Killing of tumor cells in vitro by macrophages from mice treated with synthetic dehydrodipeptides.
Treatment of NMRI mice i.p. with dehydrodipeptides [acetyldehydro-3-(2-thienyl)alanyltyrosine (SI); acetyldehydro-3-(2-furyl)alanyltyrosine (SII)] rendered macrophages cytolytic for several tumor cells in vitro. Normal peritoneal mouse macrophages from untreated mice not given injections of the peptides or from control mice given injections of phosphate-buffered saline were not cytotoxic. Moreover, supernatants from these in vivo-activated mouse peritoneal macrophages significantly increased the release of the cytoplasmic enzyme lactate dehydrogenase from freshly added target cells, showing that these cells had been killed. The macrophage activation to lyse tumor cells was sharply dose dependent and appeared about 48 hr after injection of the peptides. Although dehydrodipeptide SI was active in vivo at concentrations as low as 500 microgram/mouse, the same substance lacked activity in vitro at all concentrations tested up to 800 microgram/ml. Dehydrodipeptides activate macrophages through a T-cell-independent process to lyse tumor target cells. Macrophages from athymic nude (nu/nu) mice were less cytotoxic, but they still were stimulated; and the culture supernatants could kill about 50% of the tumor cells used. There are indications for a relative specific structure-activity relationship of dehydrodipeptides for inducing cytotoxic macrophages.
D000818:Animals; D002478:Cells, Cultured; D003176:Complement C3 / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D004151:Dipeptides / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D007700:Kinetics; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000276:immunology*; D013329:Structure-Activity Relationship
D003176:Complement C3; D004151:Dipeptides; C019234:acetyldehydro-3-(2-furyl)alanyltyrosine; C019235:acetyldehydro-3-(2-thienyl)alanyltyrosine