Therapeutic Efficacy of Glucan in A Murine Model of Hepatic Metastatic Disease

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Abstract
Glucan, a particulate β–1,3–polyglucose immunomodulator, was evaluated for its ability to modify hepatic metastases and survival in mice with reticulum cell sarcoma. Sarcoma M5076 cells were injected subcutaneously (1 × 105 cells) into syngeneic C57BL/6J male mice. On Day 20, histopathological studies indicated the presence of hepatic micrometastases. At this time, glucan (0.45 mg per mouse) or dextrose was administered intravenously. Therapy was continued at 3–day intervals up to Day 50. By Day 36 postchallenge, the glucan–treated group, when compared to the control group, showed a marked decrease in hepatic metastases, both grossly and histopathologically. A significant inhibition in the growth of the primary tumor also occurred. Plasma clearance of bromosulfophthalein measured on Day 36, denoted that glucan therapy maintained hepatic parenchymal cell functional integrity, while a 4–fold impairment in bromosulfopthalein removal was observed in control mice. Glucan–treated mice showed a 28% (p < 0.05) long–term survival. In contrast, control mice showed a 100% mortality by Day 42 postchallenge. Studies to evaluate the mechanism of the anti–metastatic action of glucan indicated that 8 days after glucan administration, isolated hepatic macrophages were significantly more cytotoxic to sarcoma cells in vitro than were normal Kupffer cells. At this time, the cytotoxic activity of peritoneal and splenic macrophages from glucan–treated mice were unaltered. Additionally, co–incubation of particulate glucan with diverse populations of normal or tumor cells in vitro indicated that glucan exerted a direct cytostatic effect on sarcoma and melanoma cells and, in contrast, had a proliferative effect on normal spleen and bone marrow cells. These studies denote that glucan, administered therapeutically will: (i) significantly inhibit hepatic metastases; (ii) inhibit the growth of the primary tumor, and (iii) enhance long–term survival possibly by increased Kupffer cell tumoricidal activity as well as a direct cytostatic effect of glucan on sarcoma cells.