Inhibition of poly(ADP-ribose) polymerase enhances cell death and improves tumor growth delay in irradiated lung cancer models.

Inhibition of poly(ADP-ribose) polymerase enhances cell death and improves tumor growth delay in irradiated lung cancer models. Research Abstract Details 

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Inhibition of poly(ADP-ribose) polymerase enhances cell death and improves tumor growth delay in irradiated lung cancer models. Abstract Text:

Jeffrey M Albert,Carolyn Cao,Kwang Woon Kim,Christopher D Willey,Ling Geng,Dakai Xiao,Hong Wang,Alan Sandler,David H Johnson,Alexander D Colevas,Jennifer Low,Mace L Rothenberg,Bo Lu,

PURPOSE: Poly(ADP-ribose) polymerase-1 (PARP-1) is the founding member of a family of enzymes that catalyze the addition of ADP-ribose units to proteins that mediate DNA repair pathways. Ionizing radiation induces DNA strand breaks, suggesting that PARP-1 inhibition may sensitize tumor cells to radiation. EXPERIMENTAL DESIGN: We investigated the combination of PARP-1 inhibition with radiation in lung cancer models. ABT-888, a novel potent PARP-1 inhibitor, was used to explore the effects of PARP-1 inhibition on irradiated tumors and tumor vasculature. RESULTS: ABT-888 reduced clonogenic survival in H460 lung cancer cells, and inhibited DNA repair as shown by enhanced expression of DNA strand break marker histone gamma-H2AX. Both apoptosis and autophagy contributed to the mechanism of increased cell death. Additionally, ABT-888 increased tumor growth delay at well-tolerated doses in murine models. For a 5-fold increase in tumor volume, tumor growth delay was 1 day for ABT-888 alone, 7 days for radiation alone, and 13.5 days for combination treatment. Immunohistochemical staining of tumor sections revealed an increase in terminal deoxyribonucleotide transferase-mediated nick-end labeling apoptotic staining, and a decrease in Ki-67 proliferative staining after combination treatment. Matrigel assay showed a decrease in in vitro endothelial tubule formation with ABT-888/radiation combination treatment, and von Willebrand factor staining of tumor sections revealed decreased vessel formation in vivo, suggesting that this strategy may also target tumor angiogenesis. CONCLUSIONS: We conclude that PARP-1 inhibition shows promise as an effective means of enhancing tumor sensitivity to radiation, and future clinical studies are needed to determine the potential of ABT-888 as a radiation enhancer.

Inhibition of poly(ADP-ribose) polymerase enhances cell death and improves tumor growth delay in irradiated lung cancer models. Publishing Authors By Initials

JM Albert,C Cao,KW Kim,CD Willey,L Geng,D Xiao,H Wang,A Sandler,DH Johnson,AD Colevas,J Low,ML Rothenberg,B Lu,

For similar proteins: blood proteins: blood coagulation factors: von willebrand factor research abstracts see: proteins: blood proteins: blood coagulation factors: von willebrand factor research

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Inhibition of poly(ADP-ribose) polymerase enhances cell death and improves tumor growth delay in irradiated lung cancer models. Journal Published:

PUBLICATION TYPE: Research Support, U.S. Gov't,

Journal: Clinical cancer research : an official journal of

VOLUME: 13

Page Numbers: 3033-42

Journal Abbreviation: Clin. Cancer Res.

ISSN: 1078-0432

DAY: 15

MONTH: May

YEAR: 2007

Inhibition of poly(ADP-ribose) polymerase enhances cell death and improves tumor growth delay in irradiated lung cancer models. Information

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LANGUAGE: eng

NlmUniqueID: 9502500

Inhibition of poly(ADP-ribose) polymerase enhances cell death and improves tumor growth delay in irradiated lung cancer models. Keywords Mesh Terms:

KEYWORDS: von Willebrand Factor

MESH TERMS: analysis

Chemical & Substance for Abstract: Inhibition of poly(ADP-ribose) polymerase enhances cell death and improves tumor growth delay in irradiated lung cancer models. Information

Substance Name: Poly(ADP-ribose) Polymerases

Registry Number: EC 2.4.2.30

Grant and Affiliation Information for Inhibition of poly(ADP-ribose) polymerase enhances cell death and improves tumor growth delay in irradiated lung cancer models.

AFFILIATION: Vanderbilt Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

Country: United States

AGENCY: United States NCI

GRANT: 5 U01 CA099177-04

ACRONYM: CA

MEDLINETA: Clin Cancer Res

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