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Chronic Hypoxia Decreases Synthesis of Homologous Recombination Proteins to Offset Chemoresistance and Radioresistance

¹ Princess Margaret Hospital (University Health Network) and ² Departments of Medical Biophysics and Radiation Oncology, University of Toronto, Toronto, Ontario, Canada; ³ Department of Radiation Oncology (Maastro), GROW Research Institute, Maastricht University, Maastricht, the Netherlands; ⁴ Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut; ⁵ Department of Radiation Oncology, Washington University in St. Louis, St. Louis, Missouri; and ⁶ Department of Medicine and Microbiology, Centre de Recherche, Centre Hospialier de l'Université de Montreal-Hôpital Notre-Dame, Institut du Cancer de Montréal, Université de Montréal, Montréal, Quebec, Canada

Requests for reprints: Robert G. Bristow, Radiation Medicine Program, Princess Margaret Hospital, 610 University Avenue, Toronto, Ontario, Canada M5G 2M9. Phone: 416-946-2936; Fax: 416-946-4596; E-mail: Rob.Bristow{at}rmp.uhn.on.ca.

Hypoxic and/or anoxic tumor cells can have increased rates of mutagenesis and altered DNA repair protein expression. Yet very little is known regarding the functional consequences of any hypoxia-induced changes in the expression of proteins involved in DNA double-strand break repair. We have developed a unique hypoxic model system using H1299 cells expressing an integrated direct repeat green fluorescent protein (DR-GFP) homologous recombination (HR) reporter system to study HR under prolonged chronic hypoxia (up to 72 h under 0.2% O₂) without bias from altered proliferation, cell cycle checkpoint activation, or severe cell toxicity. We observed decreased expression of HR proteins due to a novel mechanism involving decreased HR protein synthesis. Error-free HR was suppressed 3-fold under 0.2% O₂ as measured by the DR-GFP reporter system. This decrease in functional HR resulted in increased sensitivity to the DNA cross-linking agents mitomycin C and cisplatin but not to the microtubule-interfering agent, paclitaxel. Chronically hypoxic H1299 cells that had decreased functional HR were relatively radiosensitive [oxygen enhancement ratio (OER), 1.37] when compared with acutely hypoxic or anoxic cells (OER, 1.96–2.61). Using CAPAN1 cells isogenic for BRCA2 and siRNA to RAD51, we confirmed that the hypoxia-induced radiosensitivity was due to decreased HR capacity. Persistent down-regulation of HR function by the tumor microenvironment could result in low-fidelity DNA repair and have significant implications for response to therapy and genetic instability in human cancers. [Cancer Res 2008;68(2):605–14]

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