Neurotoxic effects of AZT on developing and adult neurogenesis

Frontiers in Neuroscience

Volumn 9, Issue MAR, 2015, Pages

  Demir, Meryem ^a   Laywell, Eric D ^b  

^a UNIVERSITY OF FLORIDA COLLEGE OF MEDICINE   (United States)

^b FLORIDA STATE UNIVERSITY COLLEGE OF MEDICINE   (United States)

Author keywords

AZT; Dentate gyrus; Neurogenesis; Senescence; Subependymal zone; Thymidine analogs

Indexed keywords

ZIDOVUDINE;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTICLE; ASTROCYTE; CELL EXPANSION; COLONY FORMING CELL; CONTROLLED STUDY; DENTATE GYRUS; FEMALE; MALE; MOUSE; NERVOUS SYSTEM DEVELOPMENT; NEURAL STEM CELL; NEUROBLAST; NEUROTOXICITY; NONHUMAN; SENESCENCE; SUBVENTRICULAR ZONE;

EID: 84928044872     PISSN: 16624548     EISSN: 1662453X     Source Type: Journal    
DOI: 10.3389/fnins.2015.00093     Document Type: Article

References (96)

1. Anderson, P. L., Kakuda, T. N., Kawle, S., and Fletcher, C. V. (2003). Antiviral dynamics and sex differences of zidovudine and lamivudine triphosphate concentrations in HIV-infected individuals. AIDS 17, 2159-2168. doi: 10.1097/00002030-200310170-00003
2. Antinori, A., Arendt, G., Becker, J. T., Brew, B. J., Byrd, D. A., Cherner, M., et al. (2007). Updated research nosology for HIV-associated neurocognitive disorders. Neurology 69, 1789-1799. doi: 10.1212/01.WNL.0000287431.88658.8b
3. Ayers, K. M., Clive, D., Tucker, W. E., Hajian, G., and de Miranda, P. (1996). Nonclinical toxicology studies with zidovudine: genetic toxicity tests and carcinogenicity bioassays in mice and rats. Fundam. Appl. Toxicol. 32, 148-158. doi: 10.1006/faat.1996.0118
4. Azari, H., Louis, S. A., Sharififar, S., Vedam-Mai, V., and Reynolds, B. A. (2011). Neural-colony forming Cell assay: an assay to discriminate bona fide neural stem cells from neural progenitor cells. J. Vis. Exp. 49:e2639. doi: 10.3791/2639
5. Blanche, S., Tardieu, M., Rustin, P., Slama, A., Barret, B., Firtion, G., et al. (1999). Persistent mitochondrial dysfunction and perinatal exposure to antiretroviral nucleoside analogues. Lancet 354, 1084-1089. doi: 10.1016/S0140-6736(99)07219-0
6. Blanche, S., Tardieu, M., Benhammou, V., Warszawski, J., and Rustin, P. (2006). Mitochondrial dysfunction following perinatal exposure to nucleoside analogues. AIDS 20, 1685-1690. doi: 10.1097/01.aids.0000242814.42344.77
7. Brew, B. J. (1999). AIDS dementia complex Neurol. Clin. 17, 861-881. doi: 10.1016/S0733-8619(05)70170-5
8. Busidan, Y., and Dow-Edwards, D. L. (1999). Neurobehavioral effects of perinatal AZT exposure in Sprague-Dawley weaning rats. Pharmacol. Biochem. Behav. 64, 479-485. doi: 10.1016/S0091-3057(99)00157-4
9. Busidan, Y., Shi, X., and Dow-Edwards, D. L. (2001). AZT distribution in the fetal and postnatal rat central nervous system. J. Pharm. Sci. 90, 1964-1971. doi: 10.1002/jps.1147
10. Calamandrei, G., Venerosi, A., Branchi, I., Chiarotti, F., Verdina, A., Bucci, F., et al. (1999a). Effects of prenatal AZT on mouse neurobehavioral development and passive avoidance learning. Neurotoxicol. Teratol. 21, 29-40. doi: 10.1016/S0892-0362(98)00035-X
11. Calamandrei, G., Venerosi, A., Branchi, I., and Alleva, E. (1999b). Effects of prenatal zidovudine treatment on learning and memory capacities of preweanling and young adult mice. Neurotoxicology 20, 17-25.
12. Calamandrei, G., Rufin, O., Valanzano, A., and Puopolo, M. (2002a). Long-term effects of developmental exposure to zidovudine on exploratory behavior and novelty discrimination in CD-1 mice. Neurotoxicol. Teratol. 24, 529-540. doi: 10.1016/S0892-0362(02)00234-9
13. Calamandrei, G., Valanzano, A., Puopolo, M., and Aloe, L. (2002b). Developmental exposure to the antiretroviral drug zidovudine increases brain levels of brain-derived neurotrophic factor in mice. Neurosci. Lett. 333, 111-114. doi: 10.1016/S0304-3940(02)01023-6
14. Caporaso, G. L., Lim, D. A., Alvarez-Buylla, A., and Chao, M. V. (2003). Telomerase activity in the subventriuclar zone of adult mice. Mol. Cell. Neurosci. 23, 693-702. doi: 10.1016/S1044-7431(03)00103-9
15. Chiu, D. T., and Duesberg, P. H. (1995). The toxicity of azidothymidine (AZT) on human and animal cells in culture at concentrations used for antiviral therapy. Genetica 95, 103-109. doi: 10.1007/BF01435004
16. Chow, H. H., Brookshier, G., and Tang, Y. (1997). In vivo tissue disposition of 3'-azido-3'-deoxythymidine and its anabolites in control and retrovirus-infected mice. Drug Metab. Dispos. 25, 412-422.
17. Connor, E. M., Sperling, R. S., Gelber, R., Kiselev, P., O'Sullivan, M. J., VanDyke, R., et al. (1994). Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS clinical trials group protocol 076 study group. N. Engl. J. Med. 331, 1173-1180. doi: 10.1056/NEJM199411033311801
18. Cysique, L. A., Maruff, P., and Brew, B. J. (2004). Antiretroviral therapy in HIV infection: are neurologically active drugs important? Arch. Neurol. 61, 1699-1704. doi: 10.1001/archneur.61.11.1699
19. Deleyrolle, L. P., and Reynolds, B. A. (2009). Identifying and enumerating neural stem cells: application to aging and cancer. Meth. Mol. Biol. 549, 91-101. doi: 10.1007/978-1-60327-931-4_7
20. Deleyrolle, L. P., Ericksson, G., Morrison, B. J., Lopez, J. A., Burrage, K., Burrage, P., et al. (2011). Determination of somatic and cancer stem cell self-renewing symmetric division rate using sphere assays. PLoS ONE 6:e15844. doi: 10.1371/journal.pone.0015844
21. Dimri, G. P., Lee, X., Basile, G., Acosta, M., Scott, G., Roskelley, C., et al. (1995). A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc. Natl. Acad. Sci. U.S.A. 92, 9363-9367. doi: 10.1073/pnas.92.20.9363
22. Diwan, B. A., Riggs, C. W., Logsdon, D., Haines, D. C., Olivero, O. A., Rice, J. M., et al. (1999). Multiorgan transplacental and neonatal carcinogenicity of 3'-azido- 3'-deoxythymidine in mice. Toxicol. Appl. Pharmacol. 161, 82-99. doi: 10.1006/taap.1999.8782
23. Doetsch, F., Caille, I., Lim, D. A., Garcia-Verdugo, J. M., and Alvarez-Buylla, A. (1999). Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 97, 703-716. doi: 10.1016/S0092-8674(00)80783-7
24. Durand-Gasselin, L., Pruvost, A., Dehee, A., Vaudre, G., Tabone, M. D., Grassi, J., et al. (2008). High levels of zidovudine (AZT) and its intracellular phosphate metabolites in AZT- and AZT-lamivudine-treated newborns of human immunodeficiency virus-infected mothers. Antimicrob. Agents Chemother. 52, 2555-2563. doi: 10.1128/AAC.01130-07
25. Dykstra, K. H., Arya, A., Arriola, D. M., Bungay, P. M., Morrison, P. F., and Dedrick, R. L. (1993). Microdialysis study of zidovudine (AZT) transport in rat brain. J. Pharmacol. Exp. Ther. 267, 1227-1236.
26. Eilers, M., Roy, U., and Mondal, D. (2008). MRP (ABCC) transporters-mediated efflux of anti-HIV drugs, saquinavir and zidovudine, from human endothelial cells. Exp. Biol. Med. 233, 1149-1160. doi: 10.3181/0802-RM-59
27. Eriksson, M., Brown, W. T., Gordon, L. B., Glynn, M. W., Singer, J., Scott, L., et al. (2003). Recurrent de novo point mutations in lamin A cause Hutchinson-Guilford progeria syndrome. Nature 423, 293-298. doi: 10.1038/nature01629
28. Evers, S., Rahmann, A., Schwaag, S., Frese, A., Reichelt, D., and Husstedt, I. W. (2004). Prevention of AIDS dementia by HAART does not depend on cerebrospinal fluid drug penetrance. AIDS Res. Hum. Retroviruses 20, 483-491. doi: 10.1089/088922204323087723
29. Ewings, E. L., Gerschenson, M., St. Claire, M. C., Nagashima, K., Skopets, B., Harbaugh, S. W., et al. (2000). Genotoxic and functional consequences of transplacental zidovudine exposure in fetal monkey brain mitochondria. J. Acquir. Immune Defic. Syndr. 24, 100-105. doi: 10.1097/00126334-200006010-00003
30. Ferron, S., Mira, H., Franco, S., Cano-Jaimez, M., Bellmunt, E., Ramirez, C., et al. (2004). Telomere shortening and chromosomal instability abrogates proliferation of adult but not embryonic neural stem cells. Development 131, 4059-4070. doi: 10.1242/dev.01215
31. Ferron, S. R., Marques-Torrejon, M. A., Mira, H., Flores, I., Taylor, K., Blasco, M. A., et al. (2009). Telomere shortening in neural stem cells disrupts neuronal differentiation and neuritogenesis. J. Neurosci. 29, 4394-14407. doi: 10.1523/JNEUROSCI.3836-09.2009
32. Fletcher, C. V., Anderson, P. L., Kakuda, T. N., Schacker, T. W., Gross, C. R., and Brundage, R. C. (2002). Concentration-controlled compared with conventional antiretroviral therapy for HIV infection. AIDS 16, 551-560. doi: 10.1097/00002030-200203080-00006
33. Foster, C., Lyall, H., Olmscheid, B., Pearche, G., Zhang, S., and Gibb, D. M. (2009). Tenofovir disoproxil fumarate in pregnancy and prevention of mother-to-child transmission of HIV-1, is it time to move on from zidovudine? HIV Med. 10, 397-406. doi: 10.1111/j.1468-1293.2009.00709.x
34. Furman, P. A., Fyfe, J. A., St. Clair, M. H., Weinhold, K., Rideout, J. L., Freeman, G. A., et al. (1986). Phosphorylation of 3'-azido-3'-deoxythymidine and selective interaction of the 5'-triphosphate with human immunodeficiency virus reverse transcriptase. Proc. Natl. Acad. Sci. U.S.A. 83, 8333-8337. doi: 10.1073/pnas.83.21.8333
35. Gerschenson, M., and Poirier, M. C. (2000). Fetal patas monkeys sustain mitochondrial toxicity as a result of in utero zidovudine exposure. Ann. N.Y. Acad. Sci. 918, 269-281. doi: 10.1111/j.1749-6632.2000.tb05496.x
36. Gerschenson, M., Erhart, S. W., Paik, C. Y., St. Claire, M. C., Nagashima, K., Skopets, B., et al. (2000). Fetal mitochondrial heart and skeletal muscle damage in Erythrocebus patas monkeys exposed in utero to 3'-azido-3'-deoxythymidine. AIDS Res. Hum. Retroviruses 16, 635-644. doi: 10.1089/088922200308864
37. Groothuis, D. R., and Levy, R. M. (1997). The entry of antiviral and antiretroviral drugs into the central nervous system. J. Neurovirol. 3, 387-400. doi: 10.3109/13550289709031185
38. Haik, S., Bauthier, L. R., Granotier, C., Peyrin, J.-M., Lages, C. S., Dormont, D., et al. (2000). Fibroblast growth factor 2 up regulates telomerase activity in neural precursor cells. Oncogene 19, 2957-2966. doi: 10.1038/sj.onc.1203596
39. Hobbs, G. A., Keilbaugh, S. A., Rief, P. M., and Simpson, M. V. (1995). Cellular targets of 3'-azido-3'- deoxythymidine: an early (non-delayed) effect on oxidative phosphorylation. Biochem. Pharmacol. 50, 381-390. doi: 10.1016/0006-2952(95)00141-L
40. Im, J., Kim, W., Kim, K. T., and Chung, S. K. (2009). Preparation of a 3'-azido-3'-deoxythymidine (AZT) derivative, which is blood-brain barrier permeable. Chem. Commun. 31, 4669-4671. doi: 10.1039/b909541a
41. Inoue, T., Tsushita, K., Itoh, T., Ogura, M., Hotta, T., Saneyoshi, M., et al. (1989). In vitro bone marrow toxicity of nucleoside analogs against human immunodeficiency virus. Antimicrob. Agents Chemother. 33, 576-579. doi: 10.1128/AAC.33.4.576
42. Joao, E. C., Calvet, G. A., Krauss, M. R., Freimanis Hance, L., Ortiz, J., Ivalo, S. A., et al. (2010). Maternal antiretroviral use during pregnancy and infant congenital anomalies: the NISDI perinatal study. J. Acquir. Immune Defic. Syndr. 53, 176-185. doi: 10.1097/QAI.0b013e3181c5c81f
43. Kearney, B. P., and Aweeka, F. T. (1999). The penetration of anti-infectives into the central nervous system. Neurol. Clin. 17, 883-900. doi: 10.1016/S0733-8619(05)70171-7
44. Lai, Y., Tse, C. M., and Unadkat, J. D. (2004). Mitochondrial expression of the human equilibrative nucleoside transporter 1 (hENT1) results in enhanced mitochondrial toxicity of antiviral drugs. J. Biol. Chem. 279, 4490-4497. doi: 10.1074/jbc.M307938200
45. Laywell, E. D., Rakic, P., Kukekov, V. G., Holland, E. C., and Steindler, D. A. (2000). Identification of a multipootent astrocytic stem cell in the immature and adult mouse brain. Proc. Natl. Acad. Sci.U.S.A. 97, 13883-13888. doi: 10.1073/pnas.250471697
46. Laywell, E. D., Kukekov, V. G., Suslov, O., Zheng, T., and Steindler, D. A. (2002). "Production and analysis of neurospheres from acutely dissociated and postmortem CNS specimens," in Methods in Molecular Biology. Vol. 198, Neural Stem Cells: Methods and Protocols, eds T. Zigova, P. R. Sanberg, J. R. Sanchez-Ramos (Totowa, NJ: Humana Press Inc.), 15-27.
47. Laywell, E. D., Kearns, S. M., Zheng, T., Chen, K. A., Deng, J., Chen, H. X., et al. (2005). Neuron-to-astroctye transition: phenotypic fluidity and the formation of hybrid asterons in differentiating neurospheres. J. Comp. Neurol. 493, 321-333. doi: 10.1002/cne.20722
48. Lee, H., Hanes, J., and Johnson, K. A. (2003). Toxicity of nucleoside analogues used to treat AIDS and the selectivity of the mitochondrial DNA polymerase. Biochemistry 42, 14711-14719. doi: 10.1021/bi035596s
49. Letendre, S. L., McCutchan, J. A., Childers, M. E., Woods, S. P., Lazzaretto, D., Heaton, R. K., et al. (2004). Enhancing antiretroviral therapy for human immunodeficiency virus cognitive disorders. Ann. Neurol. 56, 416-423. doi: 10.1002/ana.20198
50. Letendre, S., Marquie-Beck, J., Capparelli, E., Best, B., Clifford, D., Collier, A. C., et al. (2008). Validation of the CNS Penetration-Effectiveness rank for quantifying antiretroviral penetration into the central nervous system. Arch. Neurol. 65, 65-70. doi: 10.1001/archneurol.2007.31
51. Levkoff, L. H., Marshall, G. P. II, Ross, H. H., Caldeira, M., Reynolds, B. A., Cakiroglu, M., et al. (2008). Bromodeoxyuridine inhibits cancer cell proliferation in vitro and in vivo. Neoplasia 10, 804-816. doi: 10.1593/neo.08382
52. Lewis, W., Simpson, J. F., and Meyer, R. R. (1994). Cardiac mitochondrial DNA polymerase-gamma is inhibited competitively and noncompetitively by phosphorylated zidovudine. Circ. Res. 74, 344-348. doi: 10.1161/01.RES.74.2.344
53. Lewis, W. (2003). Mitochondrial dysfunction and nucleoside reverse transcriptase inhibitor therapy: experimental clarifications and persistent clinical questions. Antiviral Res. 58, 189-197. doi: 10.1016/S0166-3542(03)00069-X
54. Lewis, W., Day, B. J., and Copeland, W. C. (2003). Mitochondrial toxicity of NRTI antiviral drugs: an integrated cellular perspective. Nat. Rev. Drug Discov. 2, 812-822. doi: 10.1038/nrd1201
55. Lewis, L. D., Amin, S., Civin, C. I., and Lietman, P. S. (2004). Ex vivo zidovudine (AZT) treatment of CD34+ bone marrow progenitors causes decreased steady state mitochondrial DNA (mtDNA) and increased lactate production. Hum. Exp. Toxicol. 23, 173-185. doi: 10.1191/0960327104ht437oa
56. Li, W., Chang, Y., Zhan, P., Zhang, N., Liu, X., Pannecouque, C., et al. (2010). Synthesis, In vitro and In vivo release kinetics, and anti-HIV activity of a sustained-release prodrug (mPEG- AZT) of 3'-Azido-3'-deoxythymidine (AZT, Zidovudine). Chem. Med. Chem. 5, 1893-1898. doi: 10.1002/cmdc.201000352
57. Mansuri, M. M., Hitchcock, M. J., Buroker, R. A., Bregman, C. L., Ghassouli, I., Esiderio, J. V., et al. (1990). Comparison of in vitro biological properties and mouse toxicities of three thymidine analogs active against human immunodeficiency virus. Antimicrob. Agents Chemother. 34, 637-641. doi: 10.1128/AAC.34.4.637
58. Marra, C. M., Zhao, Y., Clifford, D. B., Letendre, S., Evans, S., Henry, K., et al. (2009). Impact of combination antiretroviral therapy on cerebrospinal fluid HIV RNA and neurocognitive performance. AIDS 23, 1359-1366. doi: 10.1097/QAD.0b013e32832c4152
59. Marshall, G. P. II, Laywell, E. D., Zheng, T., Steindler, D. A., and Scott, E. W. (2006). In vitro-derived "neural stem cells" function as neural progenitors without the capacity for self-renewal. Stem Cells 24, 731-738. doi: 10.1634/stemcells.2005-0245
60. Marshall, G. P. II, Reynolds, B. A., and Laywell, E. D. (2007). Using the neurosphere assay to quantify neural stem cells in vivo. Curr. Pharm. Biotechnol. 8, 141-145. doi: 10.2174/138920107780906559
61. Marshall, G. P. II, Demir, M., Steindler, D. A., and Laywell, E. D. (2008). Subventricular zone microglia possess a unique capacity for massive in vitro expansion. GLIA 56, 1799-1808. doi: 10.1002/glia.20730
62. McKee, E. E., Bentley, A. T., Hatch, M., Gingerich, J., and Susan-Resiga, D. (2004). Phosphorylation of thymidine and AZT in heart mitochondria: elucidation of a novel mechanism of AZT cardiotoxicity. Cardiovasc. Toxicol. 4, 155-167. doi: 10.1385/CT:4:2:155
63. Melnick, S. M., Weedon, J., and Dow-Edwards, D. L. (2005). Perinatal AZT exposure alters the acoustic and tactile startle response to 8-OH-DPAT and apomorphine in adult rats. Neurotoxicol. Teratol. 27, 599-608. doi: 10.1016/j.ntt.2005.05.010
64. Miller, D. S., Bauer, B., and Hartz, A. M. (2008). Modulation of P-glycoprotein at the blood-brain barrier: opportunities to improve central nervous system pharmacotherapy. Pharmacol. Rev. 60, 196-209. doi: 10.1124/pr.107.07109
65. Mirzadeh, Z., Merkle, F. T., Soriano-Navarro, M., Garcia-Verdugo, J. M., and Alvarez-Buylla, A. (2008). Neural stem cells confer unique pinwheel architecture to the ventricular surface in neurognic regions of the adult brain. Cell Stem Cell 3, 265-278. doi: 10.1016/j.stem.2008.07.004
66. Nakashima, H., Matsui, T., Harada, S., Kobayashi, N., Matsuda, A., Ueda, T., et al. (1986). Inhibition of replication and cytopathic effect of human T cell lymphotropic virus type III/lymphadenopathy-associated virus by 3'-azido-3'-deoxythymidine in vitro. Antimicrob. Agents Chemother. 30, 933-937. doi: 10.1128/AAC.30.6.933
67. Newschaffer, C. J., Cocroft, J., Anderson, C. E., Hauck, W. W., and Turner, B. J. (2000). Prenatal zidovudine use and congenital anomalies in a medicaid population. J. Acquir. Immune Defic. Synd. 24, 249-256. doi: 10.1097/00126334-200007010-00009
68. Olivero, O. A., Anderson, L. M., Diwan, B. A., Haines, D. C., Harbaugh, S. W., Moskal, T. J., et al. (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. doi: 10.1093/jnci/89.21.1602
69. Olivero, O. A. (2007). Mechanisms of genotoxicity of nucleoside reverse transcriptase inhibitors. Environ. Mol. Mutagen. 48, 215-223. doi: 10.1002/em.20195
70. Papadopulos-Eleopulos, E., Turner, V. F., Papadimitriou, J. M., Causer, D., Alponso, H., and Miller, T. (1999). A critical analysis of the pharmacology of AZT and its use in AIDS. Curr. Med. Res. Opin. 15(Suppl. 1), S1-S45. doi: 10.1185/03007999909114096
71. Petyko, Z., Lenad, L., Sumegi, B., Hajnal, A., Csete, B., Faludi, B., et al. (1997). Learning disturbances in offsprings of zidovudine (AZT) treated rats. Neurobiol. 5, 83-85.
72. Poirier, M. C., Patterson, T. A., Slikker, W. Jr., and Olivero, O. A. (1999). Incorporation of 3'-azido-3'- deoxythymidine (AZT) into fetal DNA and fetal tissue distribution of drug after infusion of pregnant late-term rhesus macaques with a human-equivalent AZT dose. J. Acquir. Immune Defic. Syndr. 22, 477-483. doi: 10.1097/00126334-199912150-00008
73. Quevedo, M. A., Ribone, S. R., Moroni, G. N., and Brinon, M. C. (2008). Binding to human serum albumin of zidovudine (AZT) and nove AZT derivatives. Experimental and theoretical analyses. Bioorg. Med. Chem. 16, 2779-2790. doi: 10.1016/j.bmc.2008.01.007
74. Read, P., Costelloe, S., Mullen, J., O'Shea, S., Lyons, F., Hay, P., et al. (2008). New mutations associated with resistance not detected following zidovudine monotherapy in pregnancy when used in accordance with British HIV Association guidelines. HIV Med. 9, 448-451. doi: 10.1111/j.1468-1293.2008.00594.x
75. Rondinini, C., Venerosi, A., Branchi, I., Calamandrei, G., and Alleva, E. (1999). Long-term effects of prenatal 3'-azido-3'-deoxythymidine (AZT) exposure on intermale aggressive behaviour of mice. Psychopharmacology 145, 317-323. doi: 10.1007/s002130051064
76. Ross, H. H., Levkoff, L. H., Marshall, G. P. II, Caldeira, M., Steindler, D. A., Reynolds, B. A., et al. (2008). Bromodeoxyuridine induces senescence in neural stem and progenitor cells. Stem Cells 26, 3218-3227. doi: 10.1634/stemcells.2008-0299
77. Ross, H. H., Rahman, M., Levkoff, L. H., Millette, S., Martin-Carreras, T., Dunbar, E. M., et al. (2011). Ethynyldeoxyuridine (EdU) suppresses in vitro population expansion and in vivo tumor progression of human glioblastoma cells. J. Neurooncol. 105, 485-498. doi: 10.1007/s11060-011-0621-6
78. Saiyed, Z. M., Gandhi, N. H., and Nair, M. P. (2010). Magnetic nanoformulation of azidothymidine 5'- triphosphate for targeted delivery across the blood-brain barrier. Int. J. Nanomed. 5, 157-166. doi: 10.2147/IJN.S8905
79. Sawchuk, R. J., and Yang, Z. (1999). Investigation of distribution, transport and uptake of anti-HIV drugs to the central nervous system. Adv. Drug Deliv. Rev. 9, 5-31. doi: 10.1016/S0169-409X(99)00017-4
80. Scheffler, B., Walton, N. M., Lin, D. D., Goetz, A. K., Enikolopov, G., Roper, S. N., et al. (2005). Phenotypic and functional characterization of adult brain neuropoiesis. Proc. Natl. Acad. Sci. U.S.A. 102, 9353-9358. doi: 10.1073/pnas.0503965102
81. Simpson, M. V., Chin, C. D., Keilbaugh, S. A., Lin, T. S., and Prusoff, W. H. (1989). Studies on the inhibition of mitochondrial DNA replication by 3'-azido-3'-deoxythymidine and other dideoxynucleoside analogs which inhibit HIV-1 replication. Biochem. Pharmacol. 38, 1033-1036. doi: 10.1016/0006-2952(89)90245-1
82. Singer, M., and Berg, P. (1990). Genes and Genomes: a Changing Perspective. Mill Valley, CA: University Science Books.
83. Slikker, W. Jr., Olivero, O. A., Patterson, T. A., and Poirier, M. C. (2000). Potential toxicities of HIV therapeutics in the developing infant. Teratology 61, 397-398. doi: 10.1002/(SICI)1096-9926(200005)61:5<397::AID-TERA16>3.0.CO;2-8
84. Takasawa, K., Suzuki, H., and Sugiyama, Y. (1997a). Transport properties of 3'-azido-3'-deoxythymidine and 2',3'-dideoxyinosine in the rat choroid plexus. Biopharm. Drug Dispos. 18, 611-622.
85. Takasawa, K., Terasaki, T., Suzuki, H., and Sugiyama, Y. (1997b). In vivo evidence for carrier-mediated efflux transport of 3'-azido-3'-deoxythymidine and 2',3'-dideoxyinosine across the blood-brain barrier via a probenecid-sensitive transport system. J. Pharmacol. Exp. Ther. 281, 369-375.
86. Tavazoie, M., Van der Veken, L., Silva-Vargas, V., Louissant, M., Colonna, L., Zaidi, B., et al. (2008). A specialized vascular niche for adult neural stem cells. Cell Stem Cell 3, 279-288. doi: 10.1016/j.stem.2008.07.025
87. Thomas, S. A., and Segal, M. B. (1997). The passage of azidodeoxythymidine into and within the central nervous system: does it follow the parent compound, thymidine? J. Pharmacol. Exp. Ther. 281, 1211-1218.
88. Torres, S. M., Walker, D. M., Carter, M. M., Cook, D. L. Jr., McCash, C. L., Cordova, E. M., et al. (2007). 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. Environ. Mol. Mutagen. 48, 224-238. doi: 10.1002/em.20264
89. Ukekawa, R., Miki, K., Fujii, M., Hirano, H., and Ayusawa, D. (2007). Accumulation of multiple forms of lamin A with down-regulation of FACE-1 suppresses growth in senescent human cells. Genes Cells 12, 397-406. doi: 10.1111/j.1365-2443.2007.01057.x
90. Venerosi, A., Cirulli, F., Lil'p, I. G., Calamandrei, G., and Alleva, E. (2000). Prolonged perinatal exposure to AZT affects aggressive behaviour of adult CD-1 mice. Psychopharmacology 150, 404-411. doi: 10.1007/s002130000455
91. Venerosi, A., Cirulli, F., Capone, F., and Alleva, E. (2003). Prolonged perinatal AZT administration and early maternal separation: effects on social and emotional behaviour of periadolescent mice. Pharmacol. Biochem. Behav. 74, 671-681. doi: 10.1016/S0091-3057(02)01068-7
92. Venerosi, A., Valanzano, A., Puopolo, M., and Calamandrei, G. (2005). Neurobehavioral effects of prenatal exposure to AZT: a preliminary investigation with the D1 receptor agonist SKF 38393 in mice. Neurotoxicol. Teratol. 27, 169-173. doi: 10.1016/j.ntt.2004.09.008
93. Walker, D. M., Malarkey, D. E., Seilkop, S. K., Ruecker, F. A., Funk, K. A., Wolfe, M. J., et al. (2007). Transplacental carcinogenicity of 3'- azido-3'-deoxythymidine in B6C3F1 mice and F344 rats. Environ. Mol. Mutagen. 48, 283-298. doi: 10.1002/em.20297
94. Wu, D., Clement, J. G., and Pardridge, W. M. (1998). Low blood-brain barrier permeability to azidothymidine (AZT), 3TC, and thymidine in the rat. Brain Res. 791, 313-316. doi: 10.1016/S0006-8993(98)00139-5
95. Zhang, Z., Diwan, B. A., Anderson, L. M., Logsdon, D., Olivero, O. A., Haines, D. C., et al. (1998). Skin tumorigenesis and Ki-ras and Ha-ras mutations in tumors from adult mice exposed in utero to 3'-azido-2',3'-dideoxythymidine. Mol. Carcinog. 23, 45-51.
96. Zhikova, Z., and Stankova, I. (2000). Stability of some novel thymidine, 5-bromo-2'-deoxyuridine and 3'- azido-2'-3'-dideoxythymidine analogues. Int. J. Pharm. 200, 181-185. doi: 10.1016/S0378-5173(00)00367-7