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Differential effects of the poly (ADP-ribose) polymerase (PARP) inhibitor NU1025 on topoisomerase I and II inhibitor cytotoxicity in L1210 cells in vitro.
Br J Cancer. 2001 Jan 05; 84(1):106-12.BJ

Abstract

The potent novel poly(ADP-ribose) polymerase (PARP) inhibitor, NU1025, enhances the cytotoxicity of DNA-methylating agents and ionizing radiation by inhibiting DNA repair. We report here an investigation of the role of PARP in the cellular responses to inhibitors of topoisomerase I and II using NU1025. The cytotoxicity of the topoisomerase I inhibitor, camptothecin, was increased 2.6-fold in L1210 cells by co-incubation with NU1025. Camptothecin-induced DNA strand breaks were also increased 2.5-fold by NU1025 and exposure to camptothecin-activated PARP. In contrast, NU1025 did not increase the DNA strand breakage or cytotoxicity caused by the topoisomerase II inhibitor etoposide. Exposure to etoposide did not activate PARP even at concentrations that caused significant levels of apoptosis. Taken together, these data suggest that potentiation of camptothecin cytotoxicity by NU1025 is a direct result of increased DNA strand breakage, and that activation of PARP by camptothecin-induced DNA damage contributes to its repair and consequently cell survival. However, in L1210 cells at least, it would appear that PARP is not involved in the cellular response to etoposide-mediated DNA damage. On the basis of these data, PARP inhibitors may be potentially useful in combination with topoisomerase I inhibitor anticancer chemotherapy.

Authors+Show Affiliations

Cancer Research Unit, University of Newcastle upon Tyne Medical School, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

11139322

Citation

Bowman, K J., et al. "Differential Effects of the Poly (ADP-ribose) Polymerase (PARP) Inhibitor NU1025 On Topoisomerase I and II Inhibitor Cytotoxicity in L1210 Cells in Vitro." British Journal of Cancer, vol. 84, no. 1, 2001, pp. 106-12.
Bowman KJ, Newell DR, Calvert AH, et al. Differential effects of the poly (ADP-ribose) polymerase (PARP) inhibitor NU1025 on topoisomerase I and II inhibitor cytotoxicity in L1210 cells in vitro. Br J Cancer. 2001;84(1):106-12.
Bowman, K. J., Newell, D. R., Calvert, A. H., & Curtin, N. J. (2001). Differential effects of the poly (ADP-ribose) polymerase (PARP) inhibitor NU1025 on topoisomerase I and II inhibitor cytotoxicity in L1210 cells in vitro. British Journal of Cancer, 84(1), 106-12.
Bowman KJ, et al. Differential Effects of the Poly (ADP-ribose) Polymerase (PARP) Inhibitor NU1025 On Topoisomerase I and II Inhibitor Cytotoxicity in L1210 Cells in Vitro. Br J Cancer. 2001 Jan 5;84(1):106-12. PubMed PMID: 11139322.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Differential effects of the poly (ADP-ribose) polymerase (PARP) inhibitor NU1025 on topoisomerase I and II inhibitor cytotoxicity in L1210 cells in vitro. AU - Bowman,K J, AU - Newell,D R, AU - Calvert,A H, AU - Curtin,N J, PY - 2001/1/5/pubmed PY - 2001/3/3/medline PY - 2001/1/5/entrez SP - 106 EP - 12 JF - British journal of cancer JO - Br. J. Cancer VL - 84 IS - 1 N2 - The potent novel poly(ADP-ribose) polymerase (PARP) inhibitor, NU1025, enhances the cytotoxicity of DNA-methylating agents and ionizing radiation by inhibiting DNA repair. We report here an investigation of the role of PARP in the cellular responses to inhibitors of topoisomerase I and II using NU1025. The cytotoxicity of the topoisomerase I inhibitor, camptothecin, was increased 2.6-fold in L1210 cells by co-incubation with NU1025. Camptothecin-induced DNA strand breaks were also increased 2.5-fold by NU1025 and exposure to camptothecin-activated PARP. In contrast, NU1025 did not increase the DNA strand breakage or cytotoxicity caused by the topoisomerase II inhibitor etoposide. Exposure to etoposide did not activate PARP even at concentrations that caused significant levels of apoptosis. Taken together, these data suggest that potentiation of camptothecin cytotoxicity by NU1025 is a direct result of increased DNA strand breakage, and that activation of PARP by camptothecin-induced DNA damage contributes to its repair and consequently cell survival. However, in L1210 cells at least, it would appear that PARP is not involved in the cellular response to etoposide-mediated DNA damage. On the basis of these data, PARP inhibitors may be potentially useful in combination with topoisomerase I inhibitor anticancer chemotherapy. SN - 0007-0920 UR - https://www.unboundmedicine.com/medline/citation/11139322/Differential_effects_of_the_poly__ADP_ribose__polymerase__PARP__inhibitor_NU1025_on_topoisomerase_I_and_II_inhibitor_cytotoxicity_in_L1210_cells_in_vitro_ L2 - http://dx.doi.org/10.1054/bjoc.2000.1555 DB - PRIME DP - Unbound Medicine ER -