Abstract

Malignant gliomas occur more frequently than other types of primary central nervous system tumors. Among the chemotherapic agents, temozolomide (TZM) and topotecan (TPT) represent important new drugs active in such neoplastic diseaseas. Moreover, preclinical studies have evaluated the combination of these agents and inhibitors of the DNA repair enzymes [1].In the present study we investigated cell growth inhibition and cell cycle perturbation induced by TPT or TZM treatment in the presence of the specific PARP-1 inhibitor NU 1025 in two gliobastoma cell lines, the D54 (p53 wt) and the U251 (p53 mut). Agar-colony-forming assay showed a different sensitivity of both cell lines to TPT or TZM. Moreover, combined treatment with TZM and non cytotoxic concentration of NU1025 induced a 25% increase of growth inhibition in D54 and U251; the same additive effect was observed mainly in U251 for TPT plus NU1025 treatment. DNA-flow cytometry showed that TZM and TPT induce an accumulation of cells in G2M phase of cell cycle and that PARP-1 inhibitor addition doubled G2M block in TZM treated cells.The characterization of the poly(ADP-ribosyl)ation system in both glioblastoma cell lines is in progress and particular attention will be made to define PARP-1 involvement in p53 dependent and independent signal transduction system.References: 1.Friedman SH, Kerby T, Calvert H: Clin Cancer Res, 2000; 6: 2585-2597

Keywords: PARP-1, temozolomide, Topotecan, p53, Cells