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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

Department of Biochemistry, University of South Florida College of Medicine [A. S. and J. G. C.], Tampa, Florida 33612, and Organic Chemistry Research Department, Southern Research Institute [J. A. M.], Birmingham, Alabama 35205

9-ß-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 µM) 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 µM) studied. The presence of Desferal in the combination served to further potentiate the synergism.

¹ Supported by Grant CA 27398 awarded by the National Cancer Institute, NIH, USPHS.

² Supported by Grant CA 24975 awarded by the National Cancer Institute, NIH, USPHS. To whom requests for reprints should be addressed.

Received 5/ 9/83. Accepted 4/27/84.