ABT-888, an Orally Active Poly(ADP-Ribose) Polymerase Inhibitor that Potentiates DNA-Damaging Agents in Preclinical Tumor Models

摘要: Purpose: To evaluate the preclinical pharmacokinetics and antitumor efficacy of a novel orally bioavailable poly(ADP-ribose) polymerase (PARP) inhibitor, ABT-888. Experimental Design: In vitro potency was determined in PARP-1 PARP-2 enzyme assay. vivo evaluated syngeneic xenograft models combination with temozolomide, platinums, cyclophosphamide, ionizing radiation. Results: ABT-888 is potent inhibitor both K i s 5.2 2.9 nmol/L, respectively. The compound has good oral bioavailability crosses blood-brain barrier. strongly potentiated temozolomide B16F10 s.c. murine melanoma model. PARP inhibition dramatically increased at doses as low 3.1 mg/kg/d maximal achieved 25 mg/kg/d. 9L orthotopic rat glioma model, alone exhibited minimal efficacy, whereas ABT-888, when combined significantly slowed tumor progression. MX-1 breast model (BRCA1 deletion BRCA2 mutation), cisplatin, carboplatin, causing regression established tumors, comparable cytotoxic agents alone, only modest exhibited. Finally, radiation (2 Gy/d × 10) an HCT-116 colon carcinoma each did not display single-agent activity. Conclusions: PARP, bioavailability, can cross barrier, potentiates models. This broad spectrum chemopotentiation radiopotentiation makes this attractive candidate for clinical evaluation.