Document Detail


Adenovirally mediated p53 overexpression diversely influence the cell cycle of HEp-2 and CAL 27 cell lines upon cisplatin and methotrexate treatment.
MedLine Citation:
PMID:  19548002     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
PURPOSE: p53 gene plays a crucial role in the response to therapy. Since it is inactivated in the majority of human cancers, it is strongly believed that the p53 mutations confer resistance to therapeutics. In this paper we analyzed the influence of two mechanistically diverse antitumor agents--cisplatin and methotrexate on the proliferation and cell cycle of two head and neck squamous cancer cell lines HEp-2 (wild type p53 gene, but HPV 18/E6-inactivated protein) and CAL 27 (mutated p53 gene), along with the influence of adenovirally mediated p53 overexpression in modulation of cisplatin and methoterexate effects, whereby subtoxic vector/compound concentrations were employed. METHODS: p53 gene was introduced into tumor cells using adenoviral vector (AdCMV-p53). The cell cycle perturbations were measured by two parameter flow cytometry. The expression of p53, p21(WAF1/CIP1) and cyclin B1 proteins was examined using immunocytochemistry and western blot methods. RESULTS: In CAL 27 cells overexpression of p53 completely abrogated high S phase content observed in methotrexate-treated cells into a G1 and slight G2 arrest, while it sustained G2 arrest of the cells treated with cisplatin, along with the reduction of DNA synthesis and cyclin B1 expression. On the other hand, in HEp-2 cell line p53 overexpression slightly slowed down the progression through S phase in cells treated with methotrexate, decreased the cyclin B1 expression only after 24 h, and failed to sustain the G2 arrest after treatment with cisplatin alone. Instead, it increased the population of S phase cells that were not actively synthesizing DNA, sustained cyclin B1 expression and allowed the G2 cells to progress through mitosis. CONCLUSIONS: This study demonstrates that adenovirally mediated p53 overexpression at sub-cytotoxic levels enhanced the activity of low doses of cisplatin and methotrexate in HEp-2 and CAL 27 cells through changes in the cell cycle. However, the mechanisms of these effects differ depending on the genetic context and on the chemotherapeutics' modality of action.
Authors:
Sandra Kraljević Pavelić; Marko Marjanović; Miroslav Poznić; Marijeta Kralj
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-06-23
Journal Detail:
Title:  Journal of cancer research and clinical oncology     Volume:  135     ISSN:  1432-1335     ISO Abbreviation:  J. Cancer Res. Clin. Oncol.     Publication Date:  2009 Dec 
Date Detail:
Created Date:  2009-09-25     Completed Date:  2009-10-08     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  7902060     Medline TA:  J Cancer Res Clin Oncol     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  1747-61     Citation Subset:  IM    
Affiliation:
Division of Molecular Medicine, Rudjer Bosković Institute, Bijenicka cesta 54, 10000 Zagreb, Croatia.
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MeSH Terms
Descriptor/Qualifier:
Adenoviridae / genetics,  physiology*
Antineoplastic Agents / administration & dosage,  pharmacology
Carcinoma, Squamous Cell / drug therapy,  genetics,  pathology
Cell Cycle / drug effects*,  genetics
Cell Line, Tumor*
Cell Proliferation / drug effects
Cells, Cultured
Cisplatin / pharmacology*
Dose-Response Relationship, Drug
Drug Evaluation, Preclinical
Gene Transfer Techniques
Genes, p53*
Head and Neck Neoplasms / drug therapy,  genetics,  pathology
Humans
Methotrexate / administration & dosage,  pharmacology*
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 15663-27-1/Cisplatin; 59-05-2/Methotrexate

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