Systemic administration of the PARP inhibitor GPI 15427 increases the anti-tumor activity of temozolomide in melanoma, glioma and lymphoma preclinical models in vivo

Temozolomide (TMZ) is a DNA methylating agent that in recent clinical trials has shown promising antitumor activity against high grade gliomas, metastatic melanoma and brain lymphoma. We previously demonstrated that the anti-tumor activity of TMZ against L5178Y lymphoma cells growing in the brain can be enhanced by intra-cerebral injection of a poly(ADP-ribose) polymerase (PARP) inhibitor. In this study we tested whether systemic administration of GPI 15427, a novel PARP inhibitor capable of crossing the blood-brain barrier, could enhance the anti-tumor efficacy of TMZ against CNS lymphoma or against an orthotopic xenograft of human glioblastoma multiforme. Animals were treated for three consecutive days with TMZ (100 mg/Kg, ip) +/- GPI 15427 (1 mg/mouse, iv) when neoplastic infiltration of the brain tissue was evident in histological sections. This schedule was chosen on the basis of preliminary toxicological studies that showed drug-related death only after 4 consecutive daily doses of the drug combination. In both lymphoma and glioma models systemic administration of GPI 15427 shortly before TMZ significantly increased life span of tumor bearing mice with respect to untreated controls, or to groups treated with GPI 15427 or TZM used as single agents (P< 0.01). The GPI 15427 + TMZ combination was also tested against B16 melanoma inoculated in BDF1 syngeneic mice. In this case, treatment of mice was started when the tumor was palpable. Combined treatment with GPI 15427 + TMZ significantly reduced tumor growth with respect to TMZ only (P< 0.01). In conclusion, these data indicate that systemic administration of the PARP inhibitor GPI 15427, at a tolerable dose, induces significant enhancement of TMZ anti-tumor efficacy against hematological or solid neoplasias