Systemic administration of the PARP-1 inhibitor GPI 15427 increases the antitumor activity of temozolomide against metastatic melanoma.

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]. TMA 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 the drug treatment was also tetsed against lung metastases.ùMurine B16 melanoma cells were injected intracranially in syngeneic mice. Animals were treated for three days with TMZ (100 mg/kg, i.p.) +/- GPI 15427 (1mg/mouse, i.v.) when neoplastin infiltration of the brain tissue was evident in histological sections. Administration of shortly before TMZ significantly increased life-span of tumor-bearing mice with respect to untreated controls, or to group treated with either GPI 15427 or TMZ only (P<0.0001). The increase in survival detected in the group treated with the drug combination was accompanied by a marked reduction of tumor ingiltration in the brain, as evidenced by histological studies. GPI 15427 aslo enhanced the anti-metastatic acitivity of TMZ. In fact, the number of pulmonary metastases obtained after iv injection of B16 cells was significantly lower in mice treated with GPI 15427+TMZ than in those receiving TMZ only (P=0.004). In conclusion, these data indicate that systemic administration of GPI 15427 induces significant enhancement of TMZ anti-tumor activity against melanoma, even at the CNS site.