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.
Footnotes
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Abbreviations: TMZ, temozolomide; PARP, poly(ADP-ribose) polymerase; pADPr, poly(ADP-ribose) polymer; % TGI, % tumor growth inhibition; SSB, single-strand breaks; DSB, double-strand breaks; BER, base excision repair; HR, homologous repair; MMR, mismatch repair; OGAT, O6 methyguanine; PK/PD, pharmacokinetic/pharmacodynamic; mg/kg/d, milligrams per kilogram per day; q.d., drug administered once-a-day; b.i.d., drug administered twice-a-day, i.e. mg/kg/day b.i.d. dose is divided into two doses per day; DMEM, Dulbecco's minimal essential medium; FBS, fetal bovine serum; IACUC, Internal Institutional Animal Care and Use Committee; NIH, National Institutes of Health; s.c., subcutaneous; TBST, Tris buffered saline-0.05% Tween 20; γ-H2AX, phosphorylated H2AX; PBMCs, peripheral blood mononuclear cells.
- Received May 14, 2008.
- Revision received June 17, 2008.
- Accepted July 1, 2008.
- Copyright© 2008 International Institute of Anticaner Research (Dr. John G. Delinassios), All rights reserved
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