Studies on the mechanism of cytotoxicity of 3'-deoxyadenosine N1-oxide in different strains of Ehrlich ascites tumor cells

The correlation between the metabolic processing of 3'-deoxyadenosine N1-oxide (3'-dANO) in vitro and its effect on tumor growth in vivo has been investigated in seven different strains of Ehrlich ascites tumor cells. The metabolism of 3'-dANO is initiated by reduction to 3'-deox...

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Bibliographic Details
Published in:	Cancer chemotherapy and pharmacology Vol. 19; no. 2; pp. 118 - 122
Main Authors:	SVENDSEN, K. R, OVERGAARD-HANSEN, K, FREDERIKSEN, S, LOFT, H, ANGELHOLM, S. A
Format:	Journal Article
Language:	English
Published:	Berlin Springer 1987
Subjects:	Adenosine Deaminase - metabolism Adenosine Kinase - metabolism Animals Antineoplastic agents Biological and medical sciences Biotransformation Carcinoma, Ehrlich Tumor Cell Line Cell Survival - drug effects Deoxyadenosines - analogs & derivatives Deoxyadenosines - toxicity General aspects Medical sciences Mice Pharmacology. Drug treatments Antineoplastic agent Cell proliferation Ascites tumor Ehrlich ascites tumor Cytotoxicity Strain specificity Mechanism of action In vitro Tumor cell
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Summary:	The correlation between the metabolic processing of 3'-deoxyadenosine N1-oxide (3'-dANO) in vitro and its effect on tumor growth in vivo has been investigated in seven different strains of Ehrlich ascites tumor cells. The metabolism of 3'-dANO is initiated by reduction to 3'-deoxyadenosine (3'-dA). This process is the rate-limiting process. The 3'-dA does not accumulate, but is converted to 3'-deoxyadenosine triphosphate (3'-dATP) or 3'-deoxyinosine (3'-dI). The ratio between 3'-dATP and 3'-dI inosine corresponds to the ratio between the activities of adenosine kinase and adenosine deaminase in the cell. Two of the cell lines were markedly inhibited by 3'-dANO in vivo. In these cells the accumulation of 3'-dATP was 1.4-2.2 nmol/h per mg cells, which accounts for the major part of the metabolized 3'-dANO. Five of the cell lines were not inhibited by 3'-dANO and the formation of 3'-dATP was 5-10 times less in these than in the sensitive strains. The low level of 3'-dATP is caused primarily by a low ratio between the activities of adenosine kinase and adenosine deaminase, which is 15 time less than in the sensitive cell lines. The rate of reduction of 3'-dANO seems to be of minor importance. These results indicate a correlation between the inhibition of tumor growth by 3'-dANO and the ability of the cell to accumulate 3'-dATP from 3'-dANO and show that this conversion is determined solely by the rate of reduction of 3'-dANO (3'-dANO reductase activity) and the ratio between the activities of adenosine kinase and adenosine deaminase in the cell. Consequently, the estimation of these enzyme activities in cell lysate of a given tumor can be used to predict whether the tumor is susceptible to inhibition by 3'-dANO.
ISSN:	0344-5704 1432-0843
DOI:	10.1007/BF00254562