Chemo-Emmunotherapy of Liver Metastases; The in Vitro and in Vivo Effects of 5-Fluorouracil Combined with Liposome-Encapsulated Muramyl Dipeptide

Abstract

While investigating the effects of 5-fluorouracil (5FU) on the tumoricidal state of rat liver macrophages activated in vitro by means of liposome-encapsulated muramyl dipeptide (MDP), we observed that 5FU in combination with macrophages produced substantially higher extents of cytolytic activity on tumor cells than 5FU alone. 5FU was able to enhance the cytolytic activity of macrophages activated by liposome-encapsulated MDP. This finding indicates that, rather than inhibiting the activation of macrophages by liposomal MDP, 5FU can act as a stimulator of macrophage activation by itself. This is further supported by the observation that a second treatment of macrophages with the drug, 24 h after the first, fails to produce increased macrophage cytotoxicity. Our results also show that 5FU does not unfavorably influence the induction of cytotoxic activity of the macrophages. Rather, combinations of 5FU and liposomal MDP may result in an additive or synergistic tumoricidal effect. The therapeutic effect of a combination of liposomal MDP and 5FU was studied in a murine tumor model of hepatic metastases of the tumor cell line C26, a colon adenocarcinoma. Liposomal MDP and a low, non-toxic, dose of 5FU were mixed and administered during six consecutive days once daily. Treatment was initiated four days after intrasplenic tumor cell injection. The combination of liposomal MDP and 5FU significantly reduced the number of liver metastases and the total tumor load in the liver. The liver weights of tumor bearing mice treated with the combination were significantly lower than the liverweights of control mice and of mice treated with 5FU alone or liposomal MDP alone. Liposomal MDP and 5FU when given as single treatment modalities had no significant effect on the number of metastases and liverweight. These results show that liposomal MDP can enhance the therapeutic effect of 5FU for the treatment of liver metastases.