Document Detail


A human T lymphoid cell variant resistant to the acyclic nucleoside phosphonate 9-(2-phosphonylmethoxyethyl)adenine shows a unique combination of a phosphorylation defect and increased efflux of the agent.
MedLine Citation:
PMID:  7870049     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
9-(2-Phosphonylmethoxyethyl)adenine (PMEA) is a new antiviral agent with activity against herpes viruses and retroviruses, including human immunodeficiency virus, but its metabolism and mechanism of action remain unclear. We have isolated a human T lymphoid cell line (CEMr-1) that is resistant to the antiproliferative effects of PMEA. The antiviral effects of PMEA against human immunodeficiency virus-1 infection were also greatly reduced in CEMr-1 cells, compared with the parental cells. This mutant showed cross-resistance to the related acyclic nucleoside phosphonates 9-(2-phosphonylmethoxyethyl)diaminopurine and 9-(2-phosphonylmethoxyethyl)guanine and the lipophilic prodrug bis(pivaloyloxymethyl)-9-(2-phosphonylmethoxyethyl)adenine-( bispome-PMEA), as well as partial resistance to the purine nucleosides 2-chlorodeoxyadenosine, 2-fluro-9-beta-D-arabinosylfuranosyladenine, and adenosine, but did not show resistance to 2'-deoxyadenosine or 9-beta-D-arabinosylfuranosyladenine. We compared the uptake and metabolism of [3H]PMEA and [3H]-bispom-PMEA in the mutant and parental cells. The analysis of radioactive products by high pressure liquid chromatography revealed marked alterations in the ability of the mutant cell line to accumulate PMEA and its anabolites, compared with the parental cells. Accumulation of PMEA, PMEA monophosphate, and PMEA bisphosphate (major metabolites formed with either PMEA or bispom-PMEA) decreased by 50, 95, and 97%, respectively. Compared with the parental cells, the variant cells showed a approximately 7-fold increase in the rate of efflux of PMEA and a 2-fold decrease in the activity of adenylate kinase. In contrast, other enzymes of nucleotide metabolism, such as adenosine kinase, deoxycytidine kinase, and 5-phosphoribosyl-1-pyrophosphate synthetase, showed no significant change in the two cell lines. Overall, these results suggest that the mutation in this resistant cell line is of a novel type, involving an alteration in the cellular efflux of PMEA as the major basis for the resistant phenotype.
Authors:
B L Robbins; M C Connelly; D R Marshall; R V Srinivas; A Fridland
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Molecular pharmacology     Volume:  47     ISSN:  0026-895X     ISO Abbreviation:  Mol. Pharmacol.     Publication Date:  1995 Feb 
Date Detail:
Created Date:  1995-03-29     Completed Date:  1995-03-29     Revised Date:  2013-05-24    
Medline Journal Info:
Nlm Unique ID:  0035623     Medline TA:  Mol Pharmacol     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  391-7     Citation Subset:  IM; X    
Affiliation:
Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee 38105.
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MeSH Terms
Descriptor/Qualifier:
Adenine / analogs & derivatives*,  metabolism,  pharmacology
Adenosine Kinase / metabolism
Antiviral Agents / metabolism,  pharmacology*
Biological Transport
Cell Line
Deoxycytidine Kinase / metabolism
Drug Resistance
Humans
Organophosphonates*
Phosphorylation
Phosphotransferases (Alcohol Group Acceptor) / metabolism
T-Lymphocytes / drug effects*,  enzymology,  metabolism
Grant Support
ID/Acronym/Agency:
P30-CA21765/CA/NCI NIH HHS; R01-AI27652/AI/NIAID NIH HHS; R01-AI31145/AI/NIAID NIH HHS
Chemical
Reg. No./Substance:
0/Antiviral Agents; 0/Organophosphonates; 6GQP90I798/adefovir; 73-24-5/Adenine; EC 2.7.1.-/Phosphotransferases (Alcohol Group Acceptor); EC 2.7.1.20/Adenosine Kinase; EC 2.7.1.74/Deoxycytidine Kinase; EC 2.7.1.76/deoxyadenosine kinase

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


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