Pharmacodynamics and proposed mechanism of therapeutic action and host toxicity of 9-beta-D-arabinofuranosyl-2-fluoroadenine monophosphate (F-araAMP) in P388 murine leukemia-bearing mice.

The cellular metabolism of 9-beta-D-arabinofuranosyl-2-fluoroadenine 5'monophosphate (F-araAMP), a soluble nucleoside analog with proven antileukemic activity in animal and human tumors, has been studied in mice bearing P388 leukemia. Earlier studies showed markedly less in vivo accumulation of F-ara ATP the principal active metabolite, in gastrointestinal mucosa (GI) and bone marrow (BM) compared with P388 after F-araA or F-araAMP administration. To elucidate the mechanism of toxicity this work has examined the pharmacodynamics of F-araAMP anabolites, F-araATP and F-ATP, in P388 cells, BM and GI mucosa tissues after nontoxic (LD1) and toxic (LD50) doses of F-araAMP. F-araATP was the major triphosphate metabolite in acid-soluble extracts from P388 cells, BM, and GI mucosa tissues. F-araATP accumulated to approximately 1 mM in P388 cells after either LD1 or LD50 treatment of F-araAMP and was eliminated with a t1/2,el of approximately 5 h. The ratio of the area under the concentration-time curve (AUC 0----infinity) of F-araATP was 1.01 after the LD50 over the LD1 doses of F-araAMP. BM and GI mucosa tissues accumulated 40-fold less F-araATP than the concentration in P388 cells. 2-Fluoro-ATP, a second toxic anabolite, accumulated in P388 cells to 156 +/- 39 microM and 447 +/- 79 microM after the two doses of the drug, respectively. The ratio of area under the curve (AUC) of F-ATP in P388 cells after the two doses of F-araAMP was 38.77, which approaches the ratio of % lethality (LD50/LD1 = 50). F-ATP was also quantitated in BM and GI mucosa reaching one-fifth to one-half the concentration of F-araATP after the LD50 dose of F-araAMP. The AUC values of F-ATP (0----24 h) were 9.5- to 12.5-fold higher after the LD50 than after the LD1 dose of F-araAMP. These results suggest that there is a selective therapeutic action of F-araAMP against P388 and that the increased cellular concentration of F-ATP in both the tumor cells and the host tissues (BM and GI mucosa) could explain the mode of toxicity of F-araAMP.