生物谷报道：围产期极有可能发生HIV母婴传播，如果置之不理，大约25％的婴儿会被HIV病毒感染。AZT （zidovudine）是一种核苷逆转录酶抑制剂（nucleoside reverse transcriptase inhibitor，NRTI），能够在非母乳喂养条件下，将HIV母婴传播风险降低到2％以下。
NRTI通过抑制病毒逆转录酶、并入病毒DNA、终止nascent strands而防止病毒复制。之前有研究人员发现，NRTI还可以并入宿主细胞的DNA，造成的破坏对宿主健康有长期影响。
最近，研究人员利用小鼠和大鼠动物模型，检测经胎盘暴露于AZT的癌变可能，结果显示肿瘤发生率上升，肿瘤中的基因变异在人类癌症中也经常出现。另外两项人类临床研究，对胚胎期接触过NRTI的婴儿，分别进行红细胞突变感应现象和大规模的基因组损伤研究。具体研究内容刊登于4月份《Environmental and Molecular Mutagenesis》。
Dale M. Walker等为处于妊娠最后7天的雌性小鼠和大鼠施加不同剂量的AZT，两年后对其后代进行组织学检测，结果发现后代小鼠中，雄性小鼠血管肉瘤(hemangiosarcoma)较多，雌性大鼠中单核细胞白血病较多。还有证据显示肝癌和生殖系统肿瘤发生率上升。文章作者说，尽管这些还不能证明胚胎期暴露于AZT会对人类婴儿的健康有长期影响，但这种引发癌症的可能性在部分儿童以及其稍后的成年阶段还是存在的。
环境科学环境卫生研究所（位于美国“三角创业园”，Research Triangle Park）研究人员Hue-Hua Hong，在小鼠研究中进一步证实AZT的致癌作用。Hong发现了在人类肺肿瘤中经常出现的K-ras 和p53 基因突变。这些小鼠的肺癌提示AZT或其代谢物并入DNA、氧化压力和遗传不稳定可能是所观察到的突变的成因。他们认为，“累计的突变数据说明，胚胎期接触过AZT的婴儿，长大后患癌风险上升。”
第一项人类临床研究中，匹兹堡大学Patricia A. Escobar率领的研究小组测量了新生儿血液中由AZT引起的DNA损伤，发现胚胎期接触过AZT外加lamivudine（另一种NRTI）的新生儿的红细胞中血型蛋白A的突变率上升。研究人员注意到尽管两种NRTI的联合使用能够更有效预防HIV母婴传播，但比单独使用AZT的遗传毒性更大。“有必要仔细检测围产期接受过AZT治疗的儿童的日后健康”，研制新型安全的NRTI，鉴定抗诱变药物需要减少NRTI的副作用。
部分英文原文：
Environmental and Molecular Mutagenesis
Volume 48, Issue 3-4 , Pages 299 - 306
Published Online: 4 Jan 2006
Genetic alterations in K-ras and p53 cancer genes in lung neoplasms from Swiss (CD-1) male mice exposed transplacentally to AZT
Hue-Hua L. Hong 1 *, June Dunnick 2, Ronald Herbert 1, Theodora R. Devereux 1, Yongbaek Kim 1, Robert C. Sills 1
1Laboratory of Experimental Pathology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina
2Toxicology Operations Branch, National Institute of Environmental HealthSciences, Research Triangle Park, North Carolina
email: Hue-Hua L. Hong (hong@niehs.nih.gov)
*Correspondence to Hue-Hua L. Hong, Molecular Pathology Group, Laboratory of Experimental Pathology, National Institute of Environmental Health Sciences, MD E1-07, 111 Alexander Drive, Research Triangle Park, NC 27709, USA
This article is a US Government work and, as such, is in the public domain in the United States of America.
Invited article on the genotoxicity of perinatal NRTI therapy.
Funded by:
National Institute of Health
National Institute of Environmental Health Sciences
Keywords
3-azido-3-deoxythymidine ?AZT ?transplacental carcinogenesis ?lung cancer ?Swiss mice ?K-ras oncogene ?p53 tumor suppressor gene
Abstract
A transplacental carcinogenicity study was conducted by exposing pregnant Swiss (CD-1) mice to 0, 50, 100, 200, or 300 mg of 3-azido-3-deoxythymidine (AZT)/kg bw/day, through a 18 to 19-day gestation [National Toxicology Program, NIH Pub. No. 04-4458, 2004]. The incidences of alveolar/bronchiolar adenomas and carcinomas, in the 200 and 300 mg/kg male treatment groups, were significantly greater than that of the controls. In the present study, we evaluated the benign and malignant lung neoplasms from this bioassay for point mutations, in the K-ras and p53 cancer genes that are often mutated in human lung tumors. K-ras and p53 mutations were detected by cycle sequencing of polymerase chain reaction-amplified DNA, isolated from formalin-fixed, paraffin-embedded neoplasms. K-ras mutations were detected in 25 of 38 (66%) of the AZT-induced lung tumors, and the predominant mutations were codon 12 GT transversions. p53 mutations were detected in 32 of 38 (84%) of the AZT-induced lung tumors, with the predominant mutations being exon 8, codon 285 AT transversions, and exon 6, codon 198 TA transversions. No K-ras or p53 mutations were detected in five tumors, examined from control mice. The patterns of mutations identified in the lung tumors suggest that incorporation of AZT or its metabolites into DNA, oxidative stress, and genomic instability may be the contributing factors to the mutation profile and development of lung cancer in these mice. Environ. Mol. Mutagen., 2006. Published 2006 Wiley-Liss, Inc.
