GPI 15427, a PARP inhibitor, enhances radiation treatment in a human xenograft head and neck model Free

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Recent studies have demonstrated that inhibition of poly (ADP-ribose) polymerase (PARP-1), an enzyme involved in the DNA repair, may represent a potential strategy to improve radiotherapy. In this study we (1) established pharmacokinetic profile of the PARP inhbitor, GPI 15427 and (2) tested if i.v. administration of GPI 15427 is able to enhance the anti-tumor efficacy of radiotherapy against human squamous head and neck cancer cells grown as a xenograft. Pharmacokinetic studies revealed that GPI 15427 reached a Cmax of 4189 + 327 ng/ml in plasma after a single iv dose of 40 mg/kg in rats. In a mouse xenograft model of human head and neck cancer, 3X106 JHU012 cells were implanted subcutaneously into female nude mice. 15 days post cell injection when the tumors were approximately 80 to 100 mm3, the tumors were irradiated with 2Gy of X-rays using a specially designed jig for 2 consecutive days. GPI 15427 (4, 10, or 40 mg/kg,) was administered i.v. 30 minutes prior to each radiation. Efficacy of treatments was evaluated by monitoring tumor size pre- and post-treatment. At all doses tested, no drug-related toxicities or deaths were observed. Additionally, GPI 15427 + radiation significantly reduced tumor volume compared to vehicle treated mice and mice treated with GPI 15427 alone or mice treated with radiation alone. In conclusion, these data indicate that iv administration of the PARP inhibitor GPI 15427 is well tolerated and induces significant enhancement of radiation anti-tumor efficacy against human head and neck cancer.