IN-VIVO MODULATION OF MACROPHAGE TUMORICIDAL ACTIVITY BY ORAL-ADMINISTRATION OF THE LIPOSOME-ENCAPSULATED MACROPHAGE ACTIVATOR CGP 19835A

The present study evaluated the in vivo biological activity of synthet ic muramyl tripeptide, CGP 19835A, when encapsulated into phosphatidyl choline liposomes (POPC-19835A) and administered as an p.o. immunomodu lator to BALB/c mice. Liposomes were rapidly absorbed in the intestine and reached the systemic circulation within 4 h. Alveolar macrophages harvested from the lungs of mice 24 h after a single p.o. feeding of POPC-19835A mere tumoricidal toward syngeneic murine renal cell carcin oma target cells. Repeated daily feedings with POPC-19835A generated s ustained activation of the alveolar macrophages. Activation of periton eal macrophages to the tumoricidal state required at least three daily feedings of POPC-19835A. In vitro studies demonstrated the release of tumor necrosis factor ct and interleukin 6 by macrophages activated b y POPC-19835A in the presence of gamma-interferon. Interleukin 1 and n itric oxide were not induced in macrophages by this liposomal preparat ion. Daily administration of POPC-19835A after i.v. injection of renal cell carcinoma tumor in BALB/c mice inhibited the development of expe rimental lung metastasis and confirmed the potential role of long-term therapy with this new p.o. immunomodulator.