Eradication of spontaneous metastases and activation of alveolar macrophages by intravenous injection of liposomes containing muramyl dipeptide.

Abstract

The multiple systemic administration of multilamellar liposomes composed of phosphatidylserine and phosphatidylcholine (molar ratio 3:7) that contained water-soluble muramyl dipeptide (MDP) activated alveolar macrophages to become tumoricidal and eradicated established spontaneous pulmonary and lymph node metastases. Spontaneously metastasizing melanoma cells were injected into the footpads of mice. After 4-5 weeks, the tumors were resected by a midfemoral amputation; 3 days later, twice-weekly injections of liposomes were initiated and continued for 4 weeks. In some experiments the mice were killed 2 weeks after the final treatment. Seventy-four Percent of animals injected with liposomes containing MDP were free of visible metastases. In a separate life-span experiment, 60% of mice treated with liposome-encapsulated MDP were tumor-free 120 days after the last liposome treatment or 110 days after all control mice treated with free MDP or control liposome preparations had died of disseminated cancer. These data suggest that the systemic administration of liposomes containing MDP, or similar compounds that produce macrophage activation, may provide an additional useful approach to the therapeutic regimens currently used to eradicate cancer metastases.Metastasis of malignant neoplasms is responsible for most therapeutic failures in clinical oncology (1-3). Recent studies suggested that metastases can result from the proliferation of a minor subpopulation of cells within the primary tumor and that tumors can be heterogeneous with regard to many phenotypic characteristics such as drug sensititivity and metastatic potential (1-3). Such biological diversity among metastases implies that successful therapy of disseminated disease must include a regimen that acts by a mechanism independent of this heterogeneity.One biological agent that appears to function against tumor cells without regard to their phenotypic diversity is the activated macrophage. At least in vitro, macrophages can distinguish tumorigenic from nontumorigenic cells by a mechanism that is independent of such phenotypic characteristics as drug sensitivity, metastatic potential, and antigenicity (4). Moreover, to date, attempts to select in vitro tumor cells resistant to macrophage-mediated cytotoxicity have been unsuccessful (5).The increasing evidence that macrophages are important in host defense against neoplasia has stimulated interest in agents that can enhance macrophage-mediated destruction of tumor cells. Normal macrophages can be activated to become tumoricidal by various agents such as lymphokines and by whole microorganisms or their products such as endotoxins (6). However, the use of whole viable microorganisms or their products to activate macrophages in vivo has been hampered by a number of undesirable side effects (7).The search for synthetic compounds that are relatively nontoxic yet possess immune potentiating activities has resulted in the demonstration that N-acetylmuramyl-L-alanyl-D-isoglutamine [muramyl dipeptide. (MDP), Mr 49...

Pulmonary perspective: immunology in diagnosis and treatment of lung cancer

“…Several studies have documented in vitro the limited response of AMs from lung cancer patients to various stimuli, including IFN-γ and GM-CSF [154,157]. More recently, synthetic macrophage activators, such as muramyl di-or tripeptide (MDP or MTP), were entrapped within liposomes in order to prolong their life and improve their targeting [158]. The liposomes injected intravenously are cleared from the circulation by phagocytic cells.…”

Limited Capability of Regional Lymph Nodes to Eradicate Metastatic Cancer Cells

“…For depletion or activation of macrophages in the meso-cecum lymph node, rats were pretreated with liposomes containing DMDP (18) or liposomes containing NAAI (19,20). About 0.05 mL of the liposome suspension in PBS was injected with a 30-gauge needle into four different regions of the submucosa of the posterior wall in the rat cecum.…”

Antimetastatic effects of synthetic polypeptides containing repeated structures of the cell adhesive Arg-Gly-Asp (RGD) and Tyr-Ile-Gly-Ser-Arg (YIGSR) sequences

“…On the other hand, natural killer (NK) cells and macrophages in certain blood cell populations appear to have an important role in the destruction of metastatic tumour cells. The activation of macrophages and NK cells by various immunostimulants led to the reduction of metastatic colonisation (Herberman, 1984;Hanna, 1985;Fidler et al, 1981).…”