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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    • " 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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    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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    • "For ethical reasons, the current study did not include a treatment-control group of drug-naïve infants born to untreated HIV-1-infected mothers to assess the mutagenic potential of the fetal environment in the presence of maternal HIV-1 infection. In the United States, women are routinely treated with ARVs upon diagnosis of HIV-1 infection, making it problematic to address the degree to which fetal responses to " HIV-1 exposure, " in the absence of maternal ARV treatment, contributes to perinatal toxicities and long-term health risks in the offspring [Poirier et al., 2003, 2004; Funk et al., 2007]. Consequently, there is limited evidence that fetal responses and/or " HIV-1 exposure " damage mitochondria of fetal cells/ tissues, perhaps increasing the risk for mtDNA mutations. "
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