PT  - JOURNAL ARTICLE
AU  - PALMA, JOANN P.
AU  - RODRIGUEZ, LUIS E.
AU  - BONTCHEVA-DIAZ, VELITCHKA D.
AU  - BOUSKA, JENNIFER J.
AU  - BUKOFZER, GAIL
AU  - COLON-LOPEZ, MILAGROS
AU  - GUAN, RAN
AU  - JARVIS, KENNETH
AU  - JOHNSON, ERIC F.
AU  - KLINGHOFER, VERED
AU  - LIU, XUESONG
AU  - OLSON, AMANDA
AU  - SALTARELLI, MARY J.
AU  - SHI, YAN
AU  - STAVROPOULOS, JASON A.
AU  - ZHU, GUI-DONG
AU  - PENNING, THOMAS D.
AU  - LUO, YAN
AU  - GIRANDA, VINCENT L.
AU  - ROSENBERG, SAUL H.
AU  - FROST, DAVID J.
AU  - DONAWHO, CHERRIE K.
TI  - The PARP Inhibitor, ABT-888 Potentiates Temozolomide: Correlation with Drug Levels and Reduction in PARP Activity <em>In Vivo</em>
DP  - 2008 Sep 01
TA  - Anticancer Research
PG  - 2625--2635
VI  - 28
IP  - 5A
4099  - http://ar.iiarjournals.org/content/28/5A/2625.short
4100  - http://ar.iiarjournals.org/content/28/5A/2625.full
SO  - Anticancer Res2008 Sep 01; 28
AB  - 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.