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Eradication of Hepatic Metastases of Carcinoma H-59 by Combination Chemoimmunotherapy with Liposomal Muramyl Tripeptide, 5-Fluorouracil, and Leucovorin¹

Department of Surgery, Division of Surgical Research, McGill University, and the Royal Victoria Hospital, Montréal, Québec, Canada H3A 1A3 [H. R. S., P. B.]; Department of Oncology, The Jewish General Hospital, Montréal, Québec, Canada H3T 1E2 [G. B.]; and Gunma University, Maebashi, Japan 371 [T. A.]

We have investigated the effect of a combined chemoimmunotherapy protocol with liposomal muramyl tripeptide phosphatidylethanolamine (MTP-PE), 5-fluorouracil (5-FU), and 5-formyltetrahydrofolate (leucovorin) on the growth of hepatic metastases using carcinoma H-59, a liver-homing subline of the Lewis lung carcinoma (P. Brodt, Cancer Res., 46: 2442–2448, 1986). C57BL/6 mice inoculated with the tumor cells via the intrasplenic route received three i.v. injections of liposomal MTP-PE, the first of which was administered 3 days prior to tumor cell inoculation. Chemotherapy with 5-FU and leucovorin at the maximal tolerated doses (30 mg/kg per injection) was initiated immediately after tumor inoculation and continued on alternate days for a total of 4 injections. The incidence of liver metastases in animals which received the combined therapy was compared to that in animals treated with chemotherapy or immunotherapy alone. We found that while the number of liver metastases was reduced in all of the treatment groups as compared to control untreated or placebo-treated animals, the combined effect of 5-FU leucovorin and liposomal MTP-PE was significantly better than that of chemotherapy or immunotherapy alone. This was reflected in a reduced incidence (70% as compared to 100% in all other groups) and in a significant reduction in the number and size of the liver nodules. Our results suggest that the efficacy of 5-FU and leucovorin in the treatment of hepatic metastases could be significantly augmented by the addition of the liposome-encapsulated immunoadjuvant MTP-PE.

¹ Supported by a fellowship from the Ministry of Culture and Education of Japan to T. A. and a grant from CIBA-GEIGY to P. B.

² To whom requests for reprints should be addressed, at Division of Surgical Research, McGill University, 740 Dr. Penfield Ave., Montréal, Québec, Canada H3A 1A3 (Dr. Pnina Brodt), or Department of Surgery, Gunma University Maebashi, 371, Japan (Dr. Takayuki Asao).

Received 5/14/92. Accepted 9/11/92.

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