title: Radiosensitization of human cervical cancer cells by inhibiting ribonucleotide reductase: enhanced radiation response at low-dose rates.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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(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.affiliation: Department of Radiation Oncology, University Hospitals Case Medical Center and Case Western Reserve School of Medicine, Cleveland, OH 44106, USA. charles.kunos@UHhospitals.org
authors.forename: Charles A
authors.initials: CA
authors.lastname: Kunos
authors.forename: Valdir C
authors.initials: VC
authors.lastname: Colussi
authors.forename: John
authors.initials: J
authors.lastname: Pink
authors.forename: Tomas
authors.initials: T
authors.lastname: Radivoyevitch
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Oleinick
mesh_terms: D002453:Cell Cycle / Q000528:radiation effects; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D016193:G1 Phase / Q000528:radiation effects; D006801:Humans; D007496:Iridium Radioisotopes / Q000627:therapeutic use; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000494:pharmacology*; D011829:Radiation Dosage; D011836:Radiation Tolerance / Q000187:drug effects*; D011878:Radiotherapy / Q000295:instrumentation; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors*; D013882:Thiosemicarbazones / Q000494:pharmacology*; D014410:Tumor Stem Cell Assay / Q000379:methods; D002583:Uterine Cervical Neoplasms / Q000201:enzymology / Q000532:radiotherapy*
chemical_list: D004791:Enzyme Inhibitors; D007496:Iridium Radioisotopes; D009363:Neoplasm Proteins; D011725:Pyridines; D013882:Thiosemicarbazones; C078157:3-aminopyridine-2-carboxaldehyde thiosemicarbazone; D012264:Ribonucleotide Reductases