Mutagenicity of zidovudine, lamivudine, and abacavir following in vitro exposure of human lymphoblastoid cells or in utero exposure of CD-1 mice to single agents or drug combinations

Environmental and Molecular Mutagenesis

Volumn 48, Issue 3-4, 2007, Pages 224-238

  Torres, Salina M ^a   Walker, Dale M ^a   Carter, Meghan M ^a   Cook Jr , Dennis L ^a   McCash, Consuelo L ^a   Cordova, Edmund M ^a   Olivero, Ofelia A ^b   Poirier, Miriam C ^b   Walker, Vernon E ^a  

^a LOVELACE RESPIRATORY RESEARCH INSTITUTE   (United States)

^b NATIONAL CANCER INSTITUTE   (United States)

Author keywords

HPRT; Nucleoside analog; TK; Transplacental

Indexed keywords

ABACAVIR; LAMIVUDINE; LAMIVUDINE PLUS ZIDOVUDINE; NUCLEOSIDE ANALOG; ZIDOVUDINE;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CELL CLONING; CELL SURVIVAL; CHEMICAL MUTAGENESIS; CONCENTRATION RESPONSE; CONTROLLED STUDY; CYTOTOXICITY; DOSE RESPONSE; DRUG EXPOSURE; DRUG MIXTURE; FEMALE; FETUS; GENE FREQUENCY; GESTATION PERIOD; HPRT GENE; HUMAN; IN VITRO STUDY; LYMPHOBLASTOID CELL; MALE; MOUSE; MUTAGENICITY; MUTATIONAL ANALYSIS; NEWBORN; NONHUMAN; REPORTER GENE; SPLEEN LYMPHOCYTE; T LYMPHOCYTE; TK GENE;

ANIMALS; ANTI-HIV AGENTS; CELL LINE; CELL SURVIVAL; DIDEOXYNUCLEOSIDES; DNA; DRUG INTERACTIONS; FEMALE; HUMANS; HYPOXANTHINE PHOSPHORIBOSYLTRANSFERASE; LAMIVUDINE; LYMPHOCYTES; MALE; MATERNAL-FETAL EXCHANGE; MICE; MICE, INBRED STRAINS; MUTAGENS; MUTATION; PREGNANCY; REVERSE TRANSCRIPTASE INHIBITORS; THYMIDINE KINASE; ZIDOVUDINE;

MUS;

EID: 34047230197     PISSN: 08936692     EISSN: 10982280     Source Type: Journal    
DOI: 10.1002/em.20264     Document Type: Article

References (57)

1. Ayers KM, Clive D, Tucker WE, Hajian G, de Mirand P. 1996. Nonclinical toxicology studies with zidovudine: Genetic toxicity test and carcinogenicity bioassays in mice and rats. Fundam Appl Toxicol 32:148-158.
2. Benhammou V, Tardieu M. Warszawskim J, Blanche B, for the French Perinatal Cohort. 2007. Clinical mitochondrial dysfunction in uninfected children born to HIV-infected mothers following perinatal exposure to nucleoside analogues. Environ Mol Mutagen 48:173-178.
3. Bishop JB, Witt KL, Tice RR, Wolfe GW. 2004. Genetic damage detected in CD1 mouse pups exposed perinatally to 3′-azido-3′-deoxythymidine and dideoxyinosine via maternal dosing, nursing, and direct gavage. Environ Mol Mutagen 43:3-9.
4. Blanche S, Tardieu M, Rustin R, Slama A, Barret B, Firtion G, Ciraru-Vigneron N, Lacroix C, Rouzioux C, Mandelbrot L, Desguerre I, Rötig A, Mayaux MJ, Delfraissy JF. 1999. Persistent mitochondrial dysfunction and perinatal exposure to antiretroviral nucleoside analogues. Lancet 354:1084-1089.
5. Bonnet F, Lewden C, May T, Heripret L, Jougla E, Bevilacqua S, Costagliola D, Salmon D, Chene G, Morlat P. 2004. Malignancy-related causes of death in human immunodeficiency virus-infected patients in the era of highly active antiretroviral therapy. Cancer 101:317-324.
6. Capparelli E, Rakhmanina, Mirochnick M. 2005. Pharmacotherapy of perinatal HIV. Semin Fetal Neonatal Med 10:151-175.
7. Carter MM, Torres SM, McCash CL, Yu M, Griegos J, Walker DM, Walker VE. 2007. Relative mutagenic potencies of several nucleoside analogs, alone or in drug pairs, at the HPRT and TK loci of human TK6 lymphoblastoid cells. Environ Mol Mutagen 48:239-247.
8. Cihlar T, Birkus G, Greenwalt DE, Hitchcock MJ. 2002. Tenofovir exhibits low cytotoxicity in various human cell types: Comparison with other nucleoside reverse transcriptase inhibitors. Antiviral Res 54:37-45.
9. Clifford GM, Polesel J, Rickenbach M, Dal Maso L, Keiser O, Kofler A, Rapiti E, Levi F, Jundt G, Fisch T, Bordoni A, De Week D, Franceschi S. 2005. Cancer risk in the Swiss HIV Cohort Study: Associations with immunodeficiency, smoking, and highly active antiretroviral therapy. J Natl Cancer Inst 97:425-432.
10. Connor EM, Sperling RS, Belber R. Kiselev P. Scott G, O'Sullivan JM, VanDyke R, Bey M, Shearer W, Jacobson RL, Jimenez E, O'Neill E, Bazin B. Delfraissy J-F, Culnane M, Coombs R, Elkins M, Moye J, Station P, Balsley J, for the Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. 1994. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. N Engl J Med 331:1173-1180.
11. Cooper ER, Di Mauro S, Sullivan M, Jones-Eaves D, Kay L, Moloney C, Regan AM. 2004. Biopsy-confirmed mitochondrial dysfunction in an HIV-exposed infant whose mother received combination antiretrovirals during the last 6 weeks of pregnancy. eJIAS 1:TuPeB4394 (Abstract).
12. Crippen TL, Jones IM. 1989. Cell proliferation in the bone marrow, thymus and spleen of mice studied by continuous, in vivo bromodeoxycytidine labelling and flow cytometric analysis. Cell Tissue Kinet 22:203-212.
13. Dagan T, Sable C, Bray J, Gerschenson M. 2002. Mitochondrial dysfunction and antiretroviral nucleoside analog toxicities: What is the evidence? Mitochondrion 1:397-412.
14. Deubel W, Bassukas ID, Schlereth W, Lorenz R, Hempel K. 1996. Age dependent selection against HPRT deficient T lymphocytes in the HPRT ± heterozygous mouse. Mutat Res 351:67-77.
15. Divi RL, Walker VE, Wade NA, Nagashima K, Seilkop SK, Adam ME, Nesel CJ, O'Neill JP, Abrams EJ, Poirier MC. 2004. Mitochondrial damage and DNA depletion in cord blood and umbilical cord from infants exposed in utero to Combivir. AIDS 18:1-9.
16. Divi RL, Leonard SL, Kuo M, Nagashima K, Thamire C, St. Claire MC, Wade NA, Walker VE, Poirier MC. 2007. Transplacentally exposed human and monkey newborn infants show similar evidence of nucleoside reverse transcriptase inhibitor (NRTI)-induced mitochondrial toxicity. Environ Mol Mutagen 48:201-209.
17. Diwan BA, Riggs CW, Logsdon D, Haines DC, Olivero OA, Rice JM. Yuspa SH, Poirier MC, Anderson LM. 1999. Multiorgan transplacental and neonatal carcinogenicity of 3′-azido-3′-deoxythymidine in mice. Toxicol Appl Pharmacol 161:82-99.
18. Dobrovolsky VN, Shaddock JG, Bishop ME, Lee FW, Lewis SM, Leakey JE, Dunnick JG, Aidoo A, Heflich RH. 2005. Effects of p53 haplo-deficiency on micronucleus induction and Hprt mutant frequency in B6C3F1 mice treated perinatally with AZT, AZT/3TC. Mutat Res 577 (Suppl 1):161.
19. Escobar P, Olivero OA, Tice RR, Day BW, Ness RB, Day RD, Bass DC, Welsh MJ, Poirier MC, Abrams E, Wade N, Walker VE, Bigbee WL, protocol team. 2007. 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 48:330-343.
20. Furman PA, Fyfe JA, St. Clair MH, Weinhold K, Rideout JL, Freeman GA, Lehrman SN, Bolognesi DP, Broder S, Mitsuya H. 1986. Phosphorylation of 3′-azido-3′-deoxythymidine and selective interaction of the 5′-triphosphate with human immunodeficiency virus reverse transcriptase. Proc Natl Acad Sci USA 83:8333-8337.
21. Grdina DJ, Dale P, Weichselbaum R. 1992. Protection against AZT-induce mutagenesis at the HGPRT locus in a human cell line by WR-151326. Int J Radiat Oncol Biol Phys 22:813-815.
22. Hong LH, Dunnick J, Herbert R, Devereux TR, Kim Y, Sills RC. 2007. Genetic alterations in K-ras and p53 cancer genes in lung neoplasms of Swiss (CD-1) male mice following AZT transplacental exposure. Environ Mol Mutagen 48:299-306.
23. Hoogard PG, Sales SD, Kewn S, Sunderland D, Khoo SH, Hart CA, Back DJ. 2000. Correlation between intracellular pharmacological activation of nucleoside analogues and HIV suppression in vitro. Antivir Chem Chemother 11:353-358.
24. IARC. 2000. General remarks; and the monograph on zidovudine. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Some Antiviral and Antineoplastic Drugs, and Other Pharmaceutical Agents. Lyon: IARC. pp 35-42 and 73-127. IARC Scientific Publication No. 76.
25. Jones IM, Burkhart-Schultz K, Strout CL, Crippen TL. 1987. Factors that affect the frequency of thioguanine-resistant lymphocytes in mice following exposure to ethylnitrosourea. Environ Mutagen 9:317-329.
26. Judice SJ. 2001. Human and mouse T-cell trafficking, mutation, and kinetics. Ph.D. Thesis, Graduate College, University of Vermont, Burlington.
27. Kakuda TM. 2000. Pharmacology of nucleoside and nucleotide reverse transcriptase inhibitor-induced mitochondrial toxicity. Clin Ther 22:685-708.
28. Liber HL, Thilly WG. 1982. Mutation assay at the thymidine kinase locus in diploid human lymphoblasts. Mutat Res 94:467-485.
29. Meng Q, Walker DM, Olivero OA, Shi X, Antiochos BB, Poirier MC, Walker VE. 2000b. AZT-ddl coexposure potentiates DNA incorporation of AZT, mutagenesis in human cells. Proc Natl Acad Sci USA 97:12667-12671.
30. Meng Q, Su T, O'Neill P, Walker VE. 2002. Molecular analysis of mutations at the HPRT and TK loci of human lymphoblastoid cells after combined treatments with 3′-azido-3′-deoxythymidine and 2′,3′-dideoxyinosine. Environ Mol Mutagen 39:282-295.
31. Meng Q, Olivero OA, Fasco MJ, Bellisario R, Kaminsky L, Pass KA, Abrams E, Wade N, Poirier MC, Walker VE. protocol team. 2007. Plasma and cellular markers of AZT metabolism as indicators of DNA damage in cord blood mononuclear cells from infants receiving prepartum NRTIs. Environ Mol Mutagen 48:307-321.
32. Meng QM, Su T, Olivero OA, Poirier MC, Shi X, Ding X, Walker VE. 2000a. Relationship between DNA incorporation, mutant frequency, and loss of heterozygosity at the TK locus in human lymphoblastoid cells exposed to 3′-azido-3′-deoxythymidine. Toxicol Sci 54:322-329.
33. Mittelstaedt RA, Von Tungeln LS, Shaddock JG, Dobrovolsky VN, Beland FA, Heflich RH. 2004. Analysis of mutations in the Tk gene of Tk(+/-) mice treated as neonates with 3′-azido-3′-deoxythymidine (AZT). Mutat Res 547:63-69.
34. NTP. 2005. Toxicology and carcinogenesis of transplacental AZT (CAS No. 30516-87-1) in Swiss (CD-1) mice (in utero studies). U.S. Department of Health and Human Services, Research Triangle Park.
35. Olivero OA, Anderson LM, Diwan BA, Haines DC, Harbaugh SW, Moskal TJ, Jones AB, Rice JM, Riggs CW, Logsdon D, Yuspa SH, Poirier MC. 1997. Transplacental effects of 3′-azido-2′,3′-dideoxythymidine (AZT): Tumorigenicity in mice and genotoxicity in mice and monkeys. J Natl Cancer Inst 89:1602-1608.
36. Olivero OA, Shearer GM, Chougnet CA, Kovacs AA, Landay AL, Baker R, Stek AM, Khoury MM, Praia LA, Kessler HA, Sha BE, Tarone RE, Poirier MC. 1999. Incorporation of zidovudine into leukocyte DNA from HIV-1-positive adults and pregnant women, and cord blood from infants exposed in utero. AIDS 13:919-925.
37. Olivero OA, Fernandez JJ, Antiochos BB, Wagner JL, St. Claire ME, Poirier MC. 2002. Transplacental genotoxicity of combined antiretroviral nucleoside analogue therapy in Erythrocehus patas monkeys. JAIDS 29:323-329.
38. O'Neill JP, Gundel RM, Trombley LM, Walker VE. 2001. HPRT mutant frequency and mutation spectra in newborns with perinatal exposure to antiviral drugs. Environ Mol Mutagen 37 (Suppl 32):58.
39. Piconi S, Trabattoni D, Fusi ML, Milazzo F, Dix LP, Rizzardini G, Colombo F, Bray D, Clerici M. 2000. Effect of two different combinations of antiretrovirals (AZT+ddl and AZT+3TC) on cytokine production and apoptosis in asymptomatic IIIV infection. Antiviral Res 46:171-179.
40. Poirier MC, Divi RL, Al-Harthi L, Olivero OA, Nguyen V, Walker B, Landay AL, Walker VE, Charurat M, Blattner WA. 2003. Long-term mitochondrial toxicity in HIV-uninfected infants born to HIV-infected mothers. JAIDS 33:175-183.
41. Poirier MC, Olivero OA, Walker DM, Walker VE. 2004. Perinatal genotoxicity and carcinogenicity of the antiretroviral nucleoside analog drugs. Toxicol Appl Pharmacol 199:151-161.
42. Senda S, Blanche S, Costagliola D, Cibert C, Nigon F, Firtion G, Floch C. Altered heterochromatin organization after perinatal expsosure to zidovudine (AZT). Antivir Ther (in press).
43. Skopek TR, Walker VE, Cochrane JE, Craft TR, Cariello NF. 1992. Mutational spectrum at the Hprt locus in splenic T cells of B6C3F1 mice exposed to N-ethyl-N-nitrosourea. Proc Natl Acad Sci U S A 89:7866-7870.
44. Snyder S, D'Argenio DZ, Weislow O, Bilello JA, Drusano GL. 2000. The triple combination indinavir-zidovudine-lamivudine is highly synergistic. Antimicrob Agents Chemother 44:1051-1058.
45. Sperling RS, Shapiro DE, Coombs RW, Todd JA, Herman SA, McSherry GD, O'Sullivan MJ, Van Dyke RB, Jimenez E, Rouzioux C, Flynn PM, Sullivan JL, for the Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. 1996. Maternal viral load, zidovudine treatment, and the risk of transmission of human immunodeficiency virus type 1 from mother to infant. N Engl J Med 335:1621-1629.
46. Sussman HE, Olivero OA, Meng Q, Pietras SM, Poirier MC, O'Neill JP, Finette BA, Bauer MJ, Walker VE. 1999. Genotoxicity of 3′-azido-3′- dideoxythymidine in the human lymphoblastoid cell line, TK6: Relationships between DNA incorporation, mutant frequency, and spectrum of deletion mutations in HPRT. Mutat Res 429:249-259.
47. Sussman HE, Bauer MJ, Shi X, Judice SA, Albertini RJ, Walker VE. 2001. Transplacental mutagenicity of N-ethyl-N-nitrosourea at the Hprt locus in T-lymphocytes of exposed B6C3F1 mice. Environ Mol Mutagen 38:30-37.
48. Torres SM, Walker VE, Olivero OA, Carter M, Cook D, Poirier M, Walker DM. 2004. Relationships between exposure concentration, exposure duration, levels of DNA incorporation of drugs, and mutagenic effects in human lymphoblastoid TK6 cells exposed in vitro to AZT, 3TC, and AZT-3TC. Environ Mol Mutagen 44:180
49. U.S. Department of Health and Human Services (USDHHS)-Public Health Service Task Force, http://aidsinfo.nih.gov/.
50. Von Tungeln LS, Hamilton LP, Dobrovolsky VN, Bishop ME, Shaddock JG, Heflich RH, Beland FA. 2002. Frequency of Tk and Hprt lymphocyte mutants and bone marrow micronuclei in B6C3F(1)/ Tk+/- mice treated neonatally with zidovudine and lamivudine. Carcinogenesis 23:1427-1432.
51. Von Tungeln LS, Dobrovolsky VN, Bishop ME, Shaddock JG, Heflich RH, Beland FA. 2004. Frequency of Tk and Hprt lymphocyte mutants and bone marrow micronuclei in mice treated neonatally with zidovudine and didanosine. Mutagen 19:307-311.
52. Von Tungeln LS, Williams LD, Doerge DR, Shaddock JG, McGarrity LJ, Morris SM, Mittelstaedt RA, Heflich RH, Beland FA. 2007. Transplacental drug transfer and frequency of Tk and Hprt lymphocyte mutants and peripheral blood micronuclei in mice treated transplacentally with zidovudine and lamivudine. Environ Mol Mutagen 48:258-269.
53. Walker DM, Poirier MC, Campen MJ, Cook DL Jr, Divi RL, Nagashima K, Lund AK, Cossey PY, Hahn FF, Walker VE. 2004. Persistence of mitochondrial toxicity in hearts of female B6C3F1 mice exposed in utero to 3′-azido-3′- deoxythymidine. Cardiovasc Toxicol 4:133-153.
54. Walker DM, Hardisty J, Rucker R, Funk K, Wolfe C, Seilkop SK, Treanor CP, Walker VE. 2007. Transplacental carcinogenicity of 3′-azido-3′- deoxythymidine in B6C3F1 mice and F344 rats. Environ Mol Mutagen 48:283-298.
55. Walker VE, Jones IM, Crippen TL, Meng Q, Walker DM, Bauer MJ, Reilly AA, Tales AD, Nakamura J, Upton PB, Skopek TR. 1999. Relationships between chemical exposure, cell loss and proliferation, and manifestation of Hprt mutant T-cells following treatment of preweanling, weanling, and adult B6C3F1 mice with N-ethyl-N-nitrosourea. Mutat Res 431:371-388.
56. Wang J, Chen T, Honma M, Chen L, Moore MM. 3′-Azido- 3′deoxythymidine (AZT) induces deletions in L5178Y mouse lymphoma cells. Environ Mol Mutagen (in press).
57. Wutzler BA, Thust R. 2001. Genetic risks of antiviral nucleoside analogues-A survey. Antivir Res 49:55-74.