生物谷報道：圍產(chǎn)期極有可能發(fā)生HIV母嬰傳播,，如果置之不理,，大約25％的嬰兒會被HIV病毒感染,。AZT （zidovudine）是一種核苷逆轉(zhuǎn)錄酶抑制劑（nucleoside reverse transcriptase inhibitor,，NRTI）,，能夠在非母乳喂養(yǎng)條件下,，將HIV母嬰傳播風(fēng)險降低到2％以下。
NRTI通過抑制病毒逆轉(zhuǎn)錄酶,、并入病毒DNA,、終止nascent strands而防止病毒復(fù)制。之前有研究人員發(fā)現(xiàn),，NRTI還可以并入宿主細(xì)胞的DNA,，造成的破壞對宿主健康有長期影響。
最近,，研究人員利用小鼠和大鼠動物模型,，檢測經(jīng)胎盤暴露于AZT的癌變可能，結(jié)果顯示腫瘤發(fā)生率上升,，腫瘤中的基因變異在人類癌癥中也經(jīng)常出現(xiàn),。另外兩項人類臨床研究，對胚胎期接觸過NRTI的嬰兒,，分別進行紅細(xì)胞突變感應(yīng)現(xiàn)象和大規(guī)模的基因組損傷研究,。具體研究內(nèi)容刊登于4月份《Environmental and Molecular Mutagenesis》。
Dale M. Walker等為處于妊娠最后7天的雌性小鼠和大鼠施加不同劑量的AZT,，兩年后對其后代進行組織學(xué)檢測,，結(jié)果發(fā)現(xiàn)后代小鼠中，雄性小鼠血管肉瘤(hemangiosarcoma)較多,，雌性大鼠中單核細(xì)胞白血病較多,。還有證據(jù)顯示肝癌和生殖系統(tǒng)腫瘤發(fā)生率上升。文章作者說,，盡管這些還不能證明胚胎期暴露于AZT會對人類嬰兒的健康有長期影響,，但這種引發(fā)癌癥的可能性在部分兒童以及其稍后的成年階段還是存在的,。
環(huán)境科學(xué)環(huán)境衛(wèi)生研究所（位于美國“三角創(chuàng)業(yè)園”，Research Triangle Park）研究人員Hue-Hua Hong,，在小鼠研究中進一步證實AZT的致癌作用,。Hong發(fā)現(xiàn)了在人類肺腫瘤中經(jīng)常出現(xiàn)的K-ras 和p53 基因突變。這些小鼠的肺癌提示AZT或其代謝物并入DNA,、氧化壓力和遺傳不穩(wěn)定可能是所觀察到的突變的成因,。他們認(rèn)為，“累計的突變數(shù)據(jù)說明,，胚胎期接觸過AZT的嬰兒,，長大后患癌風(fēng)險上升。”
第一項人類臨床研究中,，匹茲堡大學(xué)Patricia A. Escobar率領(lǐng)的研究小組測量了新生兒血液中由AZT引起的DNA損傷,，發(fā)現(xiàn)胚胎期接觸過AZT外加lamivudine（另一種NRTI）的新生兒的紅細(xì)胞中血型蛋白A的突變率上升。研究人員注意到盡管兩種NRTI的聯(lián)合使用能夠更有效預(yù)防HIV母嬰傳播,，但比單獨使用AZT的遺傳毒性更大,。“有必要仔細(xì)檢測圍產(chǎn)期接受過AZT治療的兒童的日后健康”，研制新型安全的NRTI,，鑒定抗誘變藥物需要減少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 ([email protected])
*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.
