INHIBITION OF RIBONUCLEOSIDE METABOLISM IN EHRLICH ASCITES TUMOR CELLS BY PURINE ANALOGUE RIBONUCLEOSIDES

1965 ◽  
Vol 43 (10) ◽  
pp. 1701-1710 ◽  
Author(s):  
A. R. P. Paterson ◽  
A. I. Simpson
Keyword(s):  
Tumor Cells ◽  
Ehrlich Ascites Carcinoma ◽  
Carcinoma Cells ◽  
Ehrlich Ascites Tumor Cells ◽  
Purine Analogues ◽  
Intact Cells ◽  
Ehrlich Ascites ◽  
Derivatives Of ◽  
Related Compounds

Several aspects of the metabolism of inosine and uridine by Ehrlich ascites carcinoma cells in vitro have been found to be inhibited by ribonucleoside derivatives of four purine analogues. The synthesis of both inosine and uridine by intact tumor cells was profoundly inhibited in the presence of 6-methylmercaptopurine ribonucleoside. Also inhibited were inosine and uridine cleavage, and the exchange of isotope between these ribonucleosides and the corresponding C14 labelled bases. These reactions, however, were not inhibited when they took place in broken-cell preparations. Similarly, inosine metabolism in intact cells (but not in broken cells) was profoundly inhibited by three related compounds: the ribonucleosides of the 6-chloro, 6-methylmercapto, and 6-propylmercapto derivatives of 2-aminopurine.

THE ENZYMIC FORMATION OF 6-(METHYLMERCAPTO)PURINE RIBONUCLEOSIDE 5′-PHOSPHATE

1966 ◽  
Vol 44 (2) ◽  
pp. 229-245 ◽  
Author(s):  
Ian C. Caldwell ◽  
J. Frank Henderson ◽  
A. R. P. Paterson
Keyword(s):  
Tumor Cells ◽  
Blood Cells ◽  
Intraperitoneal Injection ◽  
Ehrlich Ascites Carcinoma ◽  
Carcinoma Cells ◽  
Ehrlich Ascites ◽  
Mouse Tissues ◽  
Enzymatic Methods

6-(Methylmercapto)purine ribonucleoside (Me6MPR) is efficiently phosphorylated in mouse tissues and in Ehrlich ascites carcinoma cells in vivo; tumor cells in vitro and cell-free extracts of the tumor also phosphorylate this analogue ribonucleoside. The product of this reaction has been identified by chemical and enzymatic methods and by its chromatographic behaviour as Me6MPR 5′-phosphate. The evidence presented in this report indicates that no other major metabolites of Me6MPR are formed.The phosphorylation of Me6MPR by cell-free tumor extracts requires ATP and Mn2+ (or Mg2+), and evidence is presented that the reaction is probably mediated by adenosine kinase.Me-14C-6MPR is rapidly taken up by most mouse tissues following its intraperitoneal injection. Forty minutes after injection of the labeled drug, the highest levels of radioactivity were found in intestine, liver, blood cells, lung, and spleen, in descending order; virtually no radioactivity was found in brain tissue or in blood plasma.

ARGININE UPTAKE AND ARGINASE ACTIVITY IN EHRLICH ASCITES CARCINOMA CELLS

1959 ◽  
Vol 37 (4) ◽  
pp. 589-598 ◽  
Author(s):  
R. M. Johnstone
Keyword(s):  
Amino Acids ◽  
Tumor Cells ◽  
Ehrlich Ascites Carcinoma ◽  
Carcinoma Cells ◽  
Arginase Activity ◽  
Anaerobic Glycolysis ◽  
Ehrlich Ascites Tumor Cells ◽  
Ascites Tumor ◽  
Arginine Uptake ◽  
Ehrlich Ascites

Anaerobic glycolysis in Ehrlich ascites tumor cells exposed to amino acids leads to an increased uptake of a number of the amino acids to levels comparable with those obtained under aerobic conditions. The arginine uptake in the cell is not increased by glucose. Anaerobically the arginase activity is inhibited when glucose is present. The inhibition appears to be the result of an increased retention in the cell of the ornithine produced by arginase activity.

ARGININE UPTAKE AND ARGINASE ACTIVITY IN EHRLICH ASCITES CARCINOMA CELLS

1959 ◽  
Vol 37 (1) ◽  
pp. 589-598 ◽  
Author(s):  
R. M. Johnstone
Keyword(s):  
Amino Acids ◽  
Tumor Cells ◽  
Ehrlich Ascites Carcinoma ◽  
Carcinoma Cells ◽  
Arginase Activity ◽  
Anaerobic Glycolysis ◽  
Ehrlich Ascites Tumor Cells ◽  
Ascites Tumor ◽  
Arginine Uptake ◽  
Ehrlich Ascites

Anaerobic glycolysis in Ehrlich ascites tumor cells exposed to amino acids leads to an increased uptake of a number of the amino acids to levels comparable with those obtained under aerobic conditions. The arginine uptake in the cell is not increased by glucose. Anaerobically the arginase activity is inhibited when glucose is present. The inhibition appears to be the result of an increased retention in the cell of the ornithine produced by arginase activity.

THE SYNTHESIS OF EXTRACELLULAR RIBONUCLEOSIDES BY ASCITES TUMOR CELLS IN VITRO

1965 ◽  
Vol 43 (2) ◽  
pp. 257-269 ◽  
Author(s):  
A. R. P. Paterson
Keyword(s):  
Tumor Cells ◽  
Ehrlich Ascites Carcinoma ◽  
Carcinoma Cells ◽  
Ascites Tumor ◽  
Ehrlich Ascites ◽  
Ehrlich Ascites Cells

Ehrlich ascites carcinoma cells in vitro converted extracellular hypoxanthine to extracellular inosine if uridine or guanosine was provided in the medium at the rate of 20–30 μmoles per milliliter of cells per hour. The synthesis of external uridine also took place when cells were incubated with uracil and a purine ribonucleoside, but at a lower rate than that of inosine. Intact Ehrlich ascites cells catalyzed an exchange between labelled uracil and uridine when both were present in the incubation medium.The synthesis of the extracellular ribonucleoside appeared to be mediated by ribonucleoside phosphorylases and to take place by the transfer of the ribosyl group from a donor ribonucleoside to an acceptor base.

METABOLISM OF 6-MERCAPTOPURINE RIBONUCLEOSIDE BY EHRLICH ASCITES CARCINOMA CELLS

1964 ◽  
Vol 42 (10) ◽  
pp. 1415-1423 ◽  
Author(s):  
A. R. P. Paterson ◽  
Aiko Sutherland
Keyword(s):  
Ehrlich Ascites Carcinoma ◽  
Carcinoma Cells ◽  
Glycosidic Linkage ◽  
Ascites Tumor ◽  
Resistant Line ◽  
Cell Compartment ◽  
Ehrlich Ascites ◽  
A Cell ◽  
Derivatives Of

Ribonucleoside derivatives of 6-mercaptopurine (6-MP) and other purine bases were rapidly catabolized when incubated with Ehrlich ascites carcinoma cells in vitro. The catabolism of purine ribonucleosides proceeded by way of phosphorolytic cleavage of the glycosidic linkage and resulted in accumulation of the liberated base in the incubation medium. The ribosyl portions of ribonucleoside substrates were utilized with the formation of lactate, which also appeared extracellularly.Cells of a 6-MP-resistant subline of the Ehrlich ascites tumor degraded 6-MP ribonucleoside (6-MPR) at rates comparable to those of the parent line. This finding, when considered with other characteristics of the resistant line of cells, implied that cleavage of 6-MPR took place in a cell compartment from which inosinate pyrophosphorylase was absent.

STUDIES ON THE BIOSYNTHESIS OF NUCLEOTIDES IN EHRLICH ASCITES CARCINOMA CELLS IN VITRO

1965 ◽  
Vol 43 (2) ◽  
pp. 209-224 ◽  
Author(s):  
B. I. Uppin ◽  
P. G. Scholefield
Keyword(s):  
Exchange Reaction ◽  
Ehrlich Ascites Carcinoma ◽  
Carcinoma Cells ◽  
The Other ◽  
Metabolic Inhibitors ◽  
Ehrlich Ascites ◽  
Oxidative Pathway ◽  
Time Courses ◽  
Oxidation Of Glucose

Studies have been made of the effects of metabolic inhibitors on the oxidation and incorporation of radioactivity into nucleotides of glucose labelled in the 1, 2, and 6 positions. The results indicate that in Ehrlich ascites carcinoma cells the predominant oxidative pathway is the hexosemonophosphate shunt. Investigation of the time courses of oxidation of the labelled glucose molecules confirms this conclusion. The pattern of incorporation of radioactivity initially suggests that nucleotide ribose is not formed via this pathway. However, it is shown that the coupling of an active transketolase system with the other enzymes of the hexosemonophosphate shunt provides a sufficient explanation of all the experimental observations. The conclusion is reached that pentose is formed by oxidation of glucose through the shunt but that the labelling pattern is largely established as the result of the exchange reaction catalyzed by transketolase.

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