ABT-888, an Orally Active Poly(ADP-Ribose) Polymerase Inhibitor that Potentiates DNA-Damaging Agents in Preclinical Tumor Models
2007
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 a PARP-1 and PARP-2
enzyme assay. In vivo efficacy was evaluated in
syngeneicand xenograft models in combination with
temozolomide, platinums,
cyclophosphamide, and ionizing radiation. Results:
ABT-888 is a potent inhibitor of both PARP-1 and PARP-2 with K i s of 5.2 and 2.9 nmol/L, respectively. The compound has good oral bioavailability and crosses the
blood-brain barrier.
ABT-888 strongly potentiated
temozolomidein the B16F10 s.c. murine melanoma model. PARP inhibition dramatically increased the efficacy of
temozolomideat
ABT-888 doses as low as 3.1 mg/kg/d and a maximal efficacy achieved at 25 mg/kg/d. In the 9L orthotopic rat glioma model,
temozolomidealone exhibited minimal efficacy, whereas
ABT-888, when combined with
temozolomide, significantly slowed tumor progression. In the MX-1 breast xenograft model (BRCA1 deletion and BRCA2 mutation),
ABT-888 potentiated cisplatin, carboplatin, and
cyclophosphamide, causing regression of established tumors, whereas with comparable doses of cytotoxic agents alone, only modest tumor inhibition was exhibited. Finally,
ABT-888 potentiated radiation (2 Gy/d × 10) in an HCT-116 colon carcinoma model. In each model,
ABT-888 did not display single-agent activity. Conclusions:
ABT-888 is a potent inhibitor of PARP, has good oral bioavailability, can cross the
blood-brain barrier, and potentiates
temozolomide, platinums,
cyclophosphamide, and radiation in
syngeneicand xenograft tumor models. This broad spectrum of chemopotentiation and radiopotentiation makes this compound an attractive candidate for clinical evaluation.
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