Effective chemo-immunotherapy of L1210 leukemia in vivo using interleukin-12 combined with doxorubicin but not with cyclophosphamide, paclitaxel or cisplatin.
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.
Department of Immunology, Institute of Biostructure, Medical University of Warsaw, Poland. rzagozd@ib.amwaw.edu.pl
R
R
Zagozdzon
J
J
Gołab
T
T
Stokłosa
A
A
Giermasz
D
D
Nowicka
W
W
Feleszko
W
W
Lasek
M
M
Jakóbisiak
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002945:Cisplatin / Q000627:therapeutic use; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000627:therapeutic use; D004317:Doxorubicin / Q000627:therapeutic use*; D005260:Female; D007167:Immunotherapy; D007371:Interferon-gamma / Q000276:immunology; D018664:Interleukin-12 / Q000627:therapeutic use*; D007939:Leukemia L1210 / Q000097:blood / Q000276:immunology / Q000628:therapy*; D008262:Macrophage Activation; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D017239:Paclitaxel / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000627:therapeutic use; D016019:Survival Analysis; D013997:Time Factors; D014916:Whole-Body Irradiation
D000970:Antineoplastic Agents; D011994:Recombinant Proteins; D018664:Interleukin-12; D004317:Doxorubicin; D007371:Interferon-gamma; D003520:Cyclophosphamide; D017239:Paclitaxel; D002945:Cisplatin