Oral administration of the PARP-1 inhibitor GPI 15427 increases the anti-tumor activity of temozolomide against melanoma growing at the CNS site

Temozolomide (TMZ) is a DNA methylating agent with high oral bioavailability and ability to cross the blood brain barrier. Recent clinical trials have shown that TMZ improves progression-free survival and reduces the incidence of CNS relapse in Stage IV melanoma patients in comparison to patients treated with Dacarbazine, the standard care for this malignancy. This is particularly important for malignant melanoma in which brain metastases are common and can lead to patient death in few months. Unfortunately, resistance to TMZ occurs relatively often and strongly affects the rate and durability of clinical response. However, recent studies have demonstrated that inhibition of poly (ADP-ribose) polymerase-1 (PARP-1), an enzyme involved in the repair of methylpurines, may represent a potential strategy to improve TMZ efficacy. In this study we tested whether oral administration of a novel PARP-1 inhibitor GPI 15427 is able to enhance the anti-tumor efficacy of TMZ against B16 melanoma growing at the CNS. 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. When the same dose was given orally, the plasma Cmax was 1041 + 516 ng/ml, indicating a substantial oral bioavailability of the compound. The brain levels of GPI 15427 reached 1744 ng/g, 2301 ng/g at 0.5 and 1 h, respectively, post oral dosing of 40 mg/kg rats, indicating that the compound readily penetrates the blood brain barrier. B16 melanoma cells (104) were injected intracranially into male B6D2F1 mice. Tumor bearing mice were treated when neoplastic infiltration of the brain tissue was evident in histological sections. GPI 15427 (10, 40, or 100 mg/kg/per os) was administered for three or five consecutive days 1 h before TMZ (100 mg/Kg IP). Efficacy of treatments was evaluated by comparing the survival curves of untreated mice, mice treated with TMZ, or GPI 15427 alone to the survival curves of mice treated with TMZ + GPI 15427. At all doses tested, no drug-related deaths were observed. Moreover, GPI 15427 + TMZ significantly increased life span of tumor bearing mice compared to untreated mice, mice treated with GPI 15427 or with TMZ as single agents. In conclusion, these data indicate that oral administration of the PARP-1 inhibitor GPI 15427 is well tolerated and induces significant enhancement of TMZ anti-tumor efficacy against melanoma at the CNS site.