Improving Phenylbutyrate-based Anticancer Therapy

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DESCRIPTION (provided by applicant): The long-term goal of this work is to develop novel anticancer therapies that utilize inhibitors of histone deacetylases (HDACs) to sensitize tumors to anticancer treatments. Inhibition of HDACs results in chromatin remodeling and alteration of expression of several genes. HDAC inhibitor phenylbutyrate (PB) has been shown to sensitize glioma cells to ionizing radiation. A principal problem in this approach to chemotherapy is that PB treatment induces a G1 block that reduces the number of cells susceptible to radiation. I propose to use siRNA specific for p21 to release the G1 block and to test the cells in culture for sensitivity towards ionizing radiation as well chemotherapeutic agents. The goal of this work is to find an optimal combination therapy involving PB that is effective against gliomas. In the second part of this work, I will use a bioluminescence imaging system available at the University of Michigan to monitor tumors in live mice as they undergo apoptosis or undergo G1 arrest. This work will create the tools necessary for the monitoring of tumor cells in live animals when they are treated with PB as part of combination chemotherapy.