Synergistic effect of 3'-deoxyadenosine N1-oxide and adenosine deaminase inhibitors on growth of Ehrlich ascites tumor cells in vivo.
The simultaneous administration of 3'-deoxyadenosine N1-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.
Svendsen
K R
KR
Department of Biochemistry C, Panum Institute, University of Copenhagen, Denmark.
Overgaard-Hansen
K
K
Frederiksen
S
S
D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D058892:Adenosine Deaminase Inhibitors; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002286:Carcinoma, Ehrlich Tumor / Q000188:drug therapy*; D003070:Coformycin / Q000031:analogs & derivatives / Q000494:pharmacology*; D003838:Deoxyadenine Nucleotides / Q000378:metabolism; D003839:Deoxyadenosines / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004351:Drug Resistance; D004357:Drug Synergism; D005260:Female; D051379:Mice; D009700:Nucleoside Deaminases / Q000037:antagonists & inhibitors*; D015649:Pentostatin; D012263:Ribonucleosides / Q000494:pharmacology*
D058892:Adenosine Deaminase Inhibitors; D000970:Antineoplastic Agents; D003838:Deoxyadenine Nucleotides; D003839:Deoxyadenosines; D012263:Ribonucleosides; C052326:3'-deoxyadenosine N(1)-oxide; D003070:Coformycin; D015649:Pentostatin; C010192:9-(2-hydroxy-3-nonyl)adenine; C011746:3'-deoxyadenosine 5'-triphosphate; D009700:Nucleoside Deaminases; D000225:Adenine