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

Lookup NU author(s): Lan Wang, Suzanne Kyle, Alex White, Professor Alan Calvert, Professor Nicola Curtin, Emeritus Professor Barbara Durkacz, Professor Herbie Newell

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Abstract

Potent poly(ADP-ribose) polymerase (PARP) inhibitors have been developed that potentiate the cytotoxicity of ionizing radiation and anticenter drugs. The biological effects of two novel PARP inhibitors, NU1025 (8-hydroxy-2- methylquinazolin-4-[3H]one, K(i) = 48 nM) and NU1085 [2-(4- hydroxyphenyl)benzamidazole-4-carboxamide, K(i) = 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 μM) or NU1085 (10 μM) 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 μM) was about as effective as 10 μM NU1085 at potentiating growth inhibition and cytotoxicity, consistent with the relative potencies of the two molecules as PARP inhibitors. Potentiation of cytotoxicity was obtained 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 μM) than NU1025 alone (LC50 > 900 μM). These data demonstrate that PARP inhibitors are effective resitance- 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.


Publication metadata

Author(s): Delaney, C.A., Wang, L., Kyle, S., White, A.W., Calvert, A.H., Curtin, N.J., Durkacz, B.W., Hostomsky, Z, Newell, D.R.

Publication type: Article

Publication status: Published

Journal: Clinical Cancer Research

Year: 2000

Volume: 6

Issue: 7

Pages: 2860-2867

Print publication date: 01/07/2000

ISSN (print): 1078-0432

ISSN (electronic): 1557-3265

PubMed id: 10914735


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