Abstract
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]
- acute lymphocytic leukemia
- ALL
- acute myeloid leukemia
- AML
- base excision repair
- microsatellite instability
- mismatch repair
Footnotes
Grant support: K12 CA90433-04 (T.M. Horton), K23 CA113775 (T.M. Horton), Scott Carter NCCF Research Fellowship (T.M. Horton), Ladies Leukemia League (T.M. Horton), RO1 CA109478 (D. Pati), RO1 CA81485 (M.E. Dolan), and U01 CA63187 (University of Chicago Cancer Research Center). Pharmacologic studies were supported by the University of Chicago Cancer Research Center Pharmacology Core Facility (http://pharmacology.bsd.uchicago.edu/) through the University of Chicago Cancer Research Center Cancer Center Support Grant P30 CA14599.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Note: Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).
- Received February 16, 2009.
- Revision received May 6, 2009.
- Accepted June 2, 2009.
- © 2009 American Association for Cancer Research.
Volume 8, Issue 8
