Synergism of synthetic acyltripeptide and its analogs with recombinant interferon gamma for activation of antitumor properties of human blood monocytes.

Human blood monocytes freshly isolated by centrifugal elutriation from healthy volunteers were not cytotoxic to allogeneic A375 melanoma cells, but they were activated to the tumoricidal state by incubation in vitro with FK-565, (heptanoyl-gamma-D-Glu-(L)-meso-alpha,epsilon-A2pm(L)-D-A laOH), which is a synthetic acyltripeptide closely resembling cell wall peptidoglycan peptides of Streptomyces in structure. Among 11 different derivatives of FK-565, 7 analogs were more potent activators of monocytes for tumor cell killing than FK-565. The maximal expression of tumoricidal monocytes was dependent on the concentration of FK-565 or its analogs added and the ratio of monocytes to target tumor cells. In a parallel experiment, a combination of a subthreshold concentration of FK-565 or its analogs (FR-42148 and FR-42149) and recombinant interferon gamma (rIFN-gamma) induced significant monocyte-mediated tumorcell killing, indicating that the effects of rIFN-gamma and acyltripeptide or its analogs in monocyte activation are synergistic. In contrast to rIFN-gamma, recombinant rIFN-alpha A and rIFN-beta had additive effects with acyltripeptide or its analogs in human monocyte activation. These results suggested that synthetic acyltripeptide and its analogs combined with rIFN-gamma could be of clinical value for in situ activation of the tumoricidal activity of human blood monocytes responsible for eradication of cancer metastases.