Incorporation of zidovudine into leukocyte DNA from HIV-1-positive adults and pregnant women, and cord blood from infants exposed in utero
Incorporation of zidovudine into leukocyte DNA from HIV-1-positive adults and pregnant women, and cord blood from infants exposed in utero
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DOI：
10.1097/00002030-199905280-00007
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发表时间：
1999-05-28
期刊：
影响因子：
3.8
通讯作者：
Poirier, MC
中科院分区：
文献类型：
--
作者：
Olivero, OA;Shearer, GM;Poirier, MC
目的：核苷类似物3‘-叠氮-3’-脱氧胸腺嘧啶核苷(ZDV)在临床上有广泛的应用，但在宫内暴露的新生小鼠中也具有致癌作用，并被整合到新生小鼠的DNA中。设计：在这项前瞻性队列研究中，从28名接受ZDV治疗的非妊娠成人和12名接受ZDV治疗的孕妇、6名未接触ZDV的未怀孕成年人和6名上次接受ZDV治疗大于或等于6个月的未怀孕成年人获得外周血单个核细胞(PBMC)。此外，从22名HIV-1阳性、接触ZDV的婴儿和12名未接触ZDV的婴儿中提取脐带血白细胞。方法：从未接种ZDV的HIV-1阳性成人、孕期服用ZDV的HIV-1阳性孕妇和未服用ZDV的成人的PBMC中提取DNA。检测了宫内感染ZDV的婴儿和未接触ZDV的婴儿的脐血白细胞。结果：大多数ZDV感染者(76%)、孕妇(8/12)、未孕成人(24/28)或分娩婴儿(15/22)的ZDV-DNA水平可检测到。ZDV处理的成人和婴儿的阳性值范围分别为25-544和22-452个ZDV/10(6)核苷酸。对11对母婴的分析显示，ZDV-DNA在两对母婴中的掺入程度都不同，与母婴对或孕期药物治疗时间没有相关性。被指定为对照的24份样本中，有两份抗ZDV RIA呈阳性。成人和婴儿ZDV-DNA值的20倍范围表明ZDV的磷酸化存在很大的个体差异。结论：在大多数ZDV暴露的成人和婴儿样本中检测到ZDV掺入DNA。因此，应在大量HIV阳性人群中进一步研究ZDV-DNA损伤的生物学意义和潜在的后续事件，如致突变性。在人类中，ZDV并入DNA的个体间变异性很大，与报告的ZDV-三磷酸形成的变异性一致，(C)1999年Lippincott Williams&Wilkins。
Objective: The nucleoside analog 3'-azido-3'-deoxythymidine (ZDV) has widespread clinical use but also is carcinogenic in newborn mice exposed to the drug in utero and becomes incorporated into newborn mouse DNA. This pilot study was designed to determine ZDV incorporation into human blood cell DNA from adults and newborn infants.Design: in this prospective cohort study, peripheral brood mononuclear cells (PBMC) were obtained from 28 non-pregnant adults and 12 pregnant women given ZDV therapy, six non-pregnant adults with no exposure to ZDV, and six non-pregnant adults who last received ZDV greater than or equal to 6 months previously. In addition, cord blood leukocytes were obtained from 22 infants of HIV-1-positive, ZDV-exposed women and from 12 infants unexposed to ZDV. There were 11 mother-infant pairs involving HIV-1-positive women.Methods: DNA was extracted from PBMC obtained from non-pregnant HIV-1-positive adults taking ZDV, pregnant HIV-1-positive women given ZDV during pregnancy, and from adults not taking ZDV. Cord blood leukocytes were examined from infants exposed to ZDV in utero and from unexposed controls. DNA samples were assayed for ZDV incorporation by anti-ZDV radioimmunoassay (RIA).Results: The majority (76%) of samples from ZDV-exposed individuals, pregnant women (8 of 12), non-pregnant adults (24 of 28), or infants at delivery (15 of 22), had detectable ZDV-DNA levels. The range of positive values far ZDV-treated adults and infants was 25-544 and 22-452 molecules ZDV/10(6) nucleotides, respectively. Analysis of 11 mother-infant pairs showed variable ZDV-DNA incorporation in both, with no correlation by pair or by duration of drug treatment during pregnancy. Two of the 24 samples from individuals designated as controls were positive by anti-ZDV RIA. The 20-fold range for ZDV-DNA values in both adults and infants suggested large interindividual differences in ZDV phosphorylation.Conclusions: Incorporation of ZDV into DNA was detected in most of the samples from ZDV-exposed adults and infants. Therefore, the biologic significance of ZDV-DNA damage and potential subsequent events, such as mutagenicity, should be Further investigated in large cohorts of HIV-positive individuals. The interindividual variability of ZDV incorporation into DNA in humans is considerable and consistent with reported variability in the formation of the ZDV-trisphosphate, (C) 1999 Lippincott Williams & Wilkins.