Enhancement of 9-beta-d-arabinofuranosyladenine cytotoxicity to mouse leukemia L1210 in vitro by 2'-deoxycoformycin

Abstract

2'-Deoxycoformycin (2'-dCF), a potent inhibitor of adenosine deaminase, was tested in combination with 9-beta-D-arabinofuranosyladenine (ara-A) and 9-beta-D-arabinofuranosyladenine 5'-formate for cytotoxic activity against mouse leukemia L1210 in culture. 2'-dCF, which alone had no activity, significantly enhanced cytostatic and cytotoxic activities of ara-A and its more soluble derivative, 9-beta-D-arabinofuranosyladenine 5'-formate; the latter 2 agents, when tested at equimolar concentrations, were equivalent in their effects on proliferation and viability. The therapeutic response of mice bearing the in vitro line of L1210 cells (L1210/C2) to combination therapy with 2'-dCF and 9-beta-D-arabinofuranosyladenine 5'-phosphate was comparable to that reported elsewhere for therapy of mice bearing the parent in vivo line. Continuous exposure of cultured L1210 cells to ara-A and 2'-dCF induced a prolonged period of unbalanced growth, characterized by inhibition of proliferation and DNA synthesis while RNA and protein synthesis continued; exposure periods in excess of a single population doubling were required to achieve significant cell kill. Potentiation of ara-A activity against the relatively insensitive mouse leukemia L1210 was attributed to increased stability of ara-A resulting from 2'-dCF inhibition of adenosine deaminase.