cord-factors and Mast-Cell-Sarcoma

The antitumor activity of trehalose-6,6'-dimycolate (TDM) dispersed in saline was studied in vitro and in vivo. In vitro, macrophages from TDM-treated mice entirely abolish, even at a 1.25:1 effector/target cell ratio, the (3H)TdR incorporation of P815 mastocytoma cells to the culture in which they were added. In vivo, the number of P815 cells harvested 10 days after their injection into TDM-treated mice was reduced by a factor higher than 50. The slopes of the radiolabel elimination of TDM-treated mice injected with 10(7) 125I-UdR-labelled L1210 leukemic cells were greater than those of untreated controls. The interest of such a compound which seems to be one of the active structures responsible for the antitumor activity of BCG is its efficiency when administered dispersed in saline.

Topics: Adjuvants, Immunologic; Animals; Cell Transformation, Neoplastic; Cord Factors; Cytotoxicity, Immunologic; Glycolipids; Kinetics; Leukemia L1210; Macrophage Activation; Macrophages; Mast-Cell Sarcoma; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Pyrogens; Sodium Chloride; Suspensions

Trehalose diesters (natural 6,6'-trehalose dimycolate from Mycobacterium tuberculosis or synthetic (a 76 carbon atom analogue)), when suspended in water, give stable and well-defined emulsions. These emulsions, injected i.p. in mice significantly limit the growth of P815 syngeneic mastocytoma cells. They elicit macrophages with a cytostatic activity against P815 cells in vitro, strong enough to be expressed at low effector to target ratios (E/T = 1.4) or after a short coincubation period (2 hr). The antitumor potential of these macrophages seems to coincide with their ability to release H2O2 upon pharmacologic triggering. Depressed levels of alkaline phosphodiesterase and beta-galactosidase are proposed as other biochemical markers of cytostatic macrophages.

Topics: Animals; Cord Factors; Cytotoxicity, Immunologic; Dose-Response Relationship, Immunologic; Emulsions; Glycolipids; Hydrogen Peroxide; Macrophage Activation; Macrophages; Mast-Cell Sarcoma; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Microscopy, Electron; Time Factors

Immunomodulators of bacterial origin, such as muramyl-dipeptide (MDP) and trehalose dimycolate, are able to stimulate some important biological functions of macrophages, such as their capacity to secrete a monokine, the thymocyte mitogenic protein (TMP), and to limit the growth of mastocytoma cells in vitro. Adherent cells from the peritoneal cavity of untreated mice do not secrete significant amounts of TMP and are not cytostatic. In contrast, adherent peritoneal cells from mice injected with trehalose dimycolate (emulsified in water) secrete TMP and are strongly cytostatic for P815 cells. Trehalose dimycolate is also active when added in vitro: (a) it enhances the cytostatic action of thioglycollate-elicited macrophages; (b) alone or in sequence with MDP, it induces an appreciable cytostatic activity in resident macrophages; (c) it limits the decline of the strong cytostatic action of trehalose-dimycolate-elicited macrophages occurring during in vitro cultivation. MDP also stimulates the cytostatic activity of the macrophages in vitro. The most interesting effect of MDP is its capacity to induce a strong secretion of TMP after a short contact (1 h) with elicited macrophages.

Topics: Acetylmuramyl-Alanyl-Isoglutamine; Animals; Ascitic Fluid; Cell Adhesion; Cord Factors; Female; Glycolipids; Macrophages; Mast-Cell Sarcoma; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mitogens; T-Lymphocytes