PARP inhibitor ABT-888 as potentiating agent for topoisomerase inhibitor SN-38

BRCA1 is a tumor suppressor gene that has been implicated as being involved in DNA repair through a process known as homologous recombination. Mutations in BRCA 1 have been linked to an increased risk of breast cancer, but recent studies have tried to use their knowledge of homologous recombination in order to find new ways to treat cancer. Most notably with poly(ADP-ribose) polymerase (PARP), it is an enzyme involved in the DNA repair of single strand breaks. If a cell is BRCA1 deficient it cannot repair its double strand breaks and if we inhibit PAR activity the cell cannot repair single strand breaks as a result the cell should accumulate damage and undergo apoptosis and die. The goal of the research is to investigate the role of PAR inhibition in BRCA1 deficient cells. We hypothesized that BRCA1 deficient cells should die at a lower dosage of PAR inhibiting drugs in cytotoxic tests. We also tested the efficiency of cytotoxic therapies as an effective means of treatment and tested the maximum dose tolerable before the cells became changed. We first used immunofluroescence to check for PAR activity in different types of cells and to then see the effects of PAR inhibition. We then used PAR inhibitor ABT-888, topoisomerase inhibitor SN-38, and cisplatin, a DNA binding agent, to conduct cytotoxic tests in order to prove our hypothesis true.M.S.Includes bibliographical references (p. 49-53)by Honeah Sohai