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 JOANN P. PALMA
A1 LUIS E. RODRIGUEZ
A1 VELITCHKA D. BONTCHEVA-DIAZ
A1 JENNIFER J. BOUSKA
A1 GAIL BUKOFZER
A1 MILAGROS COLON-LOPEZ
A1 RAN GUAN
A1 KENNETH JARVIS
A1 ERIC F. JOHNSON
A1 VERED KLINGHOFER
A1 XUESONG LIU
A1 AMANDA OLSON
A1 MARY J. SALTARELLI
A1 YAN SHI
A1 JASON A. STAVROPOULOS
A1 GUI-DONG ZHU
A1 THOMAS D. PENNING
A1 YAN LUO
A1 VINCENT L. GIRANDA
A1 SAUL H. ROSENBERG
A1 DAVID J. FROST
A1 CHERRIE K. DONAWHO
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.