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Title: Radiosensitization of Human Cervical Cancer Cells by Inhibiting Ribonucleotide Reductase: Enhanced Radiation Response at Low-Dose Rates

Abstract

Purpose: To test whether pharmacologic inhibition of ribonucleotide reductase (RNR) by 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, NSC no. 663249) enhances radiation sensitivity during low-dose-rate ionizing radiation provided by a novel purpose-built iridium-192 cell irradiator. Methods and Materials: 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. Results: 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{sub 1}-phase cell cycle arrest. Conclusions: 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.

Authors:
 [1];  [1];  [2];  [3];  [1]
  1. Department of Radiation Oncology, University Hospitals Case Medical Center and Case Western Reserve School of Medicine, Cleveland, OH (United States)
  2. Department of General Medical Sciences, University Hospitals Case Medical Center and Case Western Reserve School of Medicine, Cleveland, OH (United States)
  3. Department of Epidemiology and Biostatistics, Case Comprehensive Cancer Center, University Hospitals Case Medical Center and Case Western Reserve School of Medicine, Cleveland, OH (United States)
Publication Date:
OSTI Identifier:
21587600
Resource Type:
Journal Article
Journal Name:
International Journal of Radiation Oncology, Biology and Physics
Additional Journal Information:
Journal Volume: 80; Journal Issue: 4; Other Information: DOI: 10.1016/j.ijrobp.2011.01.034; PII: S0360-3016(11)00201-X; Copyright (c) 2011 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0360-3016
Country of Publication:
United States
Language:
English
Subject:
62 RADIOLOGY AND NUCLEAR MEDICINE; CELL CYCLE; DNA DAMAGES; DOSE RATES; ENZYME INHIBITORS; IONIZING RADIATIONS; IRIDIUM 192; IRRADIATION; NEOPLASMS; RADIATION DOSES; SENSITIVITY; BETA DECAY RADIOISOTOPES; BETA-MINUS DECAY RADIOISOTOPES; DAYS LIVING RADIOISOTOPES; DISEASES; DOSES; ELECTRON CAPTURE RADIOISOTOPES; HEAVY NUCLEI; INTERNAL CONVERSION RADIOISOTOPES; IRIDIUM ISOTOPES; ISOMERIC TRANSITION ISOTOPES; ISOTOPES; MINUTES LIVING RADIOISOTOPES; NUCLEI; ODD-ODD NUCLEI; RADIATIONS; RADIOISOTOPES; YEARS LIVING RADIOISOTOPES

Citation Formats

Kunos, Charles A., E-mail: charles.kunos@UHhospitals.org, Colussi, Valdir C., Pink, John, Radivoyevitch, Tomas, and Oleinick, Nancy L. Radiosensitization of Human Cervical Cancer Cells by Inhibiting Ribonucleotide Reductase: Enhanced Radiation Response at Low-Dose Rates. United States: N. p., 2011. Web. doi:10.1016/j.ijrobp.2011.01.034.
Kunos, Charles A., E-mail: charles.kunos@UHhospitals.org, Colussi, Valdir C., Pink, John, Radivoyevitch, Tomas, & Oleinick, Nancy L. Radiosensitization of Human Cervical Cancer Cells by Inhibiting Ribonucleotide Reductase: Enhanced Radiation Response at Low-Dose Rates. United States. doi:10.1016/j.ijrobp.2011.01.034.
Kunos, Charles A., E-mail: charles.kunos@UHhospitals.org, Colussi, Valdir C., Pink, John, Radivoyevitch, Tomas, and Oleinick, Nancy L. Fri . "Radiosensitization of Human Cervical Cancer Cells by Inhibiting Ribonucleotide Reductase: Enhanced Radiation Response at Low-Dose Rates". United States. doi:10.1016/j.ijrobp.2011.01.034.
@article{osti_21587600,
title = {Radiosensitization of Human Cervical Cancer Cells by Inhibiting Ribonucleotide Reductase: Enhanced Radiation Response at Low-Dose Rates},
author = {Kunos, Charles A., E-mail: charles.kunos@UHhospitals.org and Colussi, Valdir C. and Pink, John and Radivoyevitch, Tomas and Oleinick, Nancy L.},
abstractNote = {Purpose: To test whether pharmacologic inhibition of ribonucleotide reductase (RNR) by 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, NSC no. 663249) enhances radiation sensitivity during low-dose-rate ionizing radiation provided by a novel purpose-built iridium-192 cell irradiator. Methods and Materials: 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. Results: 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{sub 1}-phase cell cycle arrest. Conclusions: 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.},
doi = {10.1016/j.ijrobp.2011.01.034},
journal = {International Journal of Radiation Oncology, Biology and Physics},
issn = {0360-3016},
number = 4,
volume = 80,
place = {United States},
year = {2011},
month = {7}
}