Metabolism of 9-β-D-Arabinosyl-2-fluoroadenine-5′-phosphate by Mice Bearing P388 Leukemia

Abstract

The metabolism of 9-β-D-arabinofuranosyl-2-fluoroadenine-5′-phosphate (F-araAMP), a soluble nucleoside analog with promising antitumor activity, has been studied in mice bearing P388 leukemia. Upon i.p. injection of an LD₁₀ dose (1485 mg/kg) in tumorbearing mice, F-araAMP disappeared from the ascitic fluid with a T_½ of 1.2 h. This was accompanied by the appearance of 9-β-D-arabinofuranosyl-2-fluoroadenine and lesser amounts of 9-β-D-arabinofuranosyl-2-fluorohypoxanthine in both the ascitic fluid and plasma. The principal active metabolite, 9-β-D-arabinofuranosyl-2-fluoroadenine-5′-triphosphate, accumulated to approximately 1 mM in P388 cells, a concentration nearly 20-fold greater than that of the bone marrow or intestinal mucosa. DNA synthesis was inhibited to a similar extent in tumor and host tissues, but the duration of maximum inhibition was twice as long in P388 cells. 2-Fluoro-ATP, a second toxic metabolite, accumulated to 27μM in P388 cells and was eliminated with a T½ of 3.7 h. The contributions of both 9-β-D-arabinofuranosyl-2-fluoroadenine-5′-triphosphate and 2-fluoro-ATP to the cytotoxicity and therapeutic action of F-araAMP should be considered in evaluations of the biochemical bases for these activities.