Document Detail


Inhibition of base excision repair potentiates iododeoxyuridine-induced cytotoxicity and radiosensitization.
MedLine Citation:
PMID:  12591735     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
5-Iodo-2'-deoxyuridine (IdUrd) is a halogenated thymidine analogue recognized as an effective in vitro and in vivo radiosensitizer in human cancers. IdUrd-related cytotoxicity and/or radiosensitization are correlated with the extent of IdUrd-DNA incorporation replacing thymidine. IdUrd cytotoxicity and radiosensitization result, in part, from induction of DNA single-strand breaks (SSB) with subsequent enhanced DNA double-strand breaks leading to cell death. Because base excision repair (BER) is a major DNA repair pathway for SSB induced by chemical agents and ionizing radiation, we initially assessed the role of BER in modulating IdUrd cytotoxicity and radiosensitization using genetically matched Chinese hamster ovary cells, with (AA8 cells) and without (EM9 cells) XRCC1 expression. XRCC1 plays a central role in processing and repairing SSBs and double-strand breaks. We found that EM9 cells were significantly more sensitive than parental AA8 cells to IdUrd alone and to IdUrd + ionizing radiation. The EM9 cells also demonstrate increased DNA damage after IdUrd treatment as evaluated by pulse field gel electrophoresis and single cell gel electrophoresis (Comet Assay). BER-competent EM9 cells, which were stably transfected with a cosmid vector carrying the human XRCC1 gene, showed responses to IdUrd similar to AA8 cells. We also assessed the role of methoxyamine, a small molecule inhibitor of BER, in the response of human colon cancer cells (HCT116) to IdUrd cytotoxicity and radiosensitization. Methoxyamine not only was able to increase IdUrd cytotoxicity but also increased the incorporation of IdUrd into DNA of HCT116 human colon cancer cells leading to greater radiosensitization. Thus, a genetic or biochemical impairment of BER results in increased IdUrd-induced cytotoxicity and radiosensitization in mammalian cells.
Authors:
Pietro Taverna; Hwa-Shin Hwang; Jane E Schupp; Tomas Radivoyevitch; Nancy Nguyen Session; Guru Reddy; David A Zarling; Timothy J Kinsella
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Cancer research     Volume:  63     ISSN:  0008-5472     ISO Abbreviation:  Cancer Res.     Publication Date:  2003 Feb 
Date Detail:
Created Date:  2003-02-19     Completed Date:  2003-03-18     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  838-46     Citation Subset:  IM    
Affiliation:
Department of Radiation Oncology and the Ireland Cancer Center, Case Western Reserve University School of Medicine and University Hospitals of Cleveland, Cleveland, Ohio 44106-4937, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
CHO Cells
Colorectal Neoplasms / drug therapy,  genetics,  radiotherapy
Cricetinae
DNA / drug effects,  metabolism,  radiation effects
DNA Damage
DNA Repair / drug effects*
DNA, Neoplasm / drug effects,  metabolism,  radiation effects
DNA-Binding Proteins / biosynthesis,  deficiency,  genetics
Drug Hypersensitivity / genetics
Drug Synergism
Hydroxylamines / pharmacology*
Idoxuridine / metabolism,  pharmacology*,  toxicity
Radiation-Sensitizing Agents / metabolism,  pharmacology*,  toxicity
Transfection
Tumor Cells, Cultured
Grant Support
ID/Acronym/Agency:
CA50595/CA/NCI NIH HHS; CA84578/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/DNA, Neoplasm; 0/DNA-Binding Proteins; 0/Hydroxylamines; 0/Radiation-Sensitizing Agents; 0/X-ray repair cross complementing protein 1; 54-42-2/Idoxuridine; 67-62-9/methoxyamine; 9007-49-2/DNA

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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