Document Detail


In vitro studies of the toxicity of nucleoside analogues used in the treatment of HIV infection.
MedLine Citation:
PMID:  20692986     Owner:  NLM     Status:  In-Data-Review    
Abstract/OtherAbstract:
The nucleoside analogues, 3'-azido-3'-deoxythymidine (AZT, zidovudine), 2',3'-dideoxyinosine (ddI, didanosine) and 2',3'-dideoxycytidine (ddC, zalcitabine), used in the treatment of human immunodeficiency virus (HIV) infection, have been associated with a number of dose-limiting toxicities in clinical studies. These include myelotoxicity (AZT), myopathy (AZT), peripheral neuropathy (ddC, ddI) and pancreatitis (ddI). Myopathy, peripheral neuropathy and pancreatitis are also observed in HIV-infected patients who have not been treated with the nucleoside analogues. Thus, nucleoside analogue toxicity can be confused with the adverse effects of HIV infection. Animal models exist for some, but not all, aspects of nucleoside analogue-related toxicity. In vitro studies have been used extensively to elucidate the mechanisms of nucleoside analogue toxicity. Cellular purine and pyrimidine metabolizing enzymes phosphorylate the analogues, which can then interact with DNA polymerases. Inhibition of one of these, HIV reverse transcriptase, is responsible for the antiviral activity of the nucleoside analogues. Toxicity is caused by inhibition of nuclear or mitochondrial DNA polymerases (or both) and by chain termination of replicating DNA at the point of insertion of the nucleoside analogue. The different toxicities observed in the case of each nucleoside analogue are most likely explained by different affinities for each of the cellular DNA polymerases.
Authors:
O P Flint
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Toxicology in vitro : an international journal published in association with BIBRA     Volume:  8     ISSN:  0887-2333     ISO Abbreviation:  Toxicol In Vitro     Publication Date:  1994 Aug 
Date Detail:
Created Date:  2010-08-09     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8712158     Medline TA:  Toxicol In Vitro     Country:  England    
Other Details:
Languages:  eng     Pagination:  677-83     Citation Subset:  -    
Affiliation:
Experimental Pathology, Bristol-Myers Squibb, 315 North Thompson Road, Syracuse NY 13221, USA.
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