Enhancement of 9-beta-d-arabinofuranosyladenine cytotoxicity to mouse leukemia L1210 in vitro by 2'-deoxycoformycin.
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.
D058892:Adenosine Deaminase Inhibitors; D000818:Animals; D001381:Azepines / Q000494:pharmacology* / Q000627:therapeutic use; D002478:Cells, Cultured; D004273:DNA, Neoplasm / Q000096:biosynthesis; D003853:Deoxyribonucleosides / Q000494:pharmacology* / Q000627:therapeutic use; D004357:Drug Synergism; D007939:Leukemia L1210 / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009363:Neoplasm Proteins / Q000096:biosynthesis; D011684:Purine Nucleosides / Q000494:pharmacology*; D012334:RNA, Neoplasm / Q000096:biosynthesis; D014740:Vidarabine / Q000494:pharmacology* / Q000627:therapeutic use
D058892:Adenosine Deaminase Inhibitors; D001381:Azepines; D004273:DNA, Neoplasm; D003853:Deoxyribonucleosides; D009363:Neoplasm Proteins; D011684:Purine Nucleosides; D012334:RNA, Neoplasm; D014740:Vidarabine