RT Journal Article
SR Electronic
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
FD International Institute of Anticancer Research
SP 2625
OP 2635
VO 28
IS 5A
A1 PALMA, JOANN P.
A1 RODRIGUEZ, LUIS E.
A1 BONTCHEVA-DIAZ, VELITCHKA D.
A1 BOUSKA, JENNIFER J.
A1 BUKOFZER, GAIL
A1 COLON-LOPEZ, MILAGROS
A1 GUAN, RAN
A1 JARVIS, KENNETH
A1 JOHNSON, ERIC F.
A1 KLINGHOFER, VERED
A1 LIU, XUESONG
A1 OLSON, AMANDA
A1 SALTARELLI, MARY J.
A1 SHI, YAN
A1 STAVROPOULOS, JASON A.
A1 ZHU, GUI-DONG
A1 PENNING, THOMAS D.
A1 LUO, YAN
A1 GIRANDA, VINCENT L.
A1 ROSENBERG, SAUL H.
A1 FROST, DAVID J.
A1 DONAWHO, CHERRIE K.
YR 2008
UL http://ar.iiarjournals.org/content/28/5A/2625.abstract
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.