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 that potentiate the cytotoxicity of ionizing radiation and anticancer drugs. The biological effects of two novel PARP inhibitors, NU1025 (8-hydroxy-2-methylquinazolin-4-[3H]one, Ki = 48 nM) and NU1085 [2-(4-hydroxyphenyl)benzamidazole-4-carboxamide, Ki = 6 nM], in combination with temozolomide (TM) or topotecan (TP) have been studied in 12 human tumor cell lines (lung, colon, ovary, and breast cancer). Cells were treated with increasing concentrations of TM or TP +/- NU1025 (50, 200 microM) or NU1085 (10 microM) for 72 h. The 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 unaffected by p53 status. Clonogenic assays undertaken in two of the cell lines confirmed that the potentiation of growth inhibition reflected the potentiation of cytotoxicity. NU1025 (50 microM) was about as effective as 10 microM NU1085 at potentiating growth inhibition and cytotoxicity, consistent with the relative potencies of the two molecules as PARP inhibitors. Potentiation of cytotoxicity was obtained at concentrations of NU1025 and NU1085 that were not toxic per se; however, NU1085 alone was 3-fold more cytotoxic (LC50 values ranged from 83 to 94 microM) than NU1025 alone (LC50 > 900 microM). These data demonstrate that PARP inhibitors are effective resistance-modifying agents in human tumor cell lines and have provided a comprehensive assessment protocol for the selection of optimum combinations of anticancer drugs, PARP inhibitors, and cell lines for in vivo studies.
Cancer Research Unit, Medical School, University of Newcastle upon Tyne, United Kingdom.
C A
CA
Delaney
L Z
LZ
Wang
S
S
Kyle
A W
AW
White
A H
AH
Calvert
N J
NJ
Curtin
B W
BW
Durkacz
Z
Z
Hostomsky
D R
DR
Newell
D000970:Antineoplastic Agents / Q000633:toxicity*; D001943:Breast Neoplasms; D002455:Cell Division / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects*; D003110:Colonic Neoplasms; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000633:toxicity; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000633:toxicity*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D010051:Ovarian Neoplasms; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011799:Quinazolines / Q000633:toxicity*; D000077204:Temozolomide; D019772:Topotecan / Q000633:toxicity*; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C115774:NU 1025; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011799:Quinazolines; D003606:Dacarbazine; D019772:Topotecan; D000077204:Temozolomide