MUTAGENICITY OF AZT IN CHILDREN OF HIV-INFECTED WOMEN

艾滋病毒感染妇女所生子女的 AZT 致突变性

• 批准号: 2421215
• 负责人: VERNON E WALKER
• 金额: $ 218.04万
• 依托单位: WADSWORTH CENTER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-11 至 2000-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2421215
• 关键词: AIDS therapy; DNA damage; HIV infections; chromosome aberrations; clinical research; embryo /fetus drug adverse effect; erythrocytes; gene mutation; glycophorin; human subject; hypoxanthine phosphoribosyltransferase; laboratory mouse; laboratory rat; lymphocyte; pediatric AIDS; vertical transmission; zidovudine

Zidovudine (AZT or ZDV) therapy has been shown to reduce the rate of maternal transmission of the human immunodeficiency virus (HIV) during pregnancy and delivery, but the long-term effects of perinatal treatment of infants is currently unknown. Because AZT produces DNA damage in several biological systems and is carcinogenic in rodents, long-term follow-up and assessment of the benefits and risks of therapy in infants should include an evaluation of the genotoxic potential of ZAT in these patients. In this study the researchers will use a set of molecular dose and effect biomarkers to determine the potential of AZT to act as a transplacental clastogen or mutagen in pregnant women at therapeutic doses, and to produce biological data that will improve the assessment of the long-term genetic risks of AZT therapy in children and adults. The genotoxic potential of in utero AZT therapy will be valuated by scoring chromosome aberrations (CAS) in lymphocytes and measuring the frequency of somatic mutations (Mfs) at the hypoxanthine-guanine phosphoribosyltransferase (HPRT) locus in T-cells and the glycophorin A (GPA) locus in erythrocytes of cord blood specimens from newborn children of: (I) HIV-infected women treated with AZT during pregnancy and delivery (AZT-treated group); (ii) HIV-infected women not given AZT (AZT- control group); and (iii) uninfected women (control-control group), with n+50/group. These date will be correlated with the plasma concentrations of AZT and the levels of AZT incorporation in cord WBC DNA, and in T-cells from AZT-exposed rodents, quantified by RIA. The potential confounding effects of substance use by the mothers will be assessed by way of interview information, medical histories, and screening for cotinine in cord blood plasma. In children with evidence of AZT-induced genotoxicity at birth, the persistence of these effects will be assessed by measuring CAs and HPRT and GPA Mfs in peripheral blood samples collected 12 months postpartum. Concurrent with these pediatric studies, the HPRT assay will also be used to examine mutations (I) in human lymphoblastoid cells exposed to AZT in vitro and (ii) in mice and rats receiving AZT doses ranging from therapeutic (in Humans) to carcinogenic (in rodents). Finally molecular methods (e.g., Southern blot and mismatch amplification mutation assays) will be developed to detect specific, frequently occurring mutations (i.e., "hotspots") found in AZT-treated human cells and then used to screen for these characteristic mutations in AZT-exposed rodents and children.

Zidovudine（AZT或ZDV）疗法已显示可降低速率 人类免疫缺陷病毒（HIV）的母体传播 在怀孕和分娩期间，但围产期的长期影响 婴儿的治疗目前尚不清楚。 因为AZT会产生 DNA损伤在几种生物系统中，并且具有致癌性 啮齿动物，长期随访以及对利益和风险的评估 婴儿的治疗应包括对遗传毒性的评估 这些患者的ZAT潜力。 在这项研究中，研究人员将 使用一组分子剂量和影响生物标志物来确定 AZT充当移植层或诱变的潜力 以治疗剂量的孕妇，并产生生物学数据 这将改善对AZT长期遗传风险的评估 儿童和成人的治疗。 子宫内的遗传毒性潜力 AZT疗法将通过得分染色体畸变来评估 （CAS）在淋巴细胞中，测量体细胞频率 低黄嘌呤 - 菜鸟磷脂转移酶的突变（MFS） （HPRT）T细胞中的基因座和糖蛋白A（GPA）基因座 来自新生孩子的脐带血标本的红细胞：（i） 怀孕和分娩期间接受AZT治疗的艾滋病毒感染的妇女 （AZT处理的组）； （ii）未给予AZT的HIV感染妇女（AZT- 对照组）; （iii）未感染的妇女（对照控制组）， 与N+50/组。 这些日期将与等离子体相关 AZT的浓度和绳索中AZT的水平 WBC DNA和来自AZT暴露啮齿动物的T细胞，由 RIA。 物质使用的潜在混杂作用 将通过面试信息，医疗来评估母亲 历史，并在脐带血等离子体中筛选可替宁。 在儿童中 有了AZT诱导的遗传毒性出生时的证据， 这些效果将通过测量CAS和HPRT和GPA来评估 外周血样本中的MFS产后12个月。 与这些儿科研究同时，HPRT分析也将是 用于检查暴露于人淋巴母细胞细胞中的突变（i） 在接受AZT剂量的小鼠和大鼠的体外和（ii）到AZT 从治疗（人类）到致癌（啮齿动物）。 最后 分子方法（例如，南部印迹和不匹配放大 突变测定）将开发以检测特定的，经常 在AZT处理的人类中发现的突变（即“热点”） 细胞，然后用于筛选这些特征突变 AZT暴露的啮齿动物和儿童。