Document Detail


Transport, phosphorylation, and toxicity of a tricyclic nucleoside in cultured Novikoff rat hepatoma cells and other cell lines and relase of its monophosphate by the cells.
MedLine Citation:
PMID:  187799     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
1,4,5,6,8-Pentaazaacenaphthylene-3-amino-1,5-dihydro-5-methyl-(5-14C)-1-beta-D-ribofuranysly (NSC-154020), a tricyclic 7-deazapurine nucleoside (TCN), was rapidly incorporated into the acid-soluble pool by cultured Novikoff rat hepatoma cells, mouse L-cells, HeLa cells, and HEp-2 cells, but little incorporation into nucleic acids occurred. More than 90% of the intracellular radioactivity was associated with the monophosphate (MP) of the substrate concentration followed normal Michaelis-Menten kinetics. Comparison of the kinetic constants for the uptake of adenosine and the TCN and of the inhibition of their uptake by each other suggests that both were transported by the same system (Michaelis constant approximately 6-10 muM) and with about the same efficiency. The TCN was also phosphorylated in a cellfree extract containing adenosine kinase activity at about the same rate as was adenosine, but not further phosphorylation of the analogue MP occurred. No significant deamination or degradation of the adenosine analogue to its base and ribose-1-phosphate was observed. TCN inhibited the replication of all four types of cells propagated in suspension culture; however, Novikoff cells were several times more sensitive than were the other three cell types, despite the finding that the TCN-MP, probably the main toxic principle, accumulated to about the same concentration in cells of all four lines. Complete inhibition of replication of Novikoff cells were several times more sensitive than were the other three cell types, despite the finding that the TCN-MP, probably the main toxic principle, accumulated to about the same concentration in cells of all four lines. Complete inhibition of replication of Novikoff cells and cell death occurred at concentration as low as 15 muM TCN. At these concentrations, TCN, within 2 hours of its addition, completely inhibited the incorporation of [14C]formate int0 nucleotides and nucleic acids of Novikoff cells. An inhibition of the denovo synthesis of purine and pyrimidines, however, was not the only toxic effect of the TCN since high concentrations of uridine, adenine, guanine, and hypoxanthine, either alone or combined, failed to prevent the inhibition of cell replication by TCN. Also, between 1 and 3 hours of treatment, 70-80% of the Novikoff cells fragmented into four to eight vesicles per cell. These fragments were impermeable to trypan blue, still exhibited some metabolic activity such as the phosphorylation of AMP and TCN, but failed to replicate when the drug was removed. No similar fragmentation was observed with the other cell lines. Novikoff and L-cells rapidly released TCN-MP into the culture fluid. After 4 hours of incubation, 70-100% of the total radioactivity in the medium was associated with the MP. Only a little TCN-MP was released from HeLa and HEp-2 cells. A TCN-resistant mutant of Novikoff cells failed to phosphorylate the analogue and was deficient in adenosine kinase.
Authors:
P G Plagemann
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Journal of the National Cancer Institute     Volume:  57     ISSN:  0027-8874     ISO Abbreviation:  J. Natl. Cancer Inst.     Publication Date:  1976 Dec 
Date Detail:
Created Date:  1977-02-26     Completed Date:  1977-02-26     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  7503089     Medline TA:  J Natl Cancer Inst     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  1283-95     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Adenosine Monophosphate / metabolism
Carcinoma, Hepatocellular / drug therapy,  metabolism*
Cell Division / drug effects
Cell Line
Cell Membrane / metabolism
Cells, Cultured
Hela Cells / drug effects
L Cells (Cell Line) / drug effects
Liver Neoplasms / drug therapy,  metabolism*
Neoplasms, Experimental / drug therapy,  metabolism
Nucleosides / metabolism
Oxidative Phosphorylation
Phosphates / metabolism
Purines / metabolism
Ribonucleosides / metabolism*,  pharmacology,  toxicity
Chemical
Reg. No./Substance:
0/Nucleosides; 0/Phosphates; 0/Purines; 0/Ribonucleosides; 61-19-8/Adenosine Monophosphate

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