Impact of Genomic Methylation on Radiation Sensitivity of Colorectal Carcinoma

Journal Article · Thu Apr 15 00:00:00 EDT 2010 · International Journal of Radiation Oncology, Biology and Physics

DOI:https://doi.org/10.1016/j.ijrobp.2009.10.037· OSTI ID:21372221

Hofstetter, Barbara ^[1]; Niemierko, Andrzej ^[2]; Forrer, Christian ^[1]; Benhattar, Jean ^[3]; Albertini, Veronica ^[4]; Pruschy, Martn ^[1]; Bosman, Fred T ^[3]; Catapano, Carlo V ^[4]

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1. Department of Radiation Oncology, Zurich University Hospital, University of Zuerich (Switzerland)
2. Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA (United States)
3. Department of Pathology, Centre Hospitalier Universitaire Vaudois, Lausanne (Switzerland)
4. Laboratory of Experimental Oncology, Oncology Institute of Southern Switzerland, Bellinzona (Switzerland)

Purpose: To investigate the influence of demethylation with 5-aza-cytidine (AZA) on radiation sensitivity and to define the intrinsic radiation sensitivity of methylation deficient colorectal carcinoma cells. Methods and Materials: Radiation sensitizing effects of AZA were investigated in four colorectal carcinoma cell lines (HCT116, SW480, L174 T, Co115), defining influence of AZA on proliferation, clonogenic survival, and cell cycling with or without ionizing radiation. The methylation status for cancer or DNA damage response-related genes silenced by promoter methylation was determined. The effect of deletion of the potential target genes (DNMT1, DNMT3b, and double mutants) on radiation sensitivity was analyzed. Results: AZA showed radiation sensitizing properties at >=1 {mu}mol/l, a concentration that does not interfere with the cell cycle by itself, in all four tested cell lines with a sensitivity-enhancing ratio (SER) of 1.6 to 2.1 (confidence interval [CI] 0.9-3.3). AZA successfully demethylated promoters of p16 and hMLH1, genes associated with ionizing radiation response. Prolonged exposure to low-dose AZA resulted in sustained radiosensitivity if associated with persistent genomic hypomethylation after recovery from AZA. Compared with maternal HCT116 cells, DNMT3b-defcient deficient cells were more sensitive to radiation with a SER of 2.0 (CI 0.9-2.1; p = 0.03), and DNMT3b/DNMT1-/- double-deficient cells showed a SER of 1.6 (CI 0.5-2.7; p = 0.09). Conclusions: AZA-induced genomic hypomethylation results in enhanced radiation sensitivity in colorectal carcinoma. The mediators leading to sensitization remain unknown. Defining the specific factors associated with radiation sensitization after genomic demethylation may open the way to better targeting for the purpose of radiation sensitization.

• OSTI ID: 21372221
• Journal Information: International Journal of Radiation Oncology, Biology and Physics, Vol. 76, Issue 5; Other Information: DOI: 10.1016/j.ijrobp.2009.10.037; PII: S0360-3016(09)03451-8; Copyright (c) 2010 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; ISSN 0360-3016
• Country of Publication: United States
• Language: English

Related Subjects

63 RADIATION, THERMAL, AND OTHER ENVIRONMENTAL POLLUTANT EFFECTS ON LIVING ORGANISMS AND BIOLOGICAL MATERIALS
62 RADIOLOGY AND NUCLEAR MEDICINE
CARCINOMAS
CYTIDINE
DNA DAMAGES
LARGE INTESTINE
METHYLATION
PROMOTERS
RADIOSENSITIVITY
AZINES
BODY
CHEMICAL REACTIONS
DIGESTIVE SYSTEM
DISEASES
GASTROINTESTINAL TRACT
HETEROCYCLIC COMPOUNDS
INTESTINES
NEOPLASMS
NUCLEOSIDES
NUCLEOTIDES
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANS
PYRIMIDINES
RIBOSIDES
SENSITIVITY