Biochemical Basis of the Increased Activity of 9-ß-D-Arabinofuranosyladenine in the Presence of Inhibitors of Adenosine Deaminase

The effects of 9-ß-D-arabinofuranosyladenine (ara-A) administered i.p. alone or in the presence of one of the adenosine deaminase inhibitors, erythro-9-(2-hydroxy-3-nonyl)adenine or 2’-deoxycoformycin, on the DNA-synthetic capacity (DSC) and 9-ß-D-arabinofuranosyladenine 5’-triphosphate levels of P388 cells, host bone marrow, and intestinal mucosa have been investigated. Inhibition of adenosine deaminase with either erythro-9-(2-hydroxy-3-nonyl)adenine or 2’-deoxycoformycin resulted in increased cellular 9-ß-D-arabinofuranosyladenine 5’-triphosphate concentrations which were associated with a decrease in DSC. Although initially inhibited to the same extent by 50 mg ara-A per kg plus either of the adenosine deaminase inhibitors, the DSC of host tissues recovered to control values by 5 hr after drug injection, whereas the tumor DSC remained maximally inhibited for 5 hr and did not attain control values until after 13 hr. The inhibition of P388 cells and host tissue DSC by a second dose of ara-A plus either of the adenosine deaminase inhibitors 6 hr after the first dose was increased slightly but recovered on a time course similar to that seen after a single dose. Sequential therapy with either 3 or 6 doses of ara-A combined with erythro-9-(2-hydroxy-3-nonyl)adenine elicited the longest survival of tumor-bearing mice when the interval of drug administration was 6 hr. Thus, the greatest increase in therapeutic activity was achieved by dose schedules that produced transient inhibition of DSC in host tissues while sustaining maximal inhibition of tumor DSC. Measurements of the extent and duration of DSC inhibition and of cellular 9-ß-D-arabinofuranosyladenine 5’-triphosphate levels may be useful biochemical determinants in the design and optimization of schedules of ara-A therapy.