The indolizidine alkaloid, swainsonine, inhibits tumor growth and metastasis, augments macrophage-mediated tumor cell killing, and stimulate bone marrow cell proliferation. The objective of these studies is to determine the potential clinical utility of swainsonine as a bone marrow proliferative agent and to elucidate the molecular mechanism of its action on immune system components. An in vitro assay for proliferation of murine hematopoietic stem cells was used to examine the ability of swainsonine to stimulate bone marrow progenitors and to block toxicity of chemotherapeutic agents. Results with non-tumor bearing mice indicate that swainsonine may prevent the toxic effects on bone marrow of chemotherapeutic drugs such as methotrexate and 5- fluorouracil. Further, macrophages isolated from various organs (spleen, liver and peritoneal cavity) have been studied and shown to have enhanced cytotoxic activity toward tumor cells following exposure to swainsonine. We are currently examining the effects of swainsonine on bone marrow cell proliferation and macrophage activation in tumor bearing animals. Additional in vitro studies have been performed with human bone marrow and demonstrate the ability of swainsonine to protect human marrow stem cells from the cytotoxicity of AZT. Studies are currently underway to test swainsonine in vivo in mice for the ability to abrogate the anemia and neutropenia caused by AZT therapy. Studies with normal and transformed cells in culture are designed to identify the genes and proteins altered by exposure to swainsonine. We are examining cell attachment and growth rates in culture, as well as the effects of swainsonine on the process of programmed cell death in untreated and drug treated murine bone marrow and in human and murine cells in culture.
