Myeloperoxidase (MPO) is found almost exclusively in granulocytes and immature myeloid cells. It plays a key role in the innate immune system, catalysing the formation of reactive oxygen species that are important in anti-microbial action, but MPO also oxidatively transforms the topoisomerase II (TOP2) poison etoposide to chemical forms that have elevated DNA damaging properties. TOP2 poisons such as etoposide are widely used anti-cancer drugs, but they are linked to cases of secondary acute myeloid leukaemias through a mechanism that involves DNA damage and presumably erroneous repair leading to leukaemogenic chromosome translocations. This leads to the possibility that myeloperoxidase inhibitors could reduce the rate of therapy-related leukaemia by protecting haematopoietic cells from TOP2 poison-mediated genotoxic damage while preserving the anti-cancer efficacy of the treatment. We show here that myeloperoxidase inhibition reduces etoposide-induced TOP2B-DNA covalent complexes and resulting DNA double-strand break formation in primary ex vivo expanded CD34⁺ progenitor cells and unfractionated bone marrow mononuclear cells. Since MPO inhibitors are currently being developed as anti-inflammatory agents this raises the possibility that repurposing of these potential new drugs could provide a means of suppressing secondary acute myeloid leukaemias associated with therapies containing TOP2 poisons.

中文翻译：

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髓过氧化物酶抑制可保护骨髓单核细胞免受 TOP2 毒物抗癌药物依托泊苷诱导的 DNA 损伤

髓过氧化物酶 (MPO) 几乎只存在于粒细胞和未成熟的骨髓细胞中。它在先天免疫系统中发挥着关键作用，催化活性氧的形成，这对于抗菌作用非常重要，但 MPO 还能将拓扑异构酶 II (TOP2) 毒物依托泊苷氧化转化为具有增强 DNA 损伤特性的化学形式。依托泊苷等 TOP2 毒物是广泛使用的抗癌药物，但它们通过一种涉及 DNA 损伤和可能导致白血病染色体易位的错误修复的机制与继发性急性髓性白血病病例相关。这导致髓过氧化物酶抑制剂可能通过保护造血细胞免受 TOP2 毒物介导的基因毒性损伤来降低治疗相关白血病的发生率，同时保留治疗的抗癌功效。我们在此表明​​，髓过氧化物酶抑制可减少依托泊苷诱导的 TOP2B-DNA 共价复合物，并减少原代体外扩增的 CD34 ⁺祖细胞和未分级骨髓单核细胞中 DNA 双链断裂的形成。由于目前正在开发 MPO 抑制剂作为抗炎剂，这增加了重新利用这些潜在新药的可能性，可以提供一种抑制与含有 TOP2 毒物的疗法相关的继发性急性髓性白血病的方法。