Perinatal genotoxicity and carcinogenicity of anti-retroviral nucleoside analog drugs

Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892-4255, USA.
Toxicology and Applied Pharmacology (Impact Factor: 3.71). 10/2004; 199(2):151-61. DOI: 10.1016/j.taap.2003.11.034
Source: PubMed


The current worldwide spread of the human immunodeficiency virus-1 (HIV-1) to the heterosexual population has resulted in approximately 800,000 children born yearly to HIV-1-infected mothers. In the absence of anti-retroviral intervention, about 25% of the approximately 7,000 children born yearly to HIV-1-infected women in the United States are HIV-1 infected. Administration of zidovudine (AZT) prophylaxis during pregnancy reduces the rate of infant HIV-1 infection to approximately 7%, and further reductions are achieved with the addition of lamivudine (3TC) in the clinical formulation Combivir. Whereas clinically this is a remarkable achievement, AZT and 3TC are DNA replication chain terminators known to induce various types of genotoxicity. Studies in rodents have demonstrated AZT-DNA incorporation, HPRT mutagenesis, telomere shortening, and tumorigenicity in organs of fetal mice exposed transplacentally to AZT. In monkeys, both AZT and 3TC become incorporated into the DNA from multiple fetal organs taken at birth after administration of human-equivalent protocols to pregnant dams during gestation, and telomere shortening has been found in monkey fetuses exposed to both drugs. In human infants, AZT-DNA and 3TC-DNA incorporation as well as HPRT and GPA mutagenesis have been documented in cord blood from infants exposed in utero to Combivir. In infants of mice, monkeys, and humans, levels of AZT-DNA incorporation were remarkably similar, and in newborn mice and humans, mutation frequencies were also very similar. Given the risk-benefit ratio, these highly successful drugs will continue to be used for prevention of vertical viral transmission, however evidence of genotoxicity in mouse and monkey models and in the infants themselves would suggest that exposed children should be followed well past adolescence for early detection of potential cancer hazard.

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Available from: Vernon Walker, Sep 17, 2015
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    • "Zidovudine (AZT) was the first nucleoside reverse transcriptase inhibitor (NRTI) approved for HIV-1 therapy. It has been shown to act as a transplacental carcinogen in mice [Olivero et al., 1997], and becomes incorporated into DNA [Poirier et al., 2004]. In vitro and in vivo, AZT-DNA incorporation induces mutations, MN, chromosomal instability, telomere shortening, and centrosomal deregulation, which leads to changes in cell cycle regulation and gene expression [Olivero, 2007]. "
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    ABSTRACT: The nucleoside reverse transcriptase inhibitor zidovudine (AZT) induces genotoxic damage that includes centrosomal amplification (CA > 2 centrosomes/cell) and micronucleus (MN) formation. Here we explored these end points in mice deficient in DNA repair and tumor suppressor function to evaluate their effect on AZT-induced DNA damage. We used mesenchymal-derived fibroblasts cultured from C57BL/6J mice that were null and wild type (WT) for Xpa, and WT, haploinsufficient and null for p53 (6 different genotypes). Dose-responses for CA formation, in cells exposed to 0, 10, and 100 μM AZT for 24 hr, were observed in all genotypes except the Xpa(+/+)p53(+/−) cells, which had very low levels of CA, and the Xpa(−/−)p53(−/−) cells, which had very high levels of CA. For CA there was a significant three-way interaction between Xpa, p53, and AZT concentration, and Xpa(−/−) cells had significantly higher levels of CA than Xpa(+/+) cells, only for p53(+/−) cells. In contrast, the MN and MN + chromosomes (MN + C) data showed a lack of AZT dose response. The Xpa(−/−) cells, with p53(+/+) or (+/−) genotypes, had levels of MN and MN + C higher than the corresponding Xpa(+/+) cells. The data show that CA is a major event induced by exposure to AZT in these cells, and that there is a complicated relationship between AZT and CA formation with respect to gene dosage of Xpa and p53. The loss of both genes resulted in high levels of damage, and p53 haploinsufficicency strongly protected Xpa(+/+) cells from AZT-induced CA damage. Environ. Mol. Mutagen., 2014. © 2014 Wiley Periodicals, Inc.
    Environmental and Molecular Mutagenesis 12/2014; 55(9). DOI:10.1002/em.21889 · 2.63 Impact Factor
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    • " 3TC is the pair of NRTIs most often used world - wide for treatment or prevention of vertical transmission of HIV - 1 infection , but these drugs may increase the long - term risks for cancer and mitochondrial disease through induction of persistent genetic , epigenetic , and mitochon - drial alterations [ IARC , 2000 ; Wutzler and Thust , 2001 ; Poirier et al . , 2004 ; Kohler and Lewis , 2007 ; Wogan , 2007 ] . AZT alone or in combination with 3TC gives rise to host cell DNA incorporation of the NRTIs , heterochro - matin defects , telomeric attrition , clastogenic effects , re - porter / cancer gene mutations , and mitochondrial DNA mutations and damage / dysfunction in humans , animal models , and"
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    ABSTRACT: The events or factors that lead from normal cell function to conditions and diseases such as aging or cancer reflect complex interactions between cells and their environment. Cellular stress responses, a group of processes involved in homeostasis and adaptation to environmental change, contribute to cell survival under stress and can be resolved with damage avoidance or damage tolerance outcomes. To investigate the impact of environmental agents/conditions upon cellular stress response outcomes in epithelium, a novel quantitative assay, the "stress response resolution" (SRR) assay, was developed. The SRR assay consists of pretreatment with a test agent or vehicle followed later by a calibrated stress conditions exposure step (here, using 6-thioguanine). Pilot studies conducted with a spontaneously-immortalized murine mammary epithelial cell line pretreated with vehicle or 20 µg N-ethyl-N-nitrososurea/ml medium for 1 hr, or two hTERT-immortalized human bronchial epithelial cell lines pretreated with vehicle or 100 µM zidovudine/lamivudine for 12 days, found minimal alterations in cell morphology, survival, or cell function through 2 weeks post-exposure. However, when these pretreatments were followed 2 weeks later by exposure to calibrated stress conditions of limited duration (for 4 days), significant alterations in stress resolution were observed in pretreated cells compared with vehicle-treated control cells, with decreased damage avoidance survival outcomes in all cell lines and increased damage tolerance outcomes in two of three cell lines. These pilot study results suggest that sub-cytotoxic pretreatments with chemical mutagens have long-term adverse impact upon the ability of cells to resolve subsequent exposure to environmental stressors. Environ. Mol. Mutagen. 00:000-000, 2013. © 2013 Wiley Periodicals, Inc.
    Environmental and Molecular Mutagenesis 05/2013; 54(4). DOI:10.1002/em.21772 · 2.63 Impact Factor
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    • "Zidovudine (AZT or 3′-azido-2′,3′-dideoxythymidine) was the first nucleoside reverse transcriptase inhibitor (NRTI) used to treat HIV-1 infection and to reduce vertical transmission of the virus during pregnancy, and the largest body of data showing the potential for NRTIs to induce long-term side effects pertains to AZT (reviewed in [IARC, 2000; Wutzler and Thust, 2001; Dagan et al., 2002; Poirier et al., 2004; NTP, 2006; Kohler and Lewis, 2007; Walker and Poirier, 2007]). Phillips et al. [1991] reported that in vivo exposure of mice to AZT caused significant increases in micronucleated cells in bone marrow; since then additional studies have described the DNA damaging effects, clastogenicity, mutagenicity, and carcinogenicity of AZT and other NRTIs in animal models and humans [Olivero et al., 1997, 1999; Bonnet et al., 2004; Poirier et al., 2004; Brock et al. 2006; NTP, 2006; Escobar et al., 2007; Meng et al., 2007; Walker et al., 2007; Witt et al., 2007]. Previous work showed that in vitro and in vivo exposure of cells to AZT caused significant increases in mutations in reporter genes and in genes associated with neoplastic transformation (reviewed in [Walker and Poirier, 2007]). "
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    ABSTRACT: The success of nucleoside reverse transcriptase inhibitors (NRTIs) in treating HIV-1 infection and reducing mother-to-child transmission of the virus during pregnancy is accompanied by evidence that NRTIs cause long-term health risks for cancer and mitochondrial disease. Thus, agents that mitigate toxicities of the current combination drug therapies are needed. Previous work had shown that the NRTI-drug pair zidovudine (AZT)-didanosine (ddI) was highly cytotoxic and mutagenic; thus, we conducted preliminary studies to investigate the ability of the active moiety of amifostine, WR1065, to protect against the deleterious effects of this NRTI-drug pair. In TK6 cells exposed to 100 muM AZT-ddI (equimolar) for 3 days with or without 150 muM WR1065, WR1065 enhanced long-term cell survival and significantly reduced AZT-ddI-induced mutations. Follow-up studies were conducted to determine if coexposure to AZT and WR1065 abrogated the antiretroviral efficacy of AZT. In human T-cell blasts infected with HIV-1 in culture, inhibition of p24 protein production was observed in cells treated with 10 muM AZT in the absence or presence of 5-1,000 muM WR1065. Surprisingly, WR1065 alone exhibited dose-related inhibition of HIV-1 p24 protein production. WR1065 also had antiviral efficacy against three species of adenovirus and influenza A and B. Intracellular levels of unbound WR1065 were measured following in vitro/in vivo drug exposure. These pilot study results indicate that WR1065, at low intracellular levels, has cytoprotective and antimutagenic activities against the most mutagenic pair of NRTIs and has broad spectrum antiviral effects. These findings suggest that the activities have a possible common mode of action that merits further investigation.
    Environmental and Molecular Mutagenesis 07/2009; 50(6):460-72. DOI:10.1002/em.20482 · 2.63 Impact Factor
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