Document Detail


Involvement of p53 in gemcitabine mediated cytotoxicity and radiosensitivity in breast cancer cell lines.
MedLine Citation:
PMID:  22353361     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Gemcitabine (2',2'-difluoro-2'-deoxycytidine; dFdCyd) is one of the anti-metabolites drugs that target DNA replication. We evaluated dFdCyd cytotoxicity and its radiosensitizing ability in human breast cancer cell lines, MCF-7 (wild-type p53) and MDA-MB-231 (mutant-type p53) along with normal mammary epithelial cell line (MCF-12) for comparison. Radiosensitivity and cytotoxicity were measured by the clonogenic survival assays. DNA DSBs was studied by Pulse Field Gel Electrophoresis (PFGE) and cell cycle distribution was analyzed by flow cytometry. MDA-MB-231 cells were the most sensitive to the cytotoxicity of dFdCyd (IC(50) 5 nM) then MCF-7 (IC(50) 10nM), whereas MCF-12 cells were the most resistant to the cytotoxicity of dFdCyd (IC(50) 70 nM). MCF-12 and MCF-7 cell lines did not show any radiosensitization to dFdCyd, whereas the MDA-MB-231 cells showed significantly increased radioresistant to dFdCyd at equimolar concentration (p=0.002) and at IC(50) concentration (p<0.001). The DNA double strand breaks (DSBs) repair showed that dFdCyd neither increases DNA DSBs nor decreases the rate of their repair in MCF-12 and MCF-7 cell lines, while the same treatment in MDA-MB-231 cell line led to decrease the rate of DSBs or increase the rate of DNA repair (p=0.034). Therefore, dFdCyd is a cytotoxic agent, especially in the cancer cells irrespective of having wild-type or mutated p53 protein, but it is not effective as radiosensitizer in the cell lines used in this study. dFdCyd combined with radiation reduces the efficacy of chemo-radiotherapy in p53 mutated cells. Therefore, p53-mutated cancer could be a counter-indication for radiation-gemcitabine combined treatment.
Authors:
Sameer D Salem; Faisal M Abou-Tarboush; Nadeem M Saeed; Waheeb D Al-Qadasi; M Abul Farah; Muneera Al-Buhairi; Najla Al-Harbi; Ibrahim Alhazza; Ghazi Alsbeih
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-02-14
Journal Detail:
Title:  Gene     Volume:  498     ISSN:  1879-0038     ISO Abbreviation:  Gene     Publication Date:  2012 May 
Date Detail:
Created Date:  2012-03-26     Completed Date:  2012-05-29     Revised Date:  2013-06-03    
Medline Journal Info:
Nlm Unique ID:  7706761     Medline TA:  Gene     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  300-7     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Elsevier B.V. All rights reserved.
Affiliation:
Biochemistry and Molecular Biology Department, Faculty of Medicine and Health Sciences, Sana'a University, Sana'a, Yemen. sameersalem@yahoo.com
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MeSH Terms
Descriptor/Qualifier:
Antimetabolites, Antineoplastic / pharmacology*
Breast Neoplasms / drug therapy*,  genetics
Cell Cycle / drug effects
Cell Line, Tumor / drug effects,  radiation effects
Cell Survival / drug effects
DNA Breaks, Double-Stranded
DNA Repair / drug effects,  genetics
Deoxycytidine / analogs & derivatives*,  pharmacology
Electrophoresis, Gel, Pulsed-Field
Epithelial Cells / cytology,  drug effects
Female
Humans
Mutation
Radiation-Sensitizing Agents / pharmacology*
Tumor Suppressor Protein p53 / genetics*
Chemical
Reg. No./Substance:
0/Antimetabolites, Antineoplastic; 0/Radiation-Sensitizing Agents; 0/Tumor Suppressor Protein p53; 951-77-9/Deoxycytidine; B76N6SBZ8R/gemcitabine

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


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