title: Preclinical evaluation of a potent novel DNA-dependent protein kinase inhibitor NU7441.
abstract: 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-PK(CS) (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 gammaH2AX 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 G(2)-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.
authors.affiliation: Northern Institute for Cancer Research, Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhao
authors.forename: Huw D
authors.initials: HD
authors.lastname: Thomas
authors.forename: Michael A
authors.initials: MA
authors.lastname: Batey
authors.forename: Ian G
authors.initials: IG
authors.lastname: Cowell
authors.forename: Caroline J
authors.initials: CJ
authors.lastname: Richardson
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Griffin
authors.forename: A Hilary
authors.initials: AH
authors.lastname: Calvert
authors.forename: David R
authors.initials: DR
authors.lastname: Newell
authors.forename: Graeme C M
authors.initials: GC
authors.lastname: Smith
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Curtin
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D016466:CHO Cells; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002867:Chromones / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000201:enzymology; D006224:Cricetinae; D004249:DNA Damage; D051747:DNA-Activated Protein Kinase / Q000037:antagonists & inhibitors*; D004357:Drug Synergism; D005047:Etoposide / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009025:Morpholines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects / Q000528:radiation effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: C499693:8-dibenzothiophen-4-yl-2-morpholin-4-yl-chromen-4-one; D002867:Chromones; D006657:Histones; D009025:Morpholines; D047428:Protein Kinase Inhibitors; D011838:Radiation-Sensitizing Agents; C475961:gamma-H2AX protein, mouse; D005047:Etoposide; D051747:DNA-Activated Protein Kinase