Inhibition of experimental liver tumor growth in mice by liposomes containing a lipophilic muramyl dipeptide derivative.

The ability of liposomes containing a synthetic lipophilic muramyl dipeptide derivative, N-acetylmuramyl-L-alanyl-D-isoglutamyl-sn-glycerol dipalmitate (MDP-GDP), to inhibit the growth of experimental B16-F1 melanoma liver metastases in syngeneic C57BL/6 mice has been determined. Multiple i.v. injections of distearoylphosphatidylcholine:dimyristoylphosphatidylglycerol liposomes (1 mumol, 10:1 molar ratio) containing 0.1 to 1 microgram of MDP-GDP given at 3- to 4-day intervals after seeding the livers with tumor cells resulted in a significant inhibition of the number of experimental B16 liver metastases. Control liposomes or free MDP (100 micrograms) failed to affect the number of experimental metastases. A single prophylactic injection of liposomes containing MDP-GDP was equally effective in eliciting a reduction in the number of experimental liver metastases. The ability of liposomal MDP-GDP to inhibit the growth of liver metastases correlated with its ability to induce Kupffer cell tumoricidal activity against the tumor cell targets; activation of C57BL/6 Kupffer cell activity in vitro was most effective with liposomal MDP-GDP, followed by liposomal MDP and free MDP. Only liposomal MDP-GDP and liposomal MDP were able to induce Kupffer cell tumoricidal activity in situ, free MDP being inactive. Liposomal muramyl dipeptide therapy using lipophilic derivatives would appear to be an effective treatment for hepatic metastases derived from primary tumors.

Epithelioid angiosarcoma of the lung: a rare late complication of Lucite plombage.

Epithelioid angiosarcoma of the lung is a rare late complication of Lucite plombage treatment of pulmonary tuberculosis. We describe the clinical, radiological and pathologic findings of a case of epithelioid angiosarcoma of the lung presenting with persistent haemoptysis who had undergone remote lung collapse therapy with Lucite plombage.

Liposomal muramyl dipeptide therapy of experimental M5076 liver metastases in mice.

The effectiveness of N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP) or of liposomes containing a lipophilic MDP derivative, MDP-glyceroyldipalmitate MDP-GDP in inhibiting the growth of M5076 reticulum cell sarcoma liver metastases in C57BL/6 mice has been determined. MDP (100 micrograms) or liposomal MDP-GDP (2.5 mumol containing 1 microgram) were equally effective in inhibiting liver metastatic growth when given as a single treatment 3 days before tumor cell injection. Therapeutic treatment, initiated 3 days after tumor cell injection and continued for a period of 2 weeks, failed to inhibit metastatic growth. Activation of thioglycollate-elicited peritoneal macrophages or Kupffer cells in vitro with MDP or liposomal MDP-GDP resulted in the expression of tumoricidal activity against M5076 tumor cells. Adoptive cellular therapy with four injections of 2 x 10(6) macrophages was ineffective: activation of the macrophages with either MDP or liposomal MDP-GDP prior to injection was effective in inhibiting liver metastatic growth. Incorporation of the macrophage toxin dichlorodimethylene diphosphonate within liposomes containing MDP-GDP abolished the ability of such liposomes to induce macrophage or Kupffer cell tumoricidal activity in vitro as well as the antitumor activity when administered 3 days before tumor cell challenge.

Activation of murine Kupffer cell tumoricidal activity by liposomes containing lipophilic muramyl dipeptide.

The ability of liposomes containing a lipophilic muramyl dipeptide, N-acetylmuramyl-L-alanyl-D-isoglutamine-glycerol dipalmitate, to induce Kupffer cell tumoricidal activity has been investigated. Liposomal N-acetylmuramyl-L-alanyl-D-isoglutamine-glycerol dipalmitate was 16-fold more potent than liposomal N-acetylmuramyl-L-alanyl-D-isoglutamine and 2,400-fold more potent than N-acetylmuramyl-L-alanyl-D-isoglutamine in inducing Kupffer cell tumoricidal activity in vitro. A single i.v. injection of liposomes containing N-acetylmuramyl-L-alanyl-D-isoglutamine-glycerol dipalmitate was capable of inducing Kupffer cell tumoricidal activity as measured against B16-melanoma cells after Kupffer cell isolation. Maximal cytotoxic activity was obtained with 1 microgram muramyl dipeptide-glycerol dipalmitate encapsulated within liposomes: doses of 10 or 100 micrograms inhibited tumoricidal activity. Kupffer cells from mice treated with liposomes containing N-acetylmuramyl-L-alanyl-D-isoglutamine-glycerol dipalmitate remained cytotoxic for at least 6 days after injection. Liposomal N-acetylmuramyl-L-alanyl-D-isoglutamine was significantly less potent than liposomal N-acetylmuramyl-L-alanyl-D-isoglutamine-glycerol dipalmitate in inducing Kupffer cell tumoricidal activity in situ. N-Acetylmuramyl-L-alanyl-D-isoglutamine was capable of inducing Kupffer cell tumoricidal activity in vitro: its failure to induce tumoricidal activity in situ at doses of 1,000 micrograms demonstrates the utility of liposomal carriers for the in vivo activation of Kupffer cells by muramyl dipeptides.