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 #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(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: Charles A Kunos, Valdir C Colussi, John Pink, Tomas Radivoyevitch, Nancy L Oleinick
• Journal: International journal of radiation oncology, biology, physics (Int J Radiat Oncol Biol Phys) Vol. 80 Issue 4 Pg. 1198-204 (Jul 15 2011) ISSN: 1879-355X [Electronic] United States
• PMID: 21470790 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• Enzyme Inhibitors
• Iridium Radioisotopes
• Neoplasm Proteins
• Pyridines
• Thiosemicarbazones
• 3-aminopyridine-2-carboxaldehyde thiosemicarbazone
• Ribonucleotide Reductases

Topics

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