ. Mol. Mutagen. 48 (2007) 283-298
66. Walker V.E., Casciano D.A., and Tweats D.J. The Viracept-EMS case: impact and outlook. Toxicol. Lett. 190 (2009) 333-339
67. Wiewrodt D., Nagel G., Dreimüller N., Hundsberger T., Perneczky A., and Kaina B. MGMT in primary and recurrent human glioblastoma after radiation and chemotherapy and comparison with p53 status and clinical outcome. Int. J. Cancer 122 (2008) 1391-1399
68. Wijsman J.A., Wijsman G., Dekaban A., and Rieder M.J. Differential toxicity of reactive metabolites of clindamycin and sulfonamides in HIV-infected cells: influence of HIV infection on clindamycin toxicity in vitro. J. Clin. Pharmacol. 45 (2005) 346-351
69. Witt K.L., Livanos E., Kissling G.E., Torous D.K., Caspary W., Tice R.R., and Recio L. Elevated frequencies of micronucleated erythrocytes in infants exposed to zidovudine in utero and postpartum to prevent mother-to-child transmission of HIV. Environ. Mol. Mutagen. 48 (2007) 322-329
70. Yeung M.L., Benasser Y., Myers T.G., Jiang G., Benkirane M., and Jeang K.T. Changes in microRNA expression profiles in HIV-1-transfected human cells. Retrovirology 2 (2005) 81 10.1186/1742-4690-2-81
71. Zagon I.S., and McLaughlin P.J. Nucleic acids and protein in brains and cerebella of rats transplancentally exposed to ethylnitrosourea. Brain Res. Bull. 6 (1981) 355-360