Swainsonine, an indolizidine alkaloid, inhibits tumor metastasis, augments macrophage-mediated tumor cell killing and stimulates hematopoietic functions in a murine model system. The objective of our studies is to determine the mechanism(s) by which swainsonine induces these effects and to optimize its possible use as an adjuvant in treatments of cancer metastasis and myelosuppression. We have demonstrated that swainsonine protects both healthy and tumor-bearing mice from the toxicity of chemotherapy with agents such as cyclophosphamide(CPM). This stimulation occurs without blocking the ability of the (CPM) to slow tumor growth. We have shown that swainsonine stimulates macrophages from treated mice and are examining the pattern of cytokine production in treated macrophages to determine the critical signal pathways that are turned on by swainsonine treatment. We also have shown that swainsonine stimulates murine bone marrow progenitor cells and are examining a variety of murine hematopoietic cell lines that have absolute dependencies on specific growth factors to delineate the range and mechanism of the response of these cells to swainsonine. We recently showed that human bone marrow progenitor cells also are stimulated by swainsonine in vitro, and that swainsonine can abrogate at least part of the cytotoxic effect of AZT on these cells, sugesting that swainsonine may have significant value in the treatment of bone marrow transplantation and AIDS. Furthermore, we have begun to examine the role of cell adhesion and motility in metastasis by human breast carcinoma cells. We have shown that a rapid stimulation of adhesion occurs when these cells interact with agents that induce protein kinase C activity and that part of this stimulation may occur through arachidonic acid, an important cellular fatty acid. We are dissecting the mechanism of this stimulation and determining whether swainsonine or other glycosylation inhibitors can interfere with adhesion or motility in this model system.
