Combination chemotherapy involving alpha-difluoromethylornithine and 1-beta-D-arabinofuranosylcytosine in murine L1210 leukemia.

Administration of 2% aqueous alpha-difluoromethylornithine (DFMO) as the sole drinking-fluid to C57BL X DBA/2 F1 (hereafter called BD2F1) mice for 5 days resulted in significant reduction of labeling index, percentage of cells in S phase, and intracellular putrescine and spermidine concentrations of bone marrow cells. DFMO treatment also resulted in moderate leukopenia. The decreases in body weight, peripheral leukocyte and erythrocyte counts, and subsequent recovery following administration of 1-beta-D-arabinofuranosylcytosine (ara-C), an S-phase-specific cytotoxic agent, to animals receiving DFMO was comparable to those observed in animals which received ara-C alone. In animals inoculated i.p. with L1210 cells, DFMO treatment produced a marginal increase in survival time and significant reductions in putrescine and spermidine concentrations of the tumor cells. However, in contrast to normal bone marrow cells, depletion of polyamines in tumor cells resulted in the progressive accumulation of these cells in S phase; by Day 5 following DFMO treatment, greater than 70% of the tumor cells were found to be in S phase compared to only 55% for cells from untreated animals. A significant synergistic increase in survival time with a combination of DFMO and ara-C was observed when the ara-C therapy was initiated at the time of maximum accumulation of tumor cells in S phase. The implications of these findings for the management of neoplasia are discussed.