Synergistic inhibition of leukemia L1210 cell growth in vitro by combinations of 2-fluoroadenine nucleosides and hydroxyurea or 2,3-dihydro-1H-pyrazole[2,3-a]imidazole.
9-beta-D-Arabinofuranosyl-2-fluoroadenine (2-F-ara-A) and 2-fluoro-2'-deoxyadenosine (2-FdAdo) were potent inhibitors of L1210 cell growth in culture. Even though these 2-fluoroadenine nucleosides are very poor substrates for adenosine deaminase, erythro-9-(2-hydroxyl-3-nonyl)adenine potentiated the growth-inhibitory properties of 2-FdAdo but not 2-F-ara-A in a synergistic manner. 2-FdAdo and 2-F-ara-A inhibited the conversion of [3H]cytidine to deoxycytidine nucleotides and incorporation into DNA, suggesting that ribonucleotide reductase was an intracellular site of action. 2-F-ara-A (6 microM) in combination with 2,3-dihydro-1H-pyrazole[2,3-a]imidazole gave synergistic inhibition of L1210 cell growth. At lower concentrations of 2-F-ara-A, the inhibition by this combination was only additive. The addition of Desferal to the combination of 2-F-ara-A plus 2,3-dihydro-1H-pyrazole[2,3-a]imidazole provided a strong synergistic combination. Similar results were obtained with combinations which included F-ara-A, hydroxyurea, and Desferal. The combinations of 2-FdAdo plus 2,3-dihydro-1H-pyrazole[2,3-a]imidazole or hydroxyurea gave strong synergistic inhibition of L1210 cell growth, even at the lowest concentration of 2-FdAdo (0.6 microM) studied. The presence of Desferal in the combination served to further potentiate the synergism.
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D003562:Cytidine / Q000378:metabolism; D003676:Deferoxamine / Q000633:toxicity; D003839:Deoxyadenosines / Q000031:analogs & derivatives* / Q000633:toxicity; D003841:Deoxycytidine / Q000096:biosynthesis; D004357:Drug Synergism; D006918:Hydroxyurea / Q000633:toxicity*; D007700:Kinetics; D007939:Leukemia L1210 / Q000503:physiopathology*; D051379:Mice; D011720:Pyrazoles / Q000633:toxicity*; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000633:toxicity
D003839:Deoxyadenosines; D011720:Pyrazoles; D003841:Deoxycytidine; D003562:Cytidine; C030964:2'-fluoro-2'-deoxyadenosine; D014740:Vidarabine; D003676:Deferoxamine; C000971:2,3-dihydro-1H-imidazo(1,2-b)pyrazole; C024352:fludarabine; D006918:Hydroxyurea