ABILITY OF THE IMMUNOMODULATING DIPEPTIDE BESTATIN TO ACTIVATE CYTO-TOXIC MONONUCLEAR PHAGOCYTES

  • 1 January 1983
    • journal article
    • research article
    • Vol. 43  (9) , 4148-4153
Abstract
The aminopeptidase inhibitor bestatin [2S,3R-(3-amino-2-hydroxy-4-phenylbutanoyl)-L-leucine] was tested for both in vitro and in vivo macrophage activation and antitumor activity in various experimental tumor systems including the metastasizing ESb lymphoma [mouse] system. Cultures of resting macrophages were rendered nonspecifically tumoricidal for the 2 lymphoma sublines ESb and 721 (ESb-Cl-18.1) [of the mouse L5178Y system], for the mastocytoma P815X [mouse], for LS lymphoma cells [mouse] and for proliferating lymphoblasts from DBA/2, C57BL/6J, and CBA mice by exposure to bestatin at 50 .mu.g/ml culture medium. Untreated mononuclear phagocytes and bestatin alone were not directly cytotoxic. Treatment of mice parenterally with bestatin also induced cytotoxic macrophages for several tumor cells when tested in vitro. Normal peritoneal mouse macrophages from untreated mice or from control mice given injections of phosphate-buffered saline were not cytotoxic. The macrophage activation to lyse tumor cells was sharply dependent on the bestatin dose and appeared .apprx. 24 h after injection of the dipeptide. Bestatin activates macrophages through a T cell-independent process to lyse tumor target cells, inasmuch as macrophages from homozygous athymic nude (nu/nu) mice treated i.p. with the dipeptide were also stimulated and cytotoxic for tumor cells. The macrophage is the prominent host cell responsible for tumor cell destruction in animals treated with bestatin and rule out the possibility that natural killer cells play a major role in the experiments described.