Shekhar Tanmay M, Green Maja M, Rayner David M, Miles Mark A, Cutts Suzanne M, Hawkins Christine J
Department of Biochemistry, La Trobe Institute for Molecular Science, La Trobe University, Bundoora 3083, Australia.
Department of Biochemistry, La Trobe Institute for Molecular Science, La Trobe University, Bundoora 3083, Australia; Department of Anatomy & Neuroscience, The University of Melbourne, Parkville 3010, Australia.
Mutat Res. 2015 Jul;777:23-32. doi: 10.1016/j.mrfmmm.2015.04.005. Epub 2015 Apr 15.
Chemotherapy and radiotherapy can cause permanent damage to the genomes of surviving cells, provoking severe side effects such as second malignancies in some cancer survivors. Drugs that mimic the activity of death ligands, or antagonise pro-survival proteins of the Bcl-2 or IAP families have yielded encouraging results in animal experiments and early phase clinical trials. Because these agents directly engage apoptosis pathways, rather than damaging DNA to indirectly provoke tumour cell death, we reasoned that they may offer another important advantage over conventional therapies: minimisation or elimination of side effects such as second cancers that result from mutation of surviving normal cells. Disappointingly, however, we previously found that concentrations of death receptor agonists like TRAIL that would be present in vivo in clinical settings provoked DNA damage in surviving cells. In this study, we used cell line model systems to investigate the mutagenic capacity of drugs from two other classes of direct apoptosis-inducing agents: the BH3-mimetic ABT-737 and the IAP antagonists LCL161 and AT-406. Encouragingly, our data suggest that IAP antagonists possess negligible genotoxic activity. Doses of ABT-737 that were required to damage DNA stimulated Bax/Bak-independent signalling and exceeded concentrations detected in the plasma of animals treated with this drug. These findings provide hope that cancer patients treated by BH3-mimetics or IAP antagonists may avoid mutation-related illnesses that afflict some cancer survivors treated with conventional DNA-damaging anti-cancer therapies.
化疗和放疗可对存活细胞的基因组造成永久性损伤，在一些癌症幸存者中引发严重的副作用，如二次恶性肿瘤。模拟死亡配体活性或拮抗Bcl-2或IAP家族促生存蛋白的药物，在动物实验和早期临床试验中已取得了令人鼓舞的结果。由于这些药物直接作用于凋亡途径，而非通过损伤DNA间接引发肿瘤细胞死亡，我们推断它们可能比传统疗法具有另一个重要优势：将因存活的正常细胞发生突变而导致的二次癌症等副作用降至最低或消除。然而，令人失望的是，我们之前发现，临床环境中体内存在的死亡受体激动剂（如TRAIL）的浓度会在存活细胞中引发DNA损伤。在本研究中，我们使用细胞系模型系统来研究另外两类直接诱导凋亡药物的致突变能力：BH3模拟物ABT-737以及IAP拮抗剂LCL161和AT-406。令人鼓舞的是，我们的数据表明IAP拮抗剂具有可忽略不计的基因毒性活性。损伤DNA所需的ABT-737剂量刺激了不依赖Bax/Bak的信号传导，且超过了用该药物治疗的动物血浆中检测到的浓度。这些发现为接受BH3模拟物或IAP拮抗剂治疗的癌症患者带来了希望，他们可能避免患上一些接受传统DNA损伤抗癌疗法治疗的癌症幸存者所遭受的与突变相关的疾病。
