The PARP inhibitor, ABT-888 potentiates temozolomide: correlation with drug levels and reduction in PARP activity in vivo
Palma, J.P.; Rodriguez, L.E.; Bontcheva-Diaz, V.D.; Bouska, J.J.; Bukofzer, G.; Colon-Lopez, M.; Guan, R.; Jarvis, K.; Johnson, E.F.; Klinghofer, V.; Liu, X.; Olson, A.; Saltarelli, M.J.; Shi, Y.; Stavropoulos, J.A.; Zhu, G.-D.; Penning, T.D.; Luo, Y.; Giranda, V.L.; Rosenberg, S.H.; Frost, D.J.; Donawho, C.K.
Anticancer Research 28(5a): 2625-2635
2008
ISSN/ISBN: 0250-7005 PMID: 19035287 Document Number: 618478
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.