Document Detail


Resistance to pyrazofurin and 6-azauridine in normal MC3T3-E1 murine osteoblasts.
MedLine Citation:
PMID:  2479415     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Stable variants resistant to pyrazofurin (PF) and 6-azauridine (AZUrd) were serially selected in increasing drug concentrations from an MC3T3-E1 nontumorigenic murine osteoblastic cell line. Monophosphates of both AZUrd and PF competitively inhibit orotidine-5'-monophosphate decarboxylase (ODCase) activity of the UMP synthase multifunctional enzyme. When compared to the wild type cells, the AZUrdr and PFr lines were 3000- and 10,000-fold more resistant, respectively. Flow cytometry indicated tetraploidy in wild type cells and a reduction of DNA content in both resistant cell lines. DNA dot blot analysis showed no amplification of the gene coding for UMP synthase in either AZUrdr or PFr cells. Measurements of UMP synthase showed a 6-fold higher activity in AZUrdr cells and no significant difference in PFr cells as compared to wild type. Sensitivity to 5-fluorouracil was increased in the AZUrdr line as opposed to PFr and normal cell lines, indicating an increased orotate phosphoribosyltransferase activity in the AZUrdr cells. In comparison to wild type cells, PFr cells were 100-fold resistant to 6-methylmercaptopurine riboside, suggesting a lack of adenosine kinase activity. The control and AZUrdr cells showed equal sensitivity to 5-fluorouridine, thus indicating unchanged uridine kinase levels. While PFr cells were not cross-resistant to AZUrd, the AZUrdr cells were cross-resistant to PF. These results indicate the possibility of an altered ODCase active site. Although amplification of unrelated sequences cannot be excluded, our findings show that bone tetraploid, nontumorigenic cells acquire drug resistance through mechanisms other than the amplification of a target gene and that this resistance is accompanied by the partial loss of a chromosomal complement.
Authors:
D R Beidler; A F Candia; M I Chernin; J F Novak
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Biochimica et biophysica acta     Volume:  1014     ISSN:  0006-3002     ISO Abbreviation:  Biochim. Biophys. Acta     Publication Date:  1989 Nov 
Date Detail:
Created Date:  1990-01-08     Completed Date:  1990-01-08     Revised Date:  2003-11-14    
Medline Journal Info:
Nlm Unique ID:  0217513     Medline TA:  Biochim Biophys Acta     Country:  NETHERLANDS    
Other Details:
Languages:  eng     Pagination:  101-7     Citation Subset:  IM    
Affiliation:
Orthopaedic Research Laboratory, Allegheny-Singer Research Institute, Pittsburgh, PA 15212.
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MeSH Terms
Descriptor/Qualifier:
Animals
Azauridine / pharmacology*
Binding, Competitive
Cell Line
DNA / analysis,  metabolism
Drug Resistance / genetics
Flow Cytometry
Fluorouracil / pharmacology
Gene Amplification
Mice
Multienzyme Complexes / genetics,  metabolism
Nucleic Acid Hybridization
Orotate Phosphoribosyltransferase / genetics,  metabolism
Orotidine-5'-Phosphate Decarboxylase / antagonists & inhibitors,  genetics,  metabolism
Osteoblasts / drug effects*,  metabolism
Ploidies
Ribonucleosides / pharmacology*
Uridine Kinase / metabolism
Chemical
Reg. No./Substance:
0/Multienzyme Complexes; 0/Ribonucleosides; 30868-30-5/pyrazofurin; 51-21-8/Fluorouracil; 54-25-1/Azauridine; 74870-74-9/uridine 5'-monophosphate synthase; 9007-49-2/DNA; EC 2.4.2.10/Orotate Phosphoribosyltransferase; EC 2.7.1.48/Uridine Kinase; EC 4.1.1.23/Orotidine-5'-Phosphate Decarboxylase

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


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