Effective chemo-immunotherapy of L1210 leukemia in vivo using interleukin-12 combined with doxorubicin but not with cyclophosphamide, paclitaxel or cisplatin

It has been wall 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 anti. leukemic 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. (C) 1998 Wiley-Liss, Inc.