%0 Journal Article
%T Radiosensitization of colorectal carcinoma cell lines by histone deacetylase inhibition
%A Kjersti Flatmark
%A Ragnhild V Nome
%A Sigurd Folkvord
%A £¿se Bratland
%A Heidi Rasmussen
%A Mali Ellefsen
%A £¿ystein Fodstad
%A Anne Ree
%J Radiation Oncology
%D 2006
%I BioMed Central
%R 10.1186/1748-717x-1-25
%X Human colorectal carcinoma cell lines were exposed to ionizing radiation and HDAC inhibitors, and cell cycle profiles and regulatory factors, as well as clonogenicity, were analyzed.In addition to G2/M phase arrest following irradiation, the cell lines displayed cell cycle responses typical for either intact or defective p53 function (the presence or absence, respectively, of radiation-induced expression of the cell cycle inhibitor p21 and subsequent accumulation of G1 phase cells). In contrast, histone acetylation was associated with complete depletion of the G1 population of cells with functional p53 but accumulation of both G1 and G2/M populations of cells with defective p53. The cellular phenotypes upon HDAC inhibition were consistent with the observed repression of Polo-like kinase-1, a regulatory G2/M phase kinase. Following pre-treatment with HDAC inhibitors currently undergoing clinical investigation, the inhibitory effect of ionizing radiation on clonogenicity was significantly amplified.In these experimental models, HDAC inhibition sensitized the tumor cells to ionizing radiation, which is in accordance with the concept of increased probability of tumor cell death when chromatin structure is modified.Standard treatment of rectal cancer that by clinical or radiological assessment reveals locally advanced growth within the pelvis involves preoperative radiotherapy aimed at down-staging the tumor, to facilitate subsequent surgical excision [1,2]. However, tumor response to preoperative therapy varies greatly from pathological complete response to lack of objective response, warranting the use of experimental models to assay the efficacy of molecular targeting agents in rectal cancer radiosensitization.The combination of radiotherapy and chemotherapy is advocated primarily because of the independent effect of each modality. Chemotherapeutics enhance radiocytotoxicity by means of increasing the initial DNA damage, inhibiting DNA repair, or slowing down cellular
%U http://www.ro-journal.com/content/1/1/25