title: The PARP inhibitor, ABT-888 potentiates temozolomide: correlation with drug levels and reduction in PARP activity in vivo.
abstract: 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.
authors.affiliation: Abbott Laboratories, Cancer Research, Abbott Park, IL 60064, USA.
authors.forename: Joann P
authors.initials: JP
authors.lastname: Palma
authors.forename: Luis E
authors.initials: LE
authors.lastname: Rodriguez
authors.forename: Velitchka D
authors.initials: VD
authors.lastname: Bontcheva-Diaz
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Bouska
authors.forename: Gail
authors.initials: G
authors.lastname: Bukofzer
authors.forename: Milagros
authors.initials: M
authors.lastname: Colon-Lopez
authors.forename: Ran
authors.initials: R
authors.lastname: Guan
authors.forename: Kenneth
authors.initials: K
authors.lastname: Jarvis
authors.forename: Eric F
authors.initials: EF
authors.lastname: Johnson
authors.forename: Vered
authors.initials: V
authors.lastname: Klinghofer
authors.forename: Xuesong
authors.initials: X
authors.lastname: Liu
authors.forename: Amanda
authors.initials: A
authors.lastname: Olson
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Saltarelli
authors.forename: Yan
authors.initials: Y
authors.lastname: Shi
authors.forename: Jason A
authors.initials: JA
authors.lastname: Stavropoulos
authors.forename: Gui-Dong
authors.initials: GD
authors.lastname: Zhu
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Penning
authors.forename: Yan
authors.initials: Y
authors.lastname: Luo
authors.forename: Vincent L
authors.initials: VL
authors.lastname: Giranda
authors.forename: Saul H
authors.initials: SH
authors.lastname: Rosenberg
authors.forename: David J
authors.initials: DJ
authors.lastname: Frost
authors.forename: Cherrie K
authors.initials: CK
authors.lastname: Donawho
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000494:pharmacology*; D001562:Benzimidazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D004334:Drug Administration Schedule; D004357:Drug Synergism; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D000077204:Temozolomide
chemical_list: D001562:Benzimidazoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C521013:veliparib; D011064:Poly Adenosine Diphosphate Ribose; D003606:Dacarbazine; D011065:Poly(ADP-ribose) Polymerases; D000077204:Temozolomide