| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Experimental Therapeutics, Molecular Targets, and Chemical Biology |
1 Northern Institute for Cancer Research, Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom and 2 KuDOS Pharmaceuticals Ltd., Cambridge, United Kingdom
Requests for reprints: Nicola Curtin, Northern Institute for Cancer Research, Medical School, University of Newcastle upon Tyne, Framlington Place, Newcastle upon Tyne, NE2 4HH, United Kingdom. Phone: 44-191-246-4415; Fax: 44-191-246-4301; E-mail: n.j.curtin{at}ncl.ac.uk.
DNA double-strand breaks (DSB) are the most cytotoxic lesions induced by ionizing radiation and topoisomerase II poisons, such as etoposide and doxorubicin. A major pathway for the repair of DSB is nonhomologous end joining, which requires DNA-dependent protein kinase (DNA-PK) activity. We investigated the therapeutic use of a potent, specific DNA-PK inhibitor (NU7441) in models of human cancer. We measured chemosensitization by NU7441 of topoisomerase II poisons and radiosensitization in cells deficient and proficient in DNA-PKCS (V3 and V3-YAC) and p53 wild type (LoVo) and p53 mutant (SW620) human colon cancer cell lines by clonogenic survival assay. Effects of NU7441 on DSB repair and cell cycle arrest were measured by 
H2AX foci and flow cytometry. Tissue distribution of NU7441 and potentiation of etoposide activity were determined in mice bearing SW620 tumors. NU7441 increased the cytotoxicity of ionizing radiation and etoposide in SW620, LoVo, and V3-YAC cells but not in V3 cells, confirming that potentiation was due to DNA-PK inhibition. NU7441 substantially retarded the repair of ionizing radiation–induced and etoposide-induced DSB. NU7441 appreciably increased G2-M accumulation induced by ionizing radiation, etoposide, and doxorubicin in both SW620 and LoVo cells. In mice bearing SW620 xenografts, NU7441 concentrations in the tumor necessary for chemopotentiation in vitro were maintained for at least 4 hours at nontoxic doses. NU7441 increased etoposide-induced tumor growth delay 2-fold without exacerbating etoposide toxicity to unacceptable levels. In conclusion, NU7441 shows sufficient proof of principle through in vitro and in vivo chemosensitization and radiosensitization to justify further development of DNA-PK inhibitors for clinical use. (Cancer Res 2006; 66(10): 5354-62)
This article has been cited by other articles:
|
|
 |
|
  I. R. Powley, A. Kondrashov, L. A. Young, H. C. Dobbyn, K. Hill, I. G. Cannell, M. Stoneley, Y.-W. Kong, J. A. Cotes, G. C.M. Smith, et al. Translational reprogramming following UVB irradiation is mediated by DNA-PKcs and allows selective recruitment to the polysomes of mRNAs encoding DNA repair enzymes Genes & Dev., May 15, 2009; 23(10): 1207 - 1220. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Quanz, N. Berthault, C. Roulin, M. Roy, A. Herbette, C. Agrario, C. Alberti, V. Josserand, J.-L. Coll, X. Sastre-Garau, et al. Small-Molecule Drugs Mimicking DNA Damage: A New Strategy for Sensitizing Tumors to Radiotherapy Clin. Cancer Res., February 15, 2009; 15(4): 1308 - 1316. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Solier, O. Sordet, K. W. Kohn, and Y. Pommier Death Receptor-Induced Activation of the Chk2- and Histone H2AX-Associated DNA Damage Response Pathways Mol. Cell. Biol., January 1, 2009; 29(1): 68 - 82. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Hingorani, C. L. White, A. Merron, I. Peerlinck, M. E. Gore, A. Slade, S. D. Scott, C. M. Nutting, H. S. Pandha, A. A. Melcher, et al. Inhibition of Repair of Radiation-Induced DNA Damage Enhances Gene Expression from Replication-Defective Adenoviral Vectors Cancer Res., December 1, 2008; 68(23): 9771 - 9778. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Wirthner, S. Wrann, K. Balamurugan, R. H. Wenger, and D. P. Stiehl Impaired DNA double-strand break repair contributes to chemoresistance in HIF-1{alpha}-deficient mouse embryonic fibroblasts Carcinogenesis, December 1, 2008; 29(12): 2306 - 2316. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Surucu, L. Bozulic, D. Hynx, A. Parcellier, and B. A. Hemmings In Vivo Analysis of Protein Kinase B (PKB)/Akt Regulation in DNA-PKcs-null Mice Reveals a Role for PKB/Akt in DNA Damage Response and Tumorigenesis J. Biol. Chem., October 31, 2008; 283(44): 30025 - 30033. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Huston, M. J. Lynch, A. Mohamed, D. M. Collins, E. V. Hill, R. MacLeod, E. Krause, G. S. Baillie, and M. D. Houslay EPAC and PKA allow cAMP dual control over DNA-PK nuclear translocation PNAS, September 2, 2008; 105(35): 12791 - 12796. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Cai, Z. Chen, K. E. Bailey, D. A. Scollard, R. M. Reilly, and K. A. Vallis Relationship Between Induction of Phosphorylated H2AX and Survival in Breast Cancer Cells Exposed to 111In-DTPA-hEGF J. Nucl. Med., August 1, 2008; 49(8): 1353 - 1361. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Willmore, S. L. Elliott, T. Mainou-Fowler, G. P. Summerfield, G. H. Jackson, F. O'Neill, C. Lowe, A. Carter, R. Harris, A. R. Pettitt, et al. DNA-Dependent Protein Kinase Is a Therapeutic Target and an Indicator of Poor Prognosis in B-Cell Chronic Lymphocytic Leukemia Clin. Cancer Res., June 15, 2008; 14(12): 3984 - 3992. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. J.H. Arlander, B. T. Greene, C. L. Innes, and R. S. Paules DNA Protein Kinase Dependent G2 Checkpoint Revealed following Knockdown of Ataxia-Telangiectasia Mutated in Human Mammary Epithelial Cells Cancer Res., January 1, 2008; 68(1): 89 - 97. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Liu, A. Matsuda, and W. Plunkett Ataxia-telangiectasia and Rad3-related and DNA-dependent protein kinase cooperate in G2 checkpoint activation by the DNA strand-breaking nucleoside analogue 2'-C-cyano-2'-deoxy-1- -D-arabino-pentofuranosylcytosine Mol. Cancer Ther., January 1, 2008; 7(1): 133 - 142. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Chen and C. S. Nirodi The Epidermal Growth Factor Receptor: A Role in Repair of Radiation-Induced DNA Damage Clin. Cancer Res., November 15, 2007; 13(22): 6555 - 6560. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. E. Lally, G. A. Geiger, S. Kridel, A. E. Arcury-Quandt, M. E. Robbins, N. D. Kock, K. Wheeler, P. Peddi, A. Georgakilas, G. D. Kao, et al. Identification and Biological Evaluation of a Novel and Potent Small Molecule Radiation Sensitizer via an Unbiased Screen of a Chemical Library Cancer Res., September 15, 2007; 67(18): 8791 - 8799. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Hong, L. Lei, B. Kunert, R. Naredla, S. E. Applequist, A. Grandien, and R. Glas Tripeptidyl-peptidase II Controls DNA Damage Responses and In vivo {gamma}-Irradiation Resistance of Tumors Cancer Res., August 1, 2007; 67(15): 7165 - 7174. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Douglas, X. Cui, W. D. Block, Y. Yu, S. Gupta, Q. Ding, R. Ye, N. Morrice, S. P. Lees-Miller, and K. Meek The DNA-Dependent Protein Kinase Catalytic Subunit Is Phosphorylated In Vivo on Threonine 3950, a Highly Conserved Amino Acid in the Protein Kinase Domain Mol. Cell. Biol., March 1, 2007; 27(5): 1581 - 1591. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
