Potentiation of temozolomide and topotecan growth inhibition and cytotoxicity by novel poly(adenosine diphosphoribose) polymerase inhibitors in a panel of human tumor cell lines

Potent poly(ADP-ribose) polymerase (PARP) inhibitors have been developed th at potentiate the cytotoxicity of ionizing radiation and anticancer drugs, The biological effects of two novel PARP inhibitors, NU1025 (8-hydroxy-2-me thylquinazolin-4-[3H]one, K-i = 48 nM) and NU1085 [2-(4-hydroxyphenyl)benza midazole-4-carboxamide K-i = 6 nM], in combination with temozolomide (TM) o r topotecan (TP) have been studied in 12 human tumor cell lines (lung, colo n, ovary, and breast cancer). Cells were treated with increasing concentrat ions of TM or TP +/- NU1025 (50, 200 mu M) or NU1085 (10 mu M) for 72 h, Th e potentiation of growth inhibition by NU1025 and NU1085 varied between the cell lines from 1.5- to 4-fold for TM and 1- to 5-fold for TP and was unaf fected by p53 status. Clonogenic assays undertaken in two of the cell lines confirmed that the potentiation of growth inhibition reflected the potenti ation of cytotoxicity, NU1025 (50 mu M) was about as effective as 10 mu M N U1085 at potentiating growth inhibition and cytotoxicity, consistent with t he relative potencies of the two molecules as PARP inhibitors. Potentiation of cytotoxicity was obtained at concentrations of NU1025 and NU1085 that w ere not toxic per se; however, NU1085 alone was 3-fold more cytotoxic (LC50 values ranged from 83 to 94 mu M) than NU1025 alone (LC50 > 900 mu M), The se data demonstrate that PARP inhibitors are effective resistance-modifying agents in human tumor cell lines and have provided a comprehensive assessm ent protocol for the selection of optimum combinations of anticancer drugs, PARP inhibitors, and cell lines for in vivo studies.