KILLING OF TUMOR-CELLS INVITRO BY MACROPHAGES FROM MICE TREATED WITH SYNTHETIC DEHYDRODIPEPTIDES

  • 1 January 1979
    • journal article
    • research article
    • Vol. 39  (5) , 1847-1853
Abstract
Treatment of NMRI mice i.p. with dehydrodipeptides [acetyldehydro-3-(2-thienyl)alanyltyrosine (SI) and acetyldehydro-3-(2-furyl)alanyltyrosine (SII)] rendered macrophages cytolytic for several tumor cells [P-815 mastocytoma, C57BL EL4 lymphoma, Meth A fibrosarcoma, leukemia P-388 (mouse) and Raji Barkitt''s lymphoma (human)] 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. 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 were killed. The macrophage activation to lyse tumor cells was sharply dose dependent and appeared about 48 h after injection of the peptides. Although SI was active in vivo at concentrations as low as 500 .mu.g/mouse, the same substance lacked activity in vitro at all concentrations tested up to 800 .mu.g/ml. Dehydrodipeptides activate macrophages through a T[thymus-derived]-cell-independent process to lyse tumor target cells. Macrophages from athymic nude (nu/nu) mice were less cytotoxic, but they still were stimulated; 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.