The PARP inhibitor, ABT-888 potentiates temozolomide: correlation with drug levels and reduction in PARP activity in vivo.
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.
Palma
Joann P
JP
Abbott Laboratories, Cancer Research, Abbott Park, IL 60064, USA.
Rodriguez
Luis E
LE
Bontcheva-Diaz
Velitchka D
VD
Bouska
Jennifer J
JJ
Bukofzer
Gail
G
Colon-Lopez
Milagros
M
Guan
Ran
R
Jarvis
Kenneth
K
Johnson
Eric F
EF
Klinghofer
Vered
V
Liu
Xuesong
X
Olson
Amanda
A
Saltarelli
Mary J
MJ
Shi
Yan
Y
Stavropoulos
Jason A
JA
Zhu
Gui-Dong
GD
Penning
Thomas D
TD
Luo
Yan
Y
Giranda
Vincent L
VL
Rosenberg
Saul H
SH
Frost
David J
DJ
Donawho
Cherrie K
CK
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
D001562:Benzimidazoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C521013:veliparib; D011064:Poly Adenosine Diphosphate Ribose; D003606:Dacarbazine; D011065:Poly(ADP-ribose) Polymerases; D000077204:Temozolomide