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首页> 外文期刊>Neoplasia: an international journal for oncology research >The Combined Use of Known Antiviral Reverse Transcriptase Inhibitors AZT and DDI Induce Anticancer Effects at Low Concentrations
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The Combined Use of Known Antiviral Reverse Transcriptase Inhibitors AZT and DDI Induce Anticancer Effects at Low Concentrations

机译：已知的抗病毒逆转录酶抑制剂AZT和DDI的结合使用在低浓度下诱导抗癌效果

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摘要

A hallmark of tumor cell survival is the maintenance of elongated telomeres. It is known that antiviral reverse transcriptase inhibitors (RTIs) such as azidothymidine (AZT) and didanosine (ddI) lead to telomere shortening at high, potentially toxic concentrations. We hypothesized that those drugs might have synergistic effects enabling successful therapy with low, nontoxic concentrations. Biologic effects of AZT and ddI were analyzed at concentrations that correspond to minimal plasma levels achieved during human immunodeficiency virus therapy. Long-term coapplication of low-dose AZT and ddI induced a significant shortening of telomeres in the tumor cell lines HCT-116, SkMel-28, MelJuso, and Jurkat. Treatment of cells with both RTI, but not with single RTI, led to a significant accumulation of γH2AX, to p53 phosphorylation, and to cell apoptosis in all cell lines. Oral low-dose dual RTI application but not low-dose single RTI application was associated with a significantly reduced tumor growth of HCT-116 cells in mice. This antiproliferative activity of the combined use of AZT and ddI at low, clinically applicable concentrations warrants clinical testing in human solid cancer.
机译：肿瘤细胞存活的标志是维持细长端粒。众所周知，抗病毒逆转录酶抑制剂（RTIS）如氮化胸苷（AZT）和脱胺（DDI）导致以高潜在毒性浓度的端粒缩短。我们假设这些药物可能具有协同效应，使得能够成功治疗低毒性浓度。以对应于人类免疫缺陷病毒治疗期间实现的最小血浆水平的浓度分析AZT和DDI的生物学效应。低剂量AZT和DDI的长期渗透诱导肿瘤细胞系HCT-116，SKMEL-28，MELJUSO和Jurkat中的端粒缩短。用RTI处理细胞，但不用单一的脂肪，导致γH2AX的显着积累，达到P53磷酸化，并在所有细胞系中的细胞凋亡。口服低剂量双RTI应用但不是低剂量单RTI应用与小鼠中HCT-116细胞的显着降低的肿瘤生长有关。这种抗增殖活性的AZT和DDI在低，临床上适用的浓度下的抗溶剂活性可证在人类实体癌症中临床测试。

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