TY - JOUR T1 - The PARP Inhibitor, ABT-888 Potentiates Temozolomide: Correlation with Drug Levels and Reduction in PARP Activity <em>In Vivo</em> JF - Anticancer Research JO - Anticancer Res SP - 2625 LP - 2635 VL - 28 IS - 5A AU - JOANN P. PALMA AU - LUIS E. RODRIGUEZ AU - VELITCHKA D. BONTCHEVA-DIAZ AU - JENNIFER J. BOUSKA AU - GAIL BUKOFZER AU - MILAGROS COLON-LOPEZ AU - RAN GUAN AU - KENNETH JARVIS AU - ERIC F. JOHNSON AU - VERED KLINGHOFER AU - XUESONG LIU AU - AMANDA OLSON AU - MARY J. SALTARELLI AU - YAN SHI AU - JASON A. STAVROPOULOS AU - GUI-DONG ZHU AU - THOMAS D. PENNING AU - YAN LUO AU - VINCENT L. GIRANDA AU - SAUL H. ROSENBERG AU - DAVID J. FROST AU - CHERRIE K. DONAWHO Y1 - 2008/09/01 UR - http://ar.iiarjournals.org/content/28/5A/2625.abstract N2 - 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. ER -