In order to establish a more effective and safer therapy for androgen-dependent prostate cancer, to be used in addition to hormonal therapy, the anti-tumor effects of intralesionally administered macrophages activated with recombinant interferon-γ (INF-γ), alone or in combination with recombinant interleukin-2 (IL-2) were studied in mouse prostate cancer models. Firstly, in terms of cellular adoptive immunotherapy, phagocytosis against Latex bead and cytotoxicity against Shionogi 115 cancer cell line (SC115) of macrophages activated with INF-γ for 24 hour were investigated. One ml of 0.25% glycogen solution was intraperitoneally administered to male DS mice. Three days later, fluid was aspirated from the abdominal cavity and macrophages were separated for use in this experiment. Phagocytosis INF-γ-dose-dependently increased and macrophages activated with 100 U/ml INF-γ phagocytosed 78.3 ± 4.5% (mean ± SD) Latex bead. Cytotoxicity (modified MTT assay) of SC 115 by macrophages activated with 100 U/ml INF-γ increased remarkably in comparison with non-activated macrophages and there was a significant increase in the effector-to-target-cell ratio to 40 in the activated group 77 ± 4.3% (mean ± SD) relative to 50 ± 6.3% (mean ± SD) in the non-activated group. Based on these in vitro findings, hormonal therapy and adoptive local immunotherapy, alone or together, were studied in mouse prostate cancer models. The prostate cancer model was prepared through the subcutaneous transplantation of SC 115 in male DS mice and the treatments were initiated after tumors were palpable. The therapy protocols were as follows: Group I control and Group II received 20 mg/kg/day diethylstilbestrol diphosphate (DES-P) subcutaneously for 10 days, Group III received DES-P in combination with ten thousand units of IL-2 administered five times intralesionally, Group IV received DES-P in combination with 2×10
6 macrophages activated with 100 U/ml INF-γ administered three times intra-lesionally, Group V received DES-P and IL-2 in combination with activated macrophages. The therapeutic efficiencies were evaluated by calculating the tumor volume and survival time. The results of the tumor volume on the 40th day post tumor transplantation were as follows (mean ± SD): Group 17, 049 ± 1, 477 mm
3, Group 114, 495 ± 654 mm
3, Group 1112, 050 ± 724 mm
3, Group IV 2, 782 ± 970 mm
3, Group V 1, 555 ± 514 mm
3. The therapeutic groups showed significant tumor reduction relative to the control. Furthermore, intralesionally IL-2, the activated macrophages injected groups, alone or together, were more effective relative to the group receiving only DES-P. Group V showed a significant advantage in survival time relative to the control, but in the other groups no significant advantage was noted. Thus, this local immunotherapeutic approach seems to be encouraging from the point of view of establishing an adoptive therapy for androgen-dependent prostate cancer in combination with hormonal therapy.
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