Experimental study of the effects of hormonal therapy and intralesional injections of interleukin 2, activated macrophages on mouse prostate cancer models

Abstract

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-gamma (INF-gamma), 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-gamma 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-gamma-dose-dependently increased and macrophages activated with 100 U/ml INF-gamma phagocytosed 78.3 +/- 4.5% (mean +/- SD) Latex bead. Cytotoxicity (modified MTT assay) of SC 115 by macrophages activated with 100 U/ml INF-gamma 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 SC115 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 x 10(6) macrophages activated with 100 U/ml INF-gamma administered three times intralesionally, 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 I 7,049 +/- 1,477 mm3, Group II 4,495 +/- 654 mm3, Group III 2,050 +/- 724 mm3, Group IV 2,782 +/- 970 mm3, Group V 1,555 +/- 514 mm3. 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.(ABSTRACT TRUNCATED AT 400 WORDS)