Abstract

We previously demonstrated that the antitumor activity of temozolomide (TMZ) can be enhanced at the CNS site by intracerebral injection of a PARP-1 inhibitor that does not permeate the blood-brain barrier [1]. TMZ is an anticancer agent with promising activity against metastatic melanoma [2,3]. Here 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 melanoma involving the CNS site. The efficacy of drug treatment was also tested against lung metastases. Murine B16 melanoma cells were injected intracranially in syngeneic mice. Animals were treated for three days with TMZ (100 mg/kg, i.p.) I GPI 15427 (1 mg/mouse, i.v.) when neoplastic infiltration of the brain tissue was evident in histological sections. 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 either GPI 15427 or TMZ only (P

Keywords: PARP-1 inhibitor, anticancer therapy, temozolomide