Influence of PARP-1 inhibitors on the antitumor activity of methylating agents.

This study is focused on the use of PARP-1 inhibitors as enhancer of cancer chemotherapy with special emphasis to methylating agents. In particular, we tested whether systemic administration of GPI 15427, a novel PARP-1 inhibitor capable of crossing the blood-brain barrier, could enhance the anti-tumor efficacy of temozolomide (TMZ), an oral anticancer agent with high CNS penetration and promising activity against metastatic melanoma. Murine B16 melanoma cells were injected subcutaneously (sc), intracranially (ic) or intravenously (iv) in syngeneic mice. Animals were treated for three days with TMZ (100 mg/kg, ip) +/- GPI 15427 (10 or 40 mg/mouse, iv). At all tumor sites, administration of GPI 15427 shortly before TMZ significantly reduced melanoma growth at a higher extent compared to treatment with TMZ only. Moreover, the drug combination significantly increased life-span of mice bearing intracranial melanoma with respect to untreated controls, or to groups treated with either GPI 15427 or TMZ, in a dose-dependent manner. Moreover, 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. These data indicate that systemic administration of GPI 15427 significantly enhanced TMZ anti-tumor activity against melanoma, even at the CNS site. In B16 melanoma cells TMZ+PARP-1 inhibitor mainly provoked cytostasis. In tumor cells of hematopoietic origin the association of PARP-1 inhibitor with TMZ, which produces a wide spectrum of methyl adducts, resulted in cell death with distinct features from death induced by the combination of PARP-1 inhibitor with a N3-Adenine selective methylating agent. The results suggest new insights on different modalities of toxicity induced by distinct methylated bases per se or in the presence of PARP inhibitors.