ABSTRACT
We studied the effect of PGRPs-Hsp70 cytotoxic complex that is analogous to natural complex secreted by cytotoxic lymphocytes and the antitumor drug paclitaxel on the development of M3 melanoma in DBA mice. Significant inhibition of tumor growth was observed in all experimental groups by days 20 and 35 of observation; paclitaxel monotherapy was less effective than administration of PGRPs-Hsp70 cytotoxic complex and its combination with paclitaxel. Pairwise comparison of Kaplan-Meier curves showed that survival was maximum in the group receiving combined therapy with PGRPs-Hsp70 cytotoxic complex and paclitaxel in comparison with groups receiving monotherapy.
Subject(s)
Antineoplastic Agents/therapeutic use , Melanoma/drug therapy , Paclitaxel/therapeutic use , Recombinant Proteins/therapeutic use , Animals , HSP70 Heat-Shock Proteins/metabolism , Kaplan-Meier Estimate , Melanoma/metabolism , Mice , Mice, Inbred DBASubject(s)
Cytokines/immunology , Golgi Apparatus/metabolism , HSP70 Heat-Shock Proteins/immunology , Killer Cells, Lymphokine-Activated/immunology , fas Receptor/immunology , Animals , Brefeldin A/pharmacology , Cells, Cultured , Cytokines/chemistry , Cytokines/isolation & purification , Cytokines/metabolism , Cytotoxicity, Immunologic , Egtazic Acid/pharmacology , Electrophoresis , Golgi Apparatus/immunology , HSP70 Heat-Shock Proteins/chemistry , HSP70 Heat-Shock Proteins/isolation & purification , HSP70 Heat-Shock Proteins/metabolism , Humans , K562 Cells , Killer Cells, Lymphokine-Activated/cytology , Membrane Proteins/chemistry , Membrane Proteins/immunology , Membrane Proteins/isolation & purification , Membrane Proteins/metabolism , Mice , Protein Synthesis Inhibitors/pharmacology , Tumor Necrosis Factor-alpha/immunology , fas Receptor/geneticsSubject(s)
Antibodies, Antinuclear/pharmacology , Apoptosis , Autoantibodies/pharmacology , Caspases/metabolism , DNA/immunology , Animals , Antibodies, Antinuclear/immunology , Autoantibodies/immunology , HL-60 Cells , Humans , Hydrolysis/drug effects , K562 Cells , Leukemia, Lymphocytic, Chronic, B-Cell/immunology , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , Lupus Erythematosus, Systemic/immunology , Lupus Erythematosus, Systemic/metabolism , Mice , Tumor Cells, CulturedABSTRACT
It was previously established that the cell death induced by natural killer cytotoxic factor (NKCF) is a complex calcium-dependent two-stage process. In the initial stage, during the first 30 min of incubation of NKCF with target cells, pore formation on the surface of the target is observed, together with temporary membrane damage. The second stage cytolytic activity occurs after a 3 h latent period, reaches maximum at 24 h, and leads to cell death. A more detailed analysis of the NKCF-dependent lysis of cells was carried out in a study of the action of antibodies to granular perforin and calmodulin on this process. It was established that pore formation in the membrane after 30 min and cell lysis over the next 24 h are interdependent stages of a single process. The interaction of antibodies to perforin with the perforin-like protein of NKCF led to blockage of pore formation and to subsequent inhibition of target cell lysis. Treatment of NKCF with antibodies to calmodulin gave rise to the appearance of pore-forming activity in the first 30 min of incubation with target cells and to the subsequent acceleration of cell lysis over the next 24 h.
