Document Detail


The combined use of known antiviral reverse transcriptase inhibitors AZT and DDI induce anticancer effects at low concentrations.
MedLine Citation:
PMID:  22355273     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
A hallmark of tumor cell survival is the maintenance of elongated telomeres. It is known that antiviral reverse transcriptase inhibitors (RTIs) such as azidothymidine (AZT) and didanosine (ddI) lead to telomere shortening at high, potentially toxic concentrations. We hypothesized that those drugs might have synergistic effects enabling successful therapy with low, nontoxic concentrations. Biologic effects of AZT and ddI were analyzed at concentrations that correspond to minimal plasma levels achieved during human immunodeficiency virus therapy. Long-term coapplication of low-dose AZT and ddI induced a significant shortening of telomeres in the tumor cell lines HCT-116, SkMel-28, MelJuso, and Jurkat. Treatment of cells with both RTI, but not with single RTI, led to a significant accumulation of γH2AX, to p53 phosphorylation, and to cell apoptosis in all cell lines. Oral low-dose dual RTI application but not low-dose single RTI application was associated with a significantly reduced tumor growth of HCT-116 cells in mice. This antiproliferative activity of the combined use of AZT and ddI at low, clinically applicable concentrations warrants clinical testing in human solid cancer.
Authors:
Thomas Aschacher; Sandra Sampl; Lisa Käser; David Bernhard; Andreas Spittler; Klaus Holzmann; Michael Bergmann
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Neoplasia (New York, N.Y.)     Volume:  14     ISSN:  1476-5586     ISO Abbreviation:  Neoplasia     Publication Date:  2012 Jan 
Date Detail:
Created Date:  2012-02-22     Completed Date:  2012-06-12     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  100886622     Medline TA:  Neoplasia     Country:  Canada    
Other Details:
Languages:  eng     Pagination:  44-53     Citation Subset:  IM    
Affiliation:
Department of Surgery, Medical University of Vienna, Vienna, Austria.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antineoplastic Combined Chemotherapy Protocols / pharmacology*
Blotting, Southern
Cell Line, Tumor
Didanosine / administration & dosage*
Fluorescent Antibody Technique
Humans
Immunohistochemistry
In Situ Hybridization, Fluorescence
Mice
Mice, Nude
Neoplasms, Experimental / drug therapy*
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Inhibitors / administration & dosage
Telomere / drug effects
Telomere Shortening / drug effects*
Xenograft Model Antitumor Assays
Zidovudine / administration & dosage*
Chemical
Reg. No./Substance:
0/Reverse Transcriptase Inhibitors; 30516-87-1/Zidovudine; 69655-05-6/Didanosine
Comments/Corrections

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