2,6-Diaminopurinedeoxyriboside as a prodrug of deoxyguanosine in L1210 cells.
The mode of action of the antiproliferative nucleoside analogue 2,6-diaminopurinedeoxyriboside (DAPdR) has been characterized in cultured L1210 cells. A marked concentration-dependent decrease in DNA synthesis and ribonucleotide reductase activity occurred in L1210 cells exposed to 0.05 to 1.0 mM DAPdR. Concomitantly, dGTP levels increased as much as 1100-fold as compared to untreated controls. Adenosine deaminase efficiently catalyzed DAPdR conversion to deoxyguanosine in vitro. In a comparative study, DAPdR and deoxyguanosine gave similar results. A 50% inhibition of cell growth during a 72-h incubation was achieved with 0.14 mM DAPdR or 0.26 mM deoxyguanosine. Deoxycytidine rescued the L1210 cells from DAPdR and deoxyguanosine toxicity to the same extent. DAPdR and deoxyguanosine counteracted the toxic effects of mycophenolic acid with the same efficiency. While DAPdR was not metabolized to its 5'-triphosphate, 2,6-diaminopurine was converted to 2,6-diaminopurineriboside 5'-triphosphate in L1210 cells; accordingly 50% inhibition of cell growth occurred at 0.015 mM 2,6-diaminopurine. Combinations of DAPdR with erythro-9-(2-hydroxy-3-nonyl)adenine or deoxycoformycin resulted in antagonism instead of an expected synergism. These data suggest that DAPdR exerts its toxicity on L1210 cells as a prodrug of deoxyguanosine.
D015075:2-Aminopurine / Q000031:analogs & derivatives / Q000627:therapeutic use; D058892:Adenosine Deaminase Inhibitors; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004261:DNA Replication / Q000187:drug effects; D003839:Deoxyadenosines / Q000031:analogs & derivatives* / Q000627:therapeutic use; D003841:Deoxycytidine / Q000494:pharmacology; D003849:Deoxyguanosine / Q000008:administration & dosage* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D007939:Leukemia L1210 / Q000188:drug therapy; D012264:Ribonucleotide Reductases / Q000378:metabolism
D058892:Adenosine Deaminase Inhibitors; D003839:Deoxyadenosines; D003841:Deoxycytidine; C003965:2'-amino-2'-deoxyadenosine; D015075:2-Aminopurine; C007300:2,6-diaminopurine; D012264:Ribonucleotide Reductases; D003849:Deoxyguanosine