Kurzfassung

Alkylating agents are ideal for the study of DNA damage triggered cell death, as the DNA lesions responsible for activating cell death along with the activated pathways have been elucidated in detail. This knowledge has, however, not completely explained why cells differ so significantly in their survival following the induction of equal levels of DNA lesions. The answer to this may be found in the epigenetic deregulation of components of the death execution or DNA repair pathways. As...Alkylating agents are ideal for the study of DNA damage triggered cell death, as the DNA lesions responsible for activating cell death along with the activated pathways have been elucidated in detail. This knowledge has, however, not completely explained why cells differ so significantly in their survival following the induction of equal levels of DNA lesions. The answer to this may be found in the epigenetic deregulation of components of the death execution or DNA repair pathways. As epigenetic deregulation often occurs during malignant transformation this would have the biggest impact in cancer cells, as epigenetic silencing of components of death pathways and mismatch recognition would lead to anticancer drug resistance and silencing of repair genes to drug sensitivity. However, whether or not reversal of epigenetic silencing has any effect on the intrinsic alkylating agent sensitivity of cancer cells is still a matter of debate. In this project we address this question in two cancer models known to be subject to epigenetic deregulation, namely malignant melanoma and glioblastoma. Using histone deacetylase inhibitors (HDACi) in combination with alkylating anti-cancer drugs like temozolomide and fotemustine we plan to determine the phenotypical and mechanistic interaction of these drugs. Specific questions that will be addressed in this project are the following: 1) Will the modulation of the cell death pathways have an effect on the sensitivity of cancer cells to alkylating agents? 2) Do HDACi have an influence on the repair of alkylating agent-induced DNA lesions? 3) Do HDACi have an influence on the death pathways triggered by alkylating agent-induced DNA lesions? 4) What are the molecular interactions between the different treatment moieties?» weiterlesen» einklappen