It has been well established that chemo-
immunotherapy using cytotoxic drugs and appropriate
cytokines offers a new approach to increasing the therapeutic index in the treatment of neoplastic diseases. This study investigates the efficacy of combinations of
interleukin-12 with
cyclophosphamide,
paclitaxel, cisplatin or
doxorubicin in the murine
L1210 leukemia model. Mice inoculated i.p. with 1 x 10(3) or 1 x 10(5)
leukemia cells were treated with
interleukin-12 and/or chemotherapeutics, and were observed daily for survival. Immunosuppression with X-irradiation or macrophage depletion with
injections of
silica were used to examine the dependence of the
therapeutic effects on the efficiency of the immune system. Treatment with
interleukin-12 or one of the studied chemotherapeutics given alone resulted in moderate antileukemic effects. Combination of
interleukin-12 with
cyclophosphamide or
paclitaxel produced no augmentation of anti-leukemic effects in comparison with these agents given alone. Combination of
interleukin-12 with
cisplatin resulted in prolongation of the survival time; however, in the experiment with mice inoculated with 1 x 10(5)
leukemia cells, no long-term survivors (>60 days) were observed; on the contrary, combination of
interleukin-12 with
doxorubicin resulted in 100% long-term survivors. This effect was completely abrogated either by X-irradiation of mice or by macrophage depletion. We also found that
doxorubicin augments IL-12-stimulated production of
interferon-gamma in vivo. Our observations demonstrating potentiation of the antileukemic effects of the
IL-12 and
doxorubicin combination suggest that the combined use of these 2 agents could be beneficial in
leukemia therapy.