Metabolism and therapeutic efficacy of 9-beta-D-arabinofuranosyl-2-fluoroadenine against murine leukemia P388.
The biochemical basis for the differential therapeutic activity of equally toxic doses of 9-beta-D-arabinofuranosyl-2-fluoroadenine (F-ara-A) administered on two schedules to tumor-bearing mice has been studied. A single dose (234 mg/kg) of F-ara-A in solution decreased the number of P388 leukemia cells by greater than 10(3), whereas a multiple-dose regimen (41 mg/kg every day for 5 days) of equal toxicity to the host was ineffective at reducing the tumor burden. No antitumor activity was seen when an equal dose of the relatively insoluble F-ara-A was injected as a suspension. The 5'-triphosphate of F-ara-A accumulated in P388 cells in levels proportional to the dose of the nucleoside and disappeared from these cells at an exponential rate with a half-life of 2.9 hr, which was independent of the cellular concentration of the nucleotide. The extent and duration of the inhibition of DNA synthesis of P388 cells was dependent on the dose of F-ara-A, but the rates of recovery were similar and in proportion to the cellular concentration of the analog triphosphate. The extent of the inhibition of DNA synthesis in host bone marrow and intestinal mucosa was also related to the dose of F-ara-A, but the recovery of these tissues proceeded to similar, incomplete levels (less than 60% of initial) 24 hr after F-ara-A injection of either 41 or 234 mg/kg. These results suggest that the equal toxicity of the two regimens of F-ara-A may be attributed to the similar extent of inhibition of host-tissue DNA synthesis evoked by each. In contrast, the greater extent and longer duration of inhibition of P388 cell DNA synthesis caused by the single dose of F-ara-A was responsible for its superior therapeutic activity. Measurements of F-ara-A triphosphate concentrations and the DNA-synthetic capacity of tumor and host tissues are determinants of the action of F-ara-A and may be used to predict optimal therapeutic dose schedules.
D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D005260:Female; D007413:Intestinal Mucosa / Q000378:metabolism; D007700:Kinetics; D007941:Leukemia P388 / Q000188:drug therapy* / Q000378:metabolism; D007942:Leukemia, Experimental / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use / Q000633:toxicity
D014740:Vidarabine; C024352:fludarabine