In this study we investigated the efficacy of a combination of
IL-12 and
5-FU, a chemotherapeutic exerting several immunomodulatory effects, in murine
L1210 leukemia. Mice inoculated with 1 x 10(5)
leukemia cells were treated with a single dose of
5-FU (50 mg/kg) and seven daily doses of
IL-12 (100 ng/dose), and were observed for survival. Treatment with
IL-12 or
5-FU given alone produced moderate anti-leukemic effects. However, combination of both drugs resulted in a significant prolongation of mouse survival time. Importantly, there were 70% of long-term (>60 days) survivors among mice treated with both agents simultaneously. Moreover, we observed 100% of long-term survivors when mice were treated with a minimally increased dose of
IL-12 (170 ng) in combination with
5-FU (50 mg/kg). The antileukemic effects were completely abrogated in scid/scid mice and in mice depleted of peritoneal macrophages and significantly decreased after administration of anti-CD3+, anti-CD4+ or anti-CD8+
monoclonal antibodies. Administration of anti-NK1.1
antibodies did not decrease the antileukemic effects indicating that NK cells are not important effectors of this treatment regimen. Collectively, these results indicate that the combination of
IL-12 and
5-FU is inducing strong antileukemic responses that are dependent on the presence and activity of macrophages and T lymphocytes and warrant further studies of combined chemo-
immunotherapy with
IL-12.