Chemoimmunotherapy of experimental hepatic metastases

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Abstract
Previous studies from our laboratory have demonstrated that particulate glucan is efficacious in the therapy of a syngeneic murine reticulum cell sarcoma (M5706), which specifically metastasizes from its primary site to the liver. The present study was undertaken to examine the therapeutic efficacy of a newly developed soluble glucan, in combination with cyclophosphamide in the treatment of hepatic metastatic disease. Male C57Bl/6J mice were injected subcutaneously on Day 0 with 1 × 104 sarcoma cells. Glucan (200 mg per kg i.v.), cyclophosphamide (45 mg per kg i.p.) or glucan and cyclophosphamide were administered beginning on Day 20, when hepatic metastases were evident, and continued at 3-day intervals up to Day 50. Combined therapy with glucan and cyclophosphamide resulted in reduction of hepatic metastatic lesions on Day 36, compared to control. Survival data revealed that the combination of glucan and cyclophosphamide significantly (p < 0.001) extended median survival time and the time to 100% mortality in an additive fashion, when compared to either therapy alone. Glucan-cyclophosphamide therapy was also effective in decreasing primary tumor weight to a level that was significantly (p < 0.05) less than when therapy was initiated. In vitro studies revealed that Kupffer cell tumoricidal activity against sarcoma was increased (p < 0.05) following glucan and cyclophosphamide. Glucan and cyclophosphamide also enhanced bone marrow proliferation and splenocyte response to mitogens in vitro. Additionally, glucan was observed to exert a direct cytostatic effect on sarcoma in vitro. Our results denote that soluble glucan-cyclophosphamide exerts antitumor activity by: (i) activation of Kupffer cell cytolytic activity; (ii) enhancing cell-mediated immunity, and (iii) exerting a direct cytostatic effect on sarcoma M5076.