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Base Excision Repair as a Target for Improving Cancer Therapy with Oxaliplatin and Radiation

Although cancer therapies are designed for the treatment of tumours, they also have damaging effects in normal tissues in the body. Recent approaches to cancer research have targeted cellular processes that go wrong during the development of cancer, such as levels of the proteins involved in repairing DNA damage in cells. It is hoped that such targeted therapies will cause more damage to the cancer cells while reducing the amount of damage to normal body tissues.

There are a number of mechanisms acting to repair DNA damage within a cell. One of these, the base excision repair (BER) pathway, acts to repair various types of DNA damage, including that caused by the ionising radiation and alkylating agents used in the treatment of some cancers. Levels of one protein involved in the BER pathway, DNA polymerase beta, have been shown to be abnormal in as many as one third of cancers studied. The proposed research project will study the levels of DNA polymerase beta within cancer cells, including some isolated from cancers that are known to be resistant to chemotherapy and radiotherapy. In cells that contain altered levels of this protein, the effects of decreasing its concentration within the cell will be investigated. We will then study the effect of these alterations on the sensitivity of those cancer cells to chemotherapy and radiotherapy.

Later in this project, tissue samples will be obtained by the project supervisor from patients with cancer who are receiving chemotherapy and radiotherapy. The levels of DNA polymerase beta in these tissue samples will be correlated to the response of the cancer to therapy. Ultimately, it may be possible to target this protein in certain patients to improve the efficacy of existing cancer therapies.