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]