Meng Q, Walker D M, Olivero O A, Shi X, Antiochos B B, Poirier M C, Walker V E
Laboratory of Human Toxicology and Molecular Epidemiology, Wadsworth Center, New York State Department of Health, Albany, NY 12201, USA.
Proc Natl Acad Sci U S A. 2000 Nov 7;97(23):12667-71. doi: 10.1073/pnas.220203197.
Drug combinations that include nucleoside reverse transcriptase inhibitors (NRTIs) are remarkably effective in preventing maternal-viral transmission of HIV during pregnancy. However, there may be potential long-term risks for children exposed in utero. Examination of the genotoxic and mutagenic effects of two NRTIs, zidovudine [AZT (3'-azido-3'-deoxythymidine)] and didanosine [ddI (2',3'-dideoxyinosine)], in cultured human lymphoblastoid cells revealed multiplicative synergistic enhancement of AZT-DNA incorporation and mutant frequency induction in response to the combined drug exposure, as compared with single-drug exposures. Dose-related increases in DNA incorporation of AZT (as measured by a competitive RIA) and mutagenicity at the HPRT and TK loci (as assessed by cell-cloning assays) were observed in cells exposed in culture to AZT, or equimolar combinations of AZT + ddI, at exposure concentrations ranging from 3 to 30 times the maximum plasma levels found in humans. Because mutagenesis is strongly associated with tumor induction in experimental models, children exposed transplacentally to combinations of NRTIs may be at risk for cancer development later in life.
包含核苷类逆转录酶抑制剂（NRTIs）的药物组合在预防孕期HIV母婴病毒传播方面极为有效。然而，对于子宫内暴露的儿童可能存在潜在的长期风险。对两种NRTIs，齐多夫定[AZT（3'-叠氮-3'-脱氧胸苷）]和去羟肌苷[ddI（2'，3'-双脱氧肌苷）]在培养的人淋巴母细胞中的遗传毒性和诱变性进行检测发现，与单药暴露相比，联合药物暴露会使AZT-DNA掺入和突变频率诱导出现倍增协同增强效应。在培养中暴露于AZT或AZT + ddI等摩尔组合的细胞中，观察到AZT的DNA掺入（通过竞争性放射免疫分析测定）以及在HPRT和TK位点的诱变性（通过细胞克隆分析评估）随剂量增加，暴露浓度范围为人血浆最高水平的3至30倍。由于在实验模型中诱变与肿瘤诱导密切相关，经胎盘暴露于NRTIs组合的儿童在日后患癌症的风险可能增加。
