Summary
The simultaneous administration of 3′-deoxyadenosine N l-oxide (3′-dANO) and the adenosine deaminase inhibitors erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA) or 2′-deoxycoformycin (2′-dCF) to mice bearing Ehrlich ascites tumor cells resistant to 3′-dANO resulted in 80%–90% inhibition of tumor growth in vivo. 3′-dANO and 2′-dCF increased the survival time of tumor-bearing mice by a factor of 2. In vitro studies showed that the 3′-dANO resistant Ehrlich cells initiate the metabolism of 3′-dANO by a reduction to 3′-deoxyadenosine, which is converted primarily to 3′-deoxyinosine by adenosine deaminase and, to a small extent, phosphorylated to the cell toxic agent 3′-dATP. By the addition of EHNA or 2′-dCF it was possible to block the formation of 3′-deoxyinosine, resulting in a profound stimulation in the accumulation of 3′-dAtP. The development of resistance to 3′-dANO was studied in cell cultures and found to be accompanied by changes in the enzyme activities of the reductase, the adenosine kinase, and the adenosine deaminase.
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Abbreviations
- 3′-dANO:
-
3′-deoxyadenosine N l-oxide
- 3′-dA:
-
3′-deoxyadenosine
- 3′-dI:
-
3′-deoxyinosine
- 3′-dATP:
-
3′-deoxyadenosine triphosphate
- EHNA:
-
erythro-9-(2-hydroxy-3-nonyl) adenine
- 2′-dCF:
-
2′-deoxycoformycin
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This work was supported by the Danish Medical Research Council, Gerda and Åge Haensch Foundation, Dirktør Åge Henriksens Foundation, P. Carl Petersens Foundation and the Danish Cancer Society
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Svendsen, K.R., Overgaard-Hansen, K. & Frederiksen, S. Synergistic effect of 3′-deoxyadenosine N 1-oxide and adenosine deaminase inhibitors on growth of Ehrlich ascites tumor cells in vivo. Cancer Chemother. Pharmacol. 21, 35–39 (1988). https://doi.org/10.1007/BF00262735
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DOI: https://doi.org/10.1007/BF00262735