title: Enhancement of radiation cytotoxicity by UCN-01 in non-small cell lung carcinoma cells.
abstract: Thoracic ionizing radiation is a standard component of combined-modality therapy for locally advanced non-small cell lung cancer. To improve low 5-year survival rates (5- 15%), new strategies for enhancing the effectiveness of ionizing radiation are needed. The kinase inhibitor UCN-01 has multiple cell cycle effects, including abrogation of DNA damage-induced S- and G(2)-phase arrest, which may limit DNA repair prior to mitosis. To test the hypothesis that therapy-induced cell cycle effects would have an impact on the efficacy of a combination of UCN-01 plus ionizing radiation, the cell cycle responses of the non-small cell lung cancer cell lines Calu1 (TP53-null) and A549 (wild-type TP53) to 2 Gy ionizing radiation were correlated with clonogenic survival after irradiation plus UCN-01. Irradiated cells were exposed to UCN-01 simultaneously and at 3-h increments after irradiation. In Calu1 cells but not A549 cells, sequence-dependent potentiation of radiation by UCN-01 was observed, with maximal interaction occurring when UCN-01 was administered 6 h after irradiation. This coincided with the postirradiation time with the greatest depletion of cells from G(1). Abrogation of G(2) arrest was observed regardless of TP53 status. The role of TP53 was investigated using siRNA to achieve gene silencing. These studies demonstrated that radiation plus UCN-01 was more effective in cells with diminished TP53 activity, associated with a reduced G(1) checkpoint arrest. These studies indicate that simultaneous elimination of multiple DNA damage-induced checkpoints in G(1), S and G(2) may enhance the effects of radiation and that drug scheduling may have an impact on clinical efficacy.
authors.affiliation: Cancer and Molecular Research Laboratory, Division of Hematology/Oncology, Department of Internal Medicine, Sacramento, California 95817, USA. pcmack@ucdavis.edu
authors.forename: Philip C
authors.initials: PC
authors.lastname: Mack
authors.forename: Angela A
authors.initials: AA
authors.lastname: Jones
authors.forename: Matthew H
authors.initials: MH
authors.lastname: Gustafsson
authors.forename: David R
authors.initials: DR
authors.lastname: Gandara
authors.forename: Paul H
authors.initials: PH
authors.lastname: Gumerlock
authors.forename: Zelanna
authors.initials: Z
authors.lastname: Goldberg
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology / Q000532:radiotherapy*; D002453:Cell Cycle / Q000528:radiation effects; D018797:Cell Cycle Proteins / Q000032:analysis; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019311:Staurosporine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000032:analysis
chemical_list: D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D047428:Protein Kinase Inhibitors; D016159:Tumor Suppressor Protein p53; C054852:7-hydroxystaurosporine; D019311:Staurosporine