| dc.description.abstracteng | The DNA molecule stands at the center of cancer origin and treatment. Cancer cells are addicted to DNA mutations and DNA replication, therapeutic non-responders are often based on the rate of mutations and ability to replicate DNA. Conversely, DNA, being the most vulnerable spot of a tumor, is also the main target for chemotherapies. The in-depth understanding of cellular processes upon errors in the DNA genetic code is therefore crucial for designing new chemotherapeutic drugs and new combinations of drugs; specifically, it is the main endeavor to induce and exacerbate DNA damage in cancer cells. The combination of new small-molecule inhibitors with established chemotherapeutics, to increase their effect on the tumor and to decrease the side effects for the patient, is currently of great interest in preclinical and clinical research. In this work we have investigated a small-molecule inhibitor against the DNA damage response kinase MK2 that increases cytotoxicity of the DNA crosslinker cisplatin but relieves replicative stress upon co-treatment with the nucleoside analogue Gemcitabine. We verified these effects using both drugs in the same biological system, with a dependence on the cell cycle phase. Taken together, the combination of new compounds with established chemotherapeutic drugs is a very promising approach to benefit cancer patients, but the effects can vary dependent on the specific chemotherapeutic and should be applied in the clinics with great care. In another project we have further developed the idea of cyclotherapy, i.e. using a pharmacological pulse activation of a tumor suppressor to halt the cell cycle, which protects non-transformed cells, while targeting tumor suppressor mutated cancer cells with DNA damaging chemotherapeutics. We used a Click Chemistry reaction of the nucleoside analogue 5-Vinyl-2'-deoxyuridine (5-VdU) and a novel DNA-intercalator in a pretargeting approach, meaning the separation of the specific targeting component and the cytotoxic component of a drug. Moreover, we utilized Nutlin-3a to stabilize p53, arresting the cell cycle in p53 proficient cells. As a result, these cells did not incorporate 5-VdU and were not susceptible to the novel DNA-intercalator, while p53 -/- cells failed to be protected by Nutlin-3a. We thereby present a promising treatment scheme to target tumor suppressor mutated cells only, while sparing tumor suppressor wildtype cells. In summary, we present strategies to enhance the specificity and efficacy of existing chemotherapeutics, and novel compounds to selectively exacerbate DNA damage in cancer cells. | de |