pentostatin and Carcinoma--Ehrlich-Tumor

Topics: Adenine; Adenosine Deaminase Inhibitors; Adult; Animals; Carcinoma, Ehrlich Tumor; Clinical Trials as Topic; Coformycin; DNA; Drug Evaluation; Drug Synergism; Humans; Leukemia P388; Leukemia, Experimental; Leukemia, Lymphoid; Male; Mice; Nucleoside Deaminases; Pentostatin; Thymidine; Vidarabine

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.

Topics: Adenine; Adenosine Deaminase Inhibitors; Animals; Antineoplastic Agents; Carcinoma, Ehrlich Tumor; Coformycin; Deoxyadenine Nucleotides; Deoxyadenosines; Drug Resistance; Drug Synergism; Female; Mice; Nucleoside Deaminases; Pentostatin; Ribonucleosides