1. The PARP inhibitor, ABT-888 potentiates temozolomide: correlation with drug levels and reduction in PARP activity in vivo
- Author
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Joann P, Palma, Luis E, Rodriguez, Velitchka D, Bontcheva-Diaz, Jennifer J, Bouska, Gail, Bukofzer, Milagros, Colon-Lopez, Ran, Guan, Kenneth, Jarvis, Eric F, Johnson, Vered, Klinghofer, Xuesong, Liu, Amanda, Olson, Mary J, Saltarelli, Yan, Shi, Jason A, Stavropoulos, Gui-Dong, Zhu, Thomas D, Penning, Yan, Luo, Vincent L, Giranda, Saul H, Rosenberg, David J, Frost, and Cherrie K, Donawho
- Subjects
Dacarbazine ,Mice ,Poly Adenosine Diphosphate Ribose ,Cell Line, Tumor ,Antineoplastic Combined Chemotherapy Protocols ,Melanoma, Experimental ,Temozolomide ,Animals ,Benzimidazoles ,Drug Synergism ,Poly(ADP-ribose) Polymerase Inhibitors ,Poly(ADP-ribose) Polymerases ,Drug Administration Schedule - Abstract
ABT-888 is a potent, orally bioavailable PARP-1/2 inhibitor shown to potentiate DNA damaging agents. The ability to potentiate temozolomide (TMZ) and develop a biological marker for PARP inhibition was evaluated in vivo. Doses/schedules that achieve TMZ potentiation in the B16F10 syngeneic melanoma model were utilized to develop an ELISA to detect a pharmacodynamic marker, ADP ribose polymers (pADPr), after ABT 888 treatment. ABT-888 enhanced TMZ antitumor activity, in a dose-proportional manner with no observed toxicity (44-75% tumor growth inhibition vs. TMZ monotherapy), but did not show single agent activity. Extended ABT-888 dosing schedules showed no advantage compared to simultaneous TMZ administration. Efficacy correlated with plasma/tumor drug concentrations. Intratumor drug levels correlated with a dose-proportional/time-dependent reduction in pADPr. Potentiation of TMZ activity by ABT-888 correlated with drug levels and inhibition of PARP activity in vivo. ABT-888 is in Phase 1 trials using a validated ELISA based on the assay developed here to assess pharmacological effect.
- Published
- 2008