Poly(ADP-ribose) polymerase (PARP) is essential in recognizing DNA-damage and facilitating DNA repair. This is consistent with the observation that PARP-1/-2 knockout mice have increased sensitivity to DNA damaging agents including radiation. Therefore, inhibition of PARP should enhance the efficacy of chemotherapeutic agents by increasing the extent of DNA damage. ABT-888 is a potent, orally bioavailable PARP-1/-2 inhibitor (Ki 2-2.5 nM). ABT-888 has been shown to potentiate the activity of DNA damaging agents in a variety of preclinical models. The ability of ABT-888 to enhance the antitumor efficacy of temozolomide (TMZ) was evaluated in the current study. ABT-888 showed significant potentiation of TMZ in vivo in a dose-responsive manner with no observed toxicity. In the B16F10 model, TMZ as a single agent demonstrated significant efficacy (%TGI= 60-80), however, when TMZ and ABT-888 were administered in combination, significant improvement over TMZ alone was obtained (%TGI=75-93). As expected, ABT-888 did not show single agent activity in this model or other xenograft models evaluated. Various schedules of ABT-888 (administered prior to TMZ or overlaying several days prior to and/or after TMZ) showed no advantage in increasing potentiation compared to co-administration with TMZ. Pharmacokinetic levels (plasma and tumor) of ABT-888 correlated with antitumor efficacy. Moreover, in mice treated with ABT-888 at timepoints corresponding to the Cmax of ABT-888, intratumor drug levels also correlated with the significant poly(ADP-ribose)/PAR polymer inhibition in a dose-proportional/time-dependent manner as determined by ELISA. Overall, our studies demonstrated that the potentiation of TMZ activity by ABT-888 correlated with the plasma and tumor drug levels, as well as inhibition of a pharmacodynamic marker, PAR polymer, in this preclinical model. ABT-888 is currently being evaluated in clinical trials (CTEP/NCI) utilizing a PAR ELISA to assess the reduction in PAR/PARP activity in patients.
98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA