Kurzfassung

Topoisomerase II (TOP2) alpha (A) and beta (B) modulate DNA topology by generating transient double-stranded DNA breaks. TOP2 poisons stabilize the TOP2-DNA complex and prevent re-ligation of DNA breaks, ultimately triggering cellular death. The efficacy of these and other classic anti-DNA or antimitotic cancer drugs is individually variable and additionally compromised by toxicity towards normal tissues. Our unpublished data indicate that the DNA damage evoked by TOP2 poisons etoposide...Topoisomerase II (TOP2) alpha (A) and beta (B) modulate DNA topology by generating transient double-stranded DNA breaks. TOP2 poisons stabilize the TOP2-DNA complex and prevent re-ligation of DNA breaks, ultimately triggering cellular death. The efficacy of these and other classic anti-DNA or antimitotic cancer drugs is individually variable and additionally compromised by toxicity towards normal tissues. Our unpublished data indicate that the DNA damage evoked by TOP2 poisons etoposide (VP16) or doxorubicin suppresses the expression of specific genes expressed at high levels in cancer cells. This is consistent with the emerging role of TOP2 in transcriptional regulation, e.g. via the recruitment of RNA polymerase II. Furthermore, some of gene repressions evoked by TOP2 poisons contribute to the cancer-cell killing effect of these drugs. These observations raise the prospect of developing drugs mimicking the transcriptional and clinical effects of TOP2 poisons but less toxic towards normal cells. Such drugs, acting synergistically to TOP2 poisons, could be used to reduce the dose of TOP2 poisons and to overcome the partial or total resistance to TOP2 poisons. The purpose of this project is to validate the concept of transcriptional repressions contributing to the efficacy of TOP2 poisons on a selected cancer entity (acute myeloid leukemia, AML) and to explore this concept’s applicability to other cancer entities and other classic anticancer drugs by identifying global transcriptional changes in response to VP16 and using using an innovative combination of publicly available cancer-related gene expression, gene function, and drug response resources.» weiterlesen» einklappen