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Antimicrob Agents Chemother. 1994 December; 38(12): 2743–2749.
PMCID: PMC188279

Effects of antiviral nucleoside analogs on human DNA polymerases and mitochondrial DNA synthesis.


Inhibition constants were determined for 16 nucleoside analog triphosphates against human DNA polymerases alpha, beta, gamma, and epsilon, and 7 nucleoside analogs were examined as inhibitors of mitochondrial DNA synthesis in human Molt-4 cells in culture. The results demonstrate no clear quantitative or qualitative correlation between inhibition of DNA polymerases, particularly mitochondrial DNA polymerase gamma, and the inhibition of mitochondrial DNA synthesis in Molt-4 cell culture. Furthermore, the data indicate that inhibition of isolated DNA polymerases may not be predictive of in vitro or in vivo toxicity. Finally, it is not clear whether inhibition of mitochondrial DNA synthesis will be an accurate predictor of the potential in vivo toxicity of antiviral nucleoside analogs.

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  • Anderson S, Bankier AT, Barrell BG, de Bruijn MH, Coulson AR, Drouin J, Eperon IC, Nierlich DP, Roe BA, Sanger F, et al. Sequence and organization of the human mitochondrial genome. Nature. 1981 Apr 9;290(5806):457–465. [PubMed]
  • Anderson TD, Davidovich A, Arceo R, Brosnan C, Arezzo J, Schaumburg H. Peripheral neuropathy induced by 2',3'-dideoxycytidine. A rabbit model of 2',3'-dideoxycytidine neurotoxicity. Lab Invest. 1992 Jan;66(1):63–74. [PubMed]
  • Anderson TD, Davidovich A, Feldman D, Sprinkle TJ, Arezzo J, Brosnan C, Calderon RO, Fossom LH, DeVries JT, DeVries GH. Mitochondrial schwannopathy and peripheral myelinopathy in a rabbit model of dideoxycytidine neurotoxicity. Lab Invest. 1994 May;70(5):724–739. [PubMed]
  • APOSHIAN HV, KORNBERG A. Enzymatic synthesis of deoxyribonucleic acid. IX. The polymerase formed after T2 bacteriophage infection of Escherichia coli: a new enzyme. J Biol Chem. 1962 Feb;237:519–525. [PubMed]
  • Arnaudo E, Dalakas M, Shanske S, Moraes CT, DiMauro S, Schon EA. Depletion of muscle mitochondrial DNA in AIDS patients with zidovudine-induced myopathy. Lancet. 1991 Mar 2;337(8740):508–510. [PubMed]
  • Balzarini J, Herdewijn P, De Clercq E. Differential patterns of intracellular metabolism of 2',3'-didehydro-2',3'-dideoxythymidine and 3'-azido-2',3'-dideoxythymidine, two potent anti-human immunodeficiency virus compounds. J Biol Chem. 1989 Apr 15;264(11):6127–6133. [PubMed]
  • Chang CN, Doong SL, Zhou JH, Beach JW, Jeong LS, Chu CK, Tsai CH, Cheng YC, Liotta D, Schinazi R. Deoxycytidine deaminase-resistant stereoisomer is the active form of (+/-)-2',3'-dideoxy-3'-thiacytidine in the inhibition of hepatitis B virus replication. J Biol Chem. 1992 Jul 15;267(20):13938–13942. [PubMed]
  • Chen CH, Cheng YC. Delayed cytotoxicity and selective loss of mitochondrial DNA in cells treated with the anti-human immunodeficiency virus compound 2',3'-dideoxycytidine. J Biol Chem. 1989 Jul 15;264(20):11934–11937. [PubMed]
  • Chen CH, Vazquez-Padua M, Cheng YC. Effect of anti-human immunodeficiency virus nucleoside analogs on mitochondrial DNA and its implication for delayed toxicity. Mol Pharmacol. 1991 May;39(5):625–628. [PubMed]
  • Cheng YC, Gao WY, Chen CH, Vazquez-Padua M, Starnes MC. DNA polymerases versus HIV reverse transcriptase in AIDS therapy. Ann N Y Acad Sci. 1990;616:217–223. [PubMed]
  • Copeland WC, Chen MS, Wang TS. Human DNA polymerases alpha and beta are able to incorporate anti-HIV deoxynucleotides into DNA. J Biol Chem. 1992 Oct 25;267(30):21459–21464. [PubMed]
  • Dalakas MC, Illa I, Pezeshkpour GH, Laukaitis JP, Cohen B, Griffin JL. Mitochondrial myopathy caused by long-term zidovudine therapy. N Engl J Med. 1990 Apr 19;322(16):1098–1105. [PubMed]
  • Davis MG, Mar EC, Wu YM, Huang ES. Mapping and expression of a human cytomegalovirus major viral protein. J Virol. 1984 Oct;52(1):129–135. [PMC free article] [PubMed]
  • Eriksson S, Kierdaszuk B, Munch-Petersen B, Oberg B, Johansson NG. Comparison of the substrate specificities of human thymidine kinase 1 and 2 and deoxycytidine kinase toward antiviral and cytostatic nucleoside analogs. Biochem Biophys Res Commun. 1991 Apr 30;176(2):586–592. [PubMed]
  • Faraj A, Fowler DA, Bridges EG, Sommadossi JP. Effects of 2',3'-dideoxynucleosides on proliferation and differentiation of human pluripotent progenitors in liquid culture and their effects on mitochondrial DNA synthesis. Antimicrob Agents Chemother. 1994 May;38(5):924–930. [PMC free article] [PubMed]
  • Feinberg AP, Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. [PubMed]
  • Feinberg AP, Vogelstein B. "A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity". Addendum. Anal Biochem. 1984 Feb;137(1):266–267. [PubMed]
  • Feldman D, Brosnan C, Anderson TD. Ultrastructure of peripheral neuropathy induced in rabbits by 2',3'-dideoxycytidine. Lab Invest. 1992 Jan;66(1):75–85. [PubMed]
  • Fischl MA, Richman DD, Grieco MH, Gottlieb MS, Volberding PA, Laskin OL, Leedom JM, Groopman JE, Mildvan D, Schooley RT, et al. The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial. N Engl J Med. 1987 Jul 23;317(4):185–191. [PubMed]
  • Fourel I, Hantz O, Watanabe KA, Jacquet C, Chomel B, Fox JJ, Trepo C. Inhibitory effects of 2'-fluorinated arabinosyl-pyrimidine nucleosides on woodchuck hepatitis virus replication in chronically infected woodchucks. Antimicrob Agents Chemother. 1990 Mar;34(3):473–475. [PMC free article] [PubMed]
  • Gray H, Wong TW. Purification and identification of subunit structure of the human mitochondrial DNA polymerase. J Biol Chem. 1992 Mar 25;267(9):5835–5841. [PubMed]
  • Hart GJ, Orr DC, Penn CR, Figueiredo HT, Gray NM, Boehme RE, Cameron JM. Effects of (-)-2'-deoxy-3'-thiacytidine (3TC) 5'-triphosphate on human immunodeficiency virus reverse transcriptase and mammalian DNA polymerases alpha, beta, and gamma. Antimicrob Agents Chemother. 1992 Aug;36(8):1688–1694. [PMC free article] [PubMed]
  • Izuta S, Saneyoshi M, Sakurai T, Suzuki M, Kojima K, Yoshida S. The 5'-triphosphates of 3'-azido-3'-deoxythymidine and 2', 3'-dideoxynucleosides inhibit DNA polymerase gamma by different mechanisms. Biochem Biophys Res Commun. 1991 Sep 16;179(2):776–783. [PubMed]
  • Khan NN, Wright GE, Dudycz LW, Brown NC. Butylphenyl dGTP: a selective and potent inhibitor of mammalian DNA polymerase alpha. Nucleic Acids Res. 1984 Apr 25;12(8):3695–3706. [PMC free article] [PubMed]
  • Kaplan JH. Molecular biology of carrier proteins. Cell. 1993 Jan 15;72(1):13–18. [PubMed]
  • Koch MA, Volberding PA, Lagakos SW, Booth DK, Pettinelli C, Myers MW. Toxic effects of zidovudine in asymptomatic human immunodeficiency virus-infected individuals with CD4+ cell counts of 0.50 x 10(9)/L or less. Detailed and updated results from protocol 019 of the AIDS Clinical Trials Group. Arch Intern Med. 1992 Nov;152(11):2286–2292. [PubMed]
  • Lambert JS, Seidlin M, Reichman RC, Plank CS, Laverty M, Morse GD, Knupp C, McLaren C, Pettinelli C, Valentine FT, et al. 2',3'-dideoxyinosine (ddI) in patients with the acquired immunodeficiency syndrome or AIDS-related complex. A phase I trial. N Engl J Med. 1990 May 10;322(19):1333–1340. [PubMed]
  • Manji H, Harrison MJ, Round JM, Jones DA, Connolly S, Fowler CJ, Williams I, Weller IV. Muscle disease, HIV and zidovudine: the spectrum of muscle disease in HIV-infected individuals treated with zidovudine. J Neurol. 1993 Sep;240(8):479–488. [PubMed]
  • Matthes E, Lehmann C, von Janta-Lipinski M, Scholz D. Inhibition of HIV-replication by 3'-fluoro-modified nucleosides with low cytotoxicity. Biochem Biophys Res Commun. 1989 Nov 30;165(1):488–495. [PubMed]
  • Meng TC, Fischl MA, Boota AM, Spector SA, Bennett D, Bassiakos Y, Lai SH, Wright B, Richman DD. Combination therapy with zidovudine and dideoxycytidine in patients with advanced human immunodeficiency virus infection. A phase I/II study. Ann Intern Med. 1992 Jan 1;116(1):13–20. [PubMed]
  • Merigan TC, Skowron G. Safety and tolerance of dideoxycytidine as a single agent. Results of early-phase studies in patients with acquired immunodeficiency syndrome (AIDS) or advanced AIDS-related complex. Study Group of the AIDS Clinical Trials Group of the National Institute of Allergy and Infectious Diseases. Am J Med. 1990 May 21;88(5B):11S–15S. [PubMed]
  • Mhiri C, Baudrimont M, Bonne G, Geny C, Degoul F, Marsac C, Roullet E, Gherardi R. Zidovudine myopathy: a distinctive disorder associated with mitochondrial dysfunction. Ann Neurol. 1991 Jun;29(6):606–614. [PubMed]
  • Modica-Napolitano JS. AZT causes tissue-specific inhibition of mitochondrial bioenergetic function. Biochem Biophys Res Commun. 1993 Jul 15;194(1):170–177. [PubMed]
  • MONOD J, CHANGEUX JP, JACOB F. Allosteric proteins and cellular control systems. J Mol Biol. 1963 Apr;6:306–329. [PubMed]
  • Munch-Petersen B, Cloos L, Tyrsted G, Eriksson S. Diverging substrate specificity of pure human thymidine kinases 1 and 2 against antiviral dideoxynucleosides. J Biol Chem. 1991 May 15;266(14):9032–9038. [PubMed]
  • Parker WB, White EL, Shaddix SC, Ross LJ, Buckheit RW, Jr, Germany JM, Secrist JA, 3rd, Vince R, Shannon WM. Mechanism of inhibition of human immunodeficiency virus type 1 reverse transcriptase and human DNA polymerases alpha, beta, and gamma by the 5'-triphosphates of carbovir, 3'-azido-3'-deoxythymidine, 2',3'-dideoxyguanosine and 3'-deoxythymidine. A novel RNA template for the evaluation of antiretroviral drugs. J Biol Chem. 1991 Jan 25;266(3):1754–1762. [PubMed]
  • Pezeshkpour G, Krarup C, Buchthal F, DiMauro S, Bresolin N, McBurney J. Peripheral neuropathy in mitochondrial disease. J Neurol Sci. 1987 Feb;77(2-3):285–304. [PubMed]
  • Reardon JE. Herpes simplex virus type 1 and human DNA polymerase interactions with 2'-deoxyguanosine 5'-triphosphate analogues. Kinetics of incorporation into DNA and induction of inhibition. J Biol Chem. 1989 Nov 15;264(32):19039–19044. [PubMed]
  • Reardon JE. Human immunodeficiency virus reverse transcriptase: steady-state and pre-steady-state kinetics of nucleotide incorporation. Biochemistry. 1992 May 12;31(18):4473–4479. [PubMed]
  • Richman DD, Fischl MA, Grieco MH, Gottlieb MS, Volberding PA, Laskin OL, Leedom JM, Groopman JE, Mildvan D, Hirsch MS, et al. The toxicity of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial. N Engl J Med. 1987 Jul 23;317(4):192–197. [PubMed]
  • Sandström E, Oberg B. Antiviral therapy in human immunodeficiency virus infections. Current status (Part I). Drugs. 1993 Apr;45(4):488–508. [PubMed]
  • Shoffner JM, Lott MT, Lezza AM, Seibel P, Ballinger SW, Wallace DC. Myoclonic epilepsy and ragged-red fiber disease (MERRF) is associated with a mitochondrial DNA tRNA(Lys) mutation. Cell. 1990 Jun 15;61(6):931–937. [PubMed]
  • Siegal G, Turchi JJ, Jessee CB, Mallaber LM, Bambara RA, Myers TW. Structural relationships between two forms of DNA polymerase epsilon from calf thymus. J Biol Chem. 1992 Feb 25;267(6):3991–3999. [PubMed]
  • Simpson DM, Citak KA, Godfrey E, Godbold J, Wolfe DE. Myopathies associated with human immunodeficiency virus and zidovudine: can their effects be distinguished? Neurology. 1993 May;43(5):971–976. [PubMed]
  • Simpson MV, Chin CD, Keilbaugh SA, Lin TS, Prusoff WH. Studies on the inhibition of mitochondrial DNA replication by 3'-azido-3'-deoxythymidine and other dideoxynucleoside analogs which inhibit HIV-1 replication. Biochem Pharmacol. 1989 Apr 1;38(7):1033–1036. [PubMed]
  • Southern EM. Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol. 1975 Nov 5;98(3):503–517. [PubMed]
  • Stanat SC, Reardon JE, Erice A, Jordan MC, Drew WL, Biron KK. Ganciclovir-resistant cytomegalovirus clinical isolates: mode of resistance to ganciclovir. Antimicrob Agents Chemother. 1991 Nov;35(11):2191–2197. [PMC free article] [PubMed]
  • Starnes MC, Cheng YC. Cellular metabolism of 2',3'-dideoxycytidine, a compound active against human immunodeficiency virus in vitro. J Biol Chem. 1987 Jan 25;262(3):988–991. [PubMed]
  • St Clair MH, Richards CA, Spector T, Weinhold KJ, Miller WH, Langlois AJ, Furman PA. 3'-Azido-3'-deoxythymidine triphosphate as an inhibitor and substrate of purified human immunodeficiency virus reverse transcriptase. Antimicrob Agents Chemother. 1987 Dec;31(12):1972–1977. [PMC free article] [PubMed]
  • Syväoja J, Suomensaari S, Nishida C, Goldsmith JS, Chui GS, Jain S, Linn S. DNA polymerases alpha, delta, and epsilon: three distinct enzymes from HeLa cells. Proc Natl Acad Sci U S A. 1990 Sep;87(17):6664–6668. [PubMed]
  • Talanian RV, Brown NC, McKenna CE, Ye TG, Levy JN, Wright GE. Carbonyldiphosphonate, a selective inhibitor of mammalian DNA polymerase delta. Biochemistry. 1989 Oct 17;28(21):8270–8274. [PubMed]
  • Wallace DC, Zheng XX, Lott MT, Shoffner JM, Hodge JA, Kelley RI, Epstein CM, Hopkins LC. Familial mitochondrial encephalomyopathy (MERRF): genetic, pathophysiological, and biochemical characterization of a mitochondrial DNA disease. Cell. 1988 Nov 18;55(4):601–610. [PubMed]
  • Yarchoan R, Pluda JM, Thomas RV, Mitsuya H, Brouwers P, Wyvill KM, Hartman N, Johns DG, Broder S. Long-term toxicity/activity profile of 2',3'-dideoxyinosine in AIDS or AIDS-related complex. Lancet. 1990 Sep 1;336(8714):526–529. [PubMed]

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