Kurzfassung

Poisoning of topoisomerase II (TOP2) by anthracyclines or epipodophyllotoxins is the cornerstone of many anti-cancer therapies. The cytotoxic effect is attributed to the accumulation of permanent DNA double-stranded breaks (DSB) resulting in apoptosis. Our observations indicate that the cytotoxicity is contributed by expression changes of specific genes implicated e.g. in DNA repair. The aim of this project is to characterize the potential of these genes as targets for the development of more...Poisoning of topoisomerase II (TOP2) by anthracyclines or epipodophyllotoxins is the cornerstone of many anti-cancer therapies. The cytotoxic effect is attributed to the accumulation of permanent DNA double-stranded breaks (DSB) resulting in apoptosis. Our observations indicate that the cytotoxicity is contributed by expression changes of specific genes implicated e.g. in DNA repair. The aim of this project is to characterize the potential of these genes as targets for the development of more specific and therefore less toxic drugs mimicking TOP2 poisons. To this end, the TOP2 poisons-mediated gene expression changes will be identified in different cancer cell lines and expression of these genes will be manipulated by genome editing and RNAi interference in cellular and animal models of cancer. The effects will be investigated in the context of “hallmarks of cancer”. We also want to explore if the transcriptional repression of these genes may be responsible for the poorly understood radio-sensitization conferred to cancer cells by TOP2 poisons. Altogether the project is expected to explore specific, TOP2-mediated transcriptional programs to selectively target cancer cells.» weiterlesen» einklappen