Vasoactivity of AG014699, a clinically active small molecule inhibitor of poly(ADP-ribose) polymerase: A contributory factor to chemopotentiation in vivo?

Abstract

Purpose: Poly(ADP-ribose) polymerase (PARP) plays an important role in DNA repair, and PARP inhibitorscan enhance the activity of DNA-damaging agents in vitro and in vivo. AG014699 isa potent PARP inhibitor in phase II clinical development. However, the range of therapeutics with which AG014699 could interact via a DNA-repair based mechanism is limited.Weaimed to investigate a novel, vascular-based activity ofAG014699, underlying in vivo chemosensitization, which could widen its clinical application. Experimental Design: Temozolomide response was analyzed in vitro and in vivo. Vessel dynamics were monitored using "mismatch" following the administration of perfusion markers and real-time analysis of fluorescently labeled albumin uptake in to tumors established in dorsal window chambers. Further mechanistic investigations used ex vivo assays of vascular smooth muscle relaxation, gut motility, and myosin light chain kinase (MLCK) inhibition. Results: AG014699 failed to sensitize SW620 cells to temozolomide in vitro but induced pronounced enhancement in vivo. AG014699 (1 mg/kg) improved tumor perfusion comparably with the control agentsnicot inamide (1 g/kg) and AG14361 (forerunner to AG014699; 10 mg/kg). AG014699 and AG14361 relaxed preconstricted vascular smooth muscle more potently than the standard agent, hydralazine, with no impact on gut motility. AG014699 inhibited MLCK at concentrationsthat relaxed isolated arteries, whereas AG14361 had no effect. Conclusion: Increased vessel perfusion elicited by AG014699 could increase tumor drug accumulation and therapeutic response. Vasoactive concentrations of AG014699 do not cause detrimental side effects to gut motility and may increase the range of therapeuticswith which AG014699 could be combined with for clinical benefit. © 2009 American Association for Cancer Research.