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      Radiosensitization of human cervical cancer cells by inhibiting ribonucleotide reductase: enhanced radiation response at low-dose rates.

      International Journal of Radiation Oncology, Biology, Physics
      Cell Cycle, radiation effects, Cell Line, Tumor, Enzyme Inhibitors, pharmacology, Female, Flow Cytometry, methods, G1 Phase, Humans, Iridium Radioisotopes, therapeutic use, Neoplasm Proteins, antagonists & inhibitors, Pyridines, Radiation Dosage, Radiation Tolerance, drug effects, Radiotherapy, instrumentation, Ribonucleotide Reductases, Thiosemicarbazones, Tumor Stem Cell Assay, Uterine Cervical Neoplasms, enzymology, radiotherapy

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          Abstract

          To test whether pharmacologic inhibition of ribonucleotide reductase (RNR) by 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, NSC #663249) enhances radiation sensitivity during low-dose-rate ionizing radiation provided by a novel purpose-built iridium-192 cell irradiator. The cells were exposed to low-dose-rate radiation (11, 23, 37, 67 cGy/h) using a custom-fabricated cell irradiator or to high-dose-rate radiation (330 cGy/min) using a conventional cell irradiator. The radiation sensitivity of human cervical (CaSki, C33-a) cancer cells with or without RNR inhibition by 3-AP was evaluated using a clonogenic survival and an RNR activity assay. Alteration in the cell cycle distribution was monitored using flow cytometry. Increasing radiation sensitivity of both CaSki and C33-a cells was observed with the incremental increase in radiation dose rates. 3-AP treatment led to enhanced radiation sensitivity in both cell lines, eliminating differences in cell cytotoxicity from the radiation dose rate. RNR blockade by 3-AP during low-dose-rate irradiation was associated with low RNR activity and extended G(1)-phase cell cycle arrest. We conclude that RNR inhibition by 3-AP impedes DNA damage repair mechanisms that rely on deoxyribonucleotide production and thereby increases radiation sensitivity of human cervical cancers to low-dose-rate radiation. Copyright © 2011 Elsevier Inc. All rights reserved.

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