Myeloperoxidase enhances DNA damage induced by drugs targeting DNA topoisomerase II

Abstract

Topoisomerase II (TOP2) poisons are effective anti-cancer agents used to treat a wide range of neoplasms. However, TOP2 poisons are subjected to enzymatic conversion which leads to metabolites with altered DNA damaging properties. Myeloperoxidase, present exclusively within developing myeloid progenitors and granulocytes, is capable of the biotransformation of TOP2 poisons to metabolites that are potentially more genotoxic in nature. Whilst TOP2 poisons are valuable chemotherapeutic agents, their use is associated with myelosuppression and with the risk of developing therapy related acute myeloid leukaemia. The reason that myeloid progenitor cells are particularly susceptible to TOP2 poison associated genotoxicity is unclear, however the presence of myeloperoxidase could potentially make myeloid progenitor cells more vulnerable to TOP2 poison mediated damage. This lead to the hypothesis that myeloperoxidase inhibition could protect developing hematopoietic cells from TOP2 poison associated genotoxic and/or cytotoxic damage. Data generated in this thesis supports the proposed hypothesis as expression of myeloperoxidase significantly enhanced the accumulation of TOP2 poison induced TOP2-DNA covalent complexes and the level of DNA breaks within myeloid cell lines. The use of two potential clinically relevant inhibitors of myeloperoxidase showed that reduction in myeloperoxidase activity reduced the abundance of TOP2 poison stabilised TOP2-DNA complexes and DNA breaks. Furthermore, depletion of glutathione to mimic conditions experienced during chemotherapy, resulted in a myeloperoxidase dependent increase in TOP2 poison mediated DNA damage. Taken together these results show inhibition of myeloperoxidase could protect developing hematopoietic cells from TOP2 poison mediated damage without compromising the effectiveness of these drugs as antineoplastic agents.