The overall goal of this program is to investigate the role of DNA repair in chemotherapy resistance, particularly resistance to DNA damaging agents. In each project, investigators will seek to exploit molecular technology either to investigate the relationship of DNA repair protein expression to resistance of cells t alkylating agents and chemotherapy- induced oxidative damage, or to effect resistance in cells to chemotherapy in preclinical or clinical studies. Goals specifically include new approaches to the treatment of brain tumors, lymphomas, childhood solid tumors, and the pre-cancerous genetic condition, Fanconi Anemia. Individual projects explore the use of retroviral vectors and transgenic mice to effect resistance to chloroethylnitrosoureas (CENU) and other alkylating agents, such as, streptozotocin, bleomycin and cyclophosphamide. A clinical trial using gene transfer technology in patients with high risk brain tumors is proposed. An additional approach to increasing therapeutic effectiveness involves selective depletion of tumor cell DNA repair capacity, which is developed in this proposal in both pre-clinical and clinical studies. Since the organs of toxicity of intensive chemotherapy with both CENUs and other alkylating agents are the bone marrow and lung, the program also explores the role of DNA repair protein expression in these organs in protection from the cytotoxic actions of several alkylating agents. In addition, oxidative DNA damage due to chemotherapy is studied utilizing cells from patients with Fanconi Anemia as a model. The proposed research plan draws upon a group of experienced and well-funded investigators with diverse but complimentary experience in DNA repair, hematopoiesis, molecular biology, vector technology, pharmacology, and lung biology. The program seeks to weave these interests and expertise into a cohesive and interrelated research plan which can produce innovative approaches to the treatment of human cancer.
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