Laboratory of Genetic Toxicity and Cellular Toxic-Genetic Analysis, Graduate Program in Molecular and Cellular Biology Applied to Health (PPGBioSaúde), Lutheran University of Brazil, Canoas, Brazil.
Institute of Biological Science, Federal University of Goiás, Goiás, Brazil.
Drug Chem Toxicol. 2020 Jul;43(4):429-434. doi: 10.1080/01480545.2018.1504959. Epub 2018 Sep 12.
Highly active antiretroviral therapy (HAART) regimens are based on the use of nucleoside reverse transcriptase inhibitors (NRTIs), which are the main drugs used by patients infected with the human immunodeficiency virus (HIV). The use of NRTIs combinations has afforded clear clinical benefits to patients undergoing HAART. However, the combination of two NRTIs may increase the risk of genomic instability in comparison with the drugs administered individually. We analyzed the ability of zidovudine (AZT) and lamivudine (3TC), and the combination AZT +3TC to induce complex genomic alterations using the cytokinesis-block micronucleus (CBMN) assay in Chinese hamster ovary (CHO)-K1 cells. The 24-h cell treatment with individual NRTIs showed that AZT increased micronucleus frequencies and nucleoplasmic bridges (NPBs). No significant differences were observed for any parameters investigated after exposure of CHO-K1 cells to 3TC. The combination AZT +3TC significantly increased micronucleus frequencies. Analysis of interaction between these drugs suggested that antagonism occurs in all AZT +3TC concentrations. These results highlight the importance to investigate the genotoxic profile of NRTIs to develop safer intervention strategies in antiretroviral treatment protocols.
高效抗逆转录病毒疗法（HAART）方案基于使用核苷逆转录酶抑制剂（NRTIs），这是感染人类免疫缺陷病毒（HIV）的患者使用的主要药物。NRTIs 联合使用为接受 HAART 的患者提供了明显的临床益处。然而，与单独使用药物相比，两种 NRTIs 的联合使用可能会增加基因组不稳定的风险。我们使用中国仓鼠卵巢（CHO）-K1 细胞中的胞质分裂阻断微核（CBMN）试验分析了齐多夫定（AZT）和拉米夫定（3TC）以及 AZT+3TC 联合使用对诱导复杂基因组改变的能力。单独使用 NRTIs 对细胞进行 24 小时处理后，AZT 增加了微核频率和核质桥（NPB）。暴露于 3TC 的 CHO-K1 细胞后，对于任何研究的参数均未观察到显著差异。AZT+3TC 联合使用显著增加了微核频率。这些药物之间相互作用的分析表明，在所有 AZT+3TC 浓度下均发生拮抗作用。这些结果强调了研究 NRTIs 的遗传毒性特征以开发更安全的抗逆转录病毒治疗方案中的干预策略的重要性。
