Summary
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-γ-D-Glu-(L)-meso-α,ε-A2pm(L)-D-AlaOH), 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 nonocytes 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 γ (rIFN-γ) induced significant monocyte-mediated tumorcell killing, indicating that the effects of rIFN-γ and acyltripeptide or its analogs in monocyte activation are synergistic. In contrast to rIFN-γ, recombinant rIFN-αA and rIFN-β had additive effects with acyltripeptide or its analogs in human monocyte activation. These results suggested that synthetic acyltripeptide and its analogs combined with rIFN-γ could be of clinical value for in situ activation of the tumoricidal activity of human blood monocytes responsible for eradication of cancer metastases.
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References
Chirigos MA, Stulos WA (1980) Immunomodulatory effect of various molecular weight maleic anhydride-divinyl ethers and other agents in vivo. Cancer Res 40:1967
Fidler IJ (1985) Macrophages and metastases — a biological approach to cancer therapy. Presidential Address. Cancer Res 45:4714
Fidler IJ, Schroit AJ (1984) Synergism between lymphokines and muramyl dipeptide encapsulated in liposomes: in situ activation of macrophages and therapy of spontaneous cancer metastases. J Immunol 135:515
Gerrard TL, Siegel JP, Dyer DR, Zoon K (1987) Differential effects of interferon-α and interferon-γ on interleukin 1 secretion by monocytes. J Immunol 138:2535
Gotoh T, Nakahara K, Nishiura T, Hashimoto S, Kino T, Kuroda Y, Okuhara M, Kohsaka M, Aoki H, Imanaka H (1982) Studies on a new immunoactive peptide, FK-156. 2. Fermentation, extraction and chemical and biological characterization. J Antibiot (Tokyo) 35:1286
Henmi K, Aratani M, Takeno H, Okada S, Miyazaki Y, Nakaguchi O, Kitaura Y, Hashimoto M (1982) Studies on a new immunoactive peptide, FK-156, 4. Synthesis of FK-156 and its geometric isomer. J Antibiot (Tokyo) 35:1300
Inamura N, Nakahara K, Kino T, Gotoh T, Kawamura I, Aoki H, Imanaka H, Sone S (1985) Activation of tumoricidal properties in macrophages and inhibition of experimentally-induced murine metastases by a new synthetic acyltripeptide, FK-565. J Biol Response Mod 4:408
Lederer E (1980) Synthetic immunostimulants derived from the bacterial cell wall. J Med Chem 23:819
Mine Y, Yokota Y, Wakai Y, Fukad S, Nishida M, Goto S, Kuwahara S (1983) Immunoactive peptide, FK-156 and FK-565. I. Enhancement of host resistance to microbial infection in mice. J Antibiot (Tokyo) 36:1045
Pace JL, Russell SW, Torres BA, Johnson HM, Gray PW (1983) Recombinant mouse γ interferon induces the priming step in macrophage activation for tumor cell killing. J Immunol 130:2011
Ruco LP, Meltzer MS (1978) Macrophage activation for tumor cytotoxicity: development of macrophage cytotoxic activity requires completion of a sequence of short-lived intermediary reactions. J Immunol 121:2035
Saiki I, Sone S, Fogler WE, Kleinerman ES, Lopez-Berestein G, Fidler IJ (1985) Synergism between human recombinant γ-interferon and muramyl dipeptide encapsulated in liposomes for activation of antitumor properties in human blood monocytes. Cancer Res 46:6188
Sone S (1986) Role of alveolar macrophages in pulmonary neoplasias. Biochim Biophys Acta 823:227
Sone S, Fidler IJ (1980) Synergistic activation by lymphokines and muramyl dipeptide of tumoricidal properties in rat alveolar macrophages. J Immunol 125:2454
Sone S, Mutsuura S, Ogawara M, Utsugi T, Tsubura E (1984) Activation by a new synthetic acyltripeptide and its analogs entrapped in liposomes of rat alveolar macrophages to the tumoricidal state. Cancer Immunol Immunother 18:169
Sone S, Utsugi T, Shirahama T, Ishii K, Mutsuura S, Ogawara M (1985) Induction by interferon-α of tumoricidal activity of adherent mononuclear cells from human blood: Monocytes as responder and effector cells. J Biol Response Mod 4:134
Sone S, Tandon P, Utsugi T, Ogawara M, Shimizu E, Nii A, Ogura T (1986) Synergism of recombinant human interferon gamma with liposome-encapsulated muramyl tripeptide in activation of the tumoricidal properties of human monocytes. Int J Cancer 38:495
Talmadge JE, Chirigos MA (1985) Comparison of immunomodulatory and immunotherapeutic properties of biologic response modifiers. Springer Semin Immunopathol 204:1
Talmadge JE, Adams J, Phillips H, Collins M, Lenz B, Schneider M, Schlick E, Ruffman R, Wiltrout RH, Chirigos MA (1984) Immunomodulatory effects of poly ICLC in mice. Cancer Res 45:1058
Utsugi T, Sone S (1986) Comparative analysis of the priming effect of human interferon-γ, α and β on synergism with muramyl dipeptide analog for anti-tumor expression of human blood monocytes. J Immunol 136:1117
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Sone, S., Okubo, A., Inamura, N. et al. Synergism of synthetic acyltripeptide and its analogs with recombinant interferon γ for activation of antitumor properties of human blood monocytes. Cancer Immunol Immunother 27, 33–37 (1988). https://doi.org/10.1007/BF00205755
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DOI: https://doi.org/10.1007/BF00205755