Metabolism of 9-beta-D-arabinosyl-2-fluoroadenine-5'-phosphate by mice bearing P388 leukemia.
The metabolism of 9-beta-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 tumor-bearing mice, F-araAMP disappeared from the ascitic fluid with a T1/2 of 1.2 h. This was accompanied by the appearance of 9-beta-D-arabinofuranosyl-2-fluoroadenine and lesser amounts of 9-beta-D-arabinofuranosyl-2-fluorohypoxanthine in both the ascitic fluid and plasma. The principal active metabolite, 9-beta-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 27 microM in P388 cells and was eliminated with a T1/2 of 3.7 h. The contributions of both 9-beta-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.
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology / Q000633:toxicity; D001088:Arabinonucleotides / Q000378:metabolism*; D004247:DNA / Q000096:biosynthesis; D004273:DNA, Neoplasm / Q000096:biosynthesis; D005260:Female; D007941:Leukemia P388 / Q000378:metabolism*; D007942:Leukemia, Experimental / Q000378:metabolism*; D051379:Mice; D008811:Mice, Inbred DBA; D001084:Vidarabine Phosphate / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology
D000970:Antineoplastic Agents; D001088:Arabinonucleotides; D004273:DNA, Neoplasm; D001084:Vidarabine Phosphate; C038022:2-fluoro-ATP; C042382:fludarabine phosphate; D000255:Adenosine Triphosphate; D004247:DNA