MUTAGENICITY OF AZT IN CHILDREN OF HIV-INFECTED WOMEN

齐多夫定（AZT或ZDV）治疗已被证明可以降低 艾滋病毒（艾滋病毒）的母婴传播 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损伤在几个生物系统，是致癌的， 啮齿类动物，长期随访和获益与风险评估 婴儿治疗的评估应包括遗传毒性的评估。 这些患者中的ZAT潜力。 在这项研究中，研究人员将 使用一组分子剂量和效应生物标志物来确定 AZT作为经胎盘染色体断裂剂或诱变剂的潜力， 孕妇在治疗剂量，并产生生物数据 这将改善对AZT长期遗传风险的评估， 治疗儿童和成人。 子宫内的潜在遗传毒性 AZT治疗将通过染色体畸变评分进行评价 (CAS)在淋巴细胞和测量体细胞的频率 次黄嘌呤-鸟嘌呤磷酸核糖基转移酶突变（Mfs） T细胞中的HPRT基因座和T细胞中的血型糖蛋白A（GPA）基因座。 新生儿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妇女 （AZT治疗组）;（二）未服用AZT的艾滋病毒感染妇女（AZT- 对照组）;和（iii）未感染的妇女（对照-对照组）， n+50/组。 这些数据将与血浆 AZT浓度和脐带中AZT掺入水平 WBC DNA和来自AZT暴露的啮齿动物的T细胞中，通过 放免法 药物使用的潜在混杂效应 母亲将通过面谈信息、医疗信息、 病史和筛查脐带血血浆中的可替宁。 儿童 有证据表明AZT诱导的遗传毒性在出生时， 这些影响将通过测量CA、HPRT和GPA来评估 产后12个月采集外周血样本。 在这些儿科研究的同时，还将对HPRT测定进行研究。 用于检查暴露于以下物质的人淋巴母细胞中的突变（I） （二）在接受AZT剂量的小鼠和大鼠中， 从治疗性（人类）到致癌性（啮齿动物）。 最后 分子方法（例如，Southern印迹和错配扩增 突变检测）将被开发，以检测特定的，经常 发生突变（即，在AZT处理的人类中发现的“热点”） 细胞，然后用于筛选这些特征性突变， 接触AZT的啮齿动物和儿童。

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.