PT - JOURNAL ARTICLE AU - Horton, Terzah M. AU - Jenkins, Gaye AU - Pati, Debananda AU - Zhang, Linna AU - Dolan, M. Eileen AU - Ribes-Zamora, Albert AU - Bertuch, Alison A. AU - Blaney, Susan M. AU - Delaney, Shannon L. AU - Hegde, Madhuri AU - Berg, Stacey L. TI - Poly(ADP-ribose) polymerase inhibitor ABT-888 potentiates the cytotoxic activity of temozolomide in leukemia cells: influence of mismatch repair status and <em>O</em><sup>6</sup>-methylguanine-DNA methyltransferase activity AID - 10.1158/1535-7163.MCT-09-0142 DP - 2009 Aug 01 TA - Molecular Cancer Therapeutics PG - 2232--2242 VI - 8 IP - 8 4099 - http://mct.aacrjournals.org/content/8/8/2232.short 4100 - http://mct.aacrjournals.org/content/8/8/2232.full SO - Mol Cancer Ther2009 Aug 01; 8 AB - The poly(ADP-ribose) polymerase (PARP) inhibitor ABT-888 potentiates the antitumor activity of temozolomide (TMZ). TMZ resistance results from increased O6-methylguanine-DNA methyltransferase (MGMT) activity and from mismatch repair (MMR) system mutations. We evaluated the relative importance of MGMT activity, MMR deficiency, nonhomologous end joining (NHEJ), and PARP activity in ABT-888 potentiation of TMZ. MMR-proficient and MMR-deficient leukemia cells with varying MGMT activity, as well as primary leukemia samples, were used to determine TMZ IC50 alone and with ABT-888. ABT-888 effectively inhibited PARP activity and enhanced TMZ growth inhibition in most leukemia cells. ABT-888 potentiation was most effective in MMR-deficient cells with low MGMT activity [potentiation factor (PF) = 21]. ABT-888 also potentiated TMZ activity in MMR-deficient cells with elevated MGMT activity. Unexpectedly, ABT-888 also enhanced TMZ activity in MMR-proficient cells (PF = 3–7). ABT-888 potentiation was unrelated to NHEJ activity. ABT-888 potentiated TMZ (PF = 2–5) in two of four acute myeloid leukemia patient samples but showed little potentiation in primary acute lymphoblastic leukemia. In conclusion, although ABT-888 potentiation of TMZ was most pronounced in MMR-deficient cells with low MGMT activity, neither MMR proficiency nor MGMT overexpression completely abrogated ABT-888 potentiation of TMZ. [Mol Cancer Ther 2009;8(8):2232–42]