Document Detail


Inhibition by derivatives of diguanidines of cell proliferation in Ehrlich ascites cells grown in cultures.
MedLine Citation:
PMID:  7396877     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The anti-proliferative effects of 1,1'-[(methylethanediylidene)dinitrilo]diguanidine [methylglyoxal bis(guanylhydrazone)] and 1,1'-[(metHYLETHANEDIYLIDENE)dinitrilo]bis-(3-aminoguaNIDINE) HAVE BEEN STUDIED IN Ehrlich ascites carcinoma cells grown in suspension cultures. Both compounds are potent inhibitors of S-adenosyl-L-methionine decarboxylase from the tumour cells. In the presence of putrescine (but not in its absence), the inhibition produced by 1,1'-[methylethanediylidene)dinitrilo]bis-(3-aminoguanadine) was apparently irreversible, as judged by persistent depression of the enzyme activity even after extensive dialysis. The two compounds produced similar increases in adenosylmethionine decarboxylase activity, which resulted from a striking stabilization of the enzyme in cells grown in the presence of the drugs. The inhibitory effect of the two diguanidine derivatives on the synthesis of DNA and protein became evident after an exposure of 4--8 h. At that time, the only change seen in tumour polyamines in cells grown in the presence of the inhibitors was an increase in cellular putrescine. To find out whether the compounds initially interfered with the energy production of the tumour cells, the cultures were grown in the presence of uniformly labelled glucose, and the formation of lactate, as well as the oxidation of the sugar into CO2, were measured. The activation of glycolysis upon dilution of the tumour cells with fresh medium and the subsequent formation of labelled CO2 were siliar in control cells and in cells exposed to methylglyoxal bis(buanylhydrazone), 1,1'-[(methylethanediylidene)dinitrilo]bis-(3-aminoguanidine) or diaminopropanol. Only a marginal decrease in the cellular content of ATP was found in cells exposed to the inhibitors for 24 h. The diguanidine-induced growth inhibition was fully reversed by low concentrations of exogenous polyamines. However, the possibility remained that the reversal by polyamines was due to a decrease of intracellular diguanidine concentration. Our results indicate that the mode of action of 1,1'-[(methylethanediylidene)dinitrilo]bis-(3-aminoguanidine) is fully comparable to that of methylglyoxal bis(guanylhydrazone), as regards stabilization of adenosylmethionine decarboxylase and the appearance of growth inhibition in Ehrlich ascites cells. The data tend to support the view that both compounds apparently have an early anti-proliferative effect unrelated to polyamine metabolism.
Authors:
L Alhonen-Hongisto; H Pösö; J Jänne
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  The Biochemical journal     Volume:  188     ISSN:  0264-6021     ISO Abbreviation:  Biochem. J.     Publication Date:  1980 May 
Date Detail:
Created Date:  1980-09-26     Completed Date:  1980-09-26     Revised Date:  2010-09-10    
Medline Journal Info:
Nlm Unique ID:  2984726R     Medline TA:  Biochem J     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  491-501     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Adenosylmethionine Decarboxylase / antagonists & inhibitors
Animals
Carcinoma, Ehrlich Tumor
Cell Division / drug effects*
Cells, Cultured
DNA / biosynthesis
Female
Glucose / metabolism
Guanidines / pharmacology*
Mice
Mitoguazone / analogs & derivatives,  pharmacology*
Polyamines / metabolism,  pharmacology
Propanolamines / pharmacology
Chemical
Reg. No./Substance:
0/Guanidines; 0/Polyamines; 0/Propanolamines; 459-86-9/Mitoguazone; 50-99-7/Glucose; 59200-49-6/1,1'-(methylethanediylidenedinitrilo)bis(3-aminoguanidine); 616-29-5/1,3-diamino-2-propanol; 9007-49-2/DNA; EC 4.1.1.50/Adenosylmethionine Decarboxylase
Comments/Corrections

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