of Work: Swainsonine, an indolizidine alkaloid, stimulates the proliferative capacity of murine bone marrow, as manifested by increased colony forming activity in vitro. Animals treated with swainsonine also exhibit increased survival when treated with chemotherapeutic drugs known to depress hematopoietic functions. These results have led to the suggestion that swainsonine may be a valuable adjuvant therapy for cancer and bone marrow transplantation. We are investigating the potential protective effects of swainsonine against AZT and other cytotoxic drugs with applications in the treatment of AIDS. AZT causes severe anemia and neutropenia in both humans and mice at levels used in humans for the treatment of HIV-1 infection. AZT also inhibits in vitro growth of hematopoietic progenitor cells. We have observed significant swainsonine-induced increases in bone marrow cellularity and peripheral blood lymphocytes compared to AZT alone. When both AZT and swainsonine were given in the drinking water ad libidum, swainsonine significantly increased the peripheral white blood cell count over the levels seen with AZT alone. We have also observed an increase in platelets in animals treated with swainsonine alone. We have extended our studies to assays of bone marrow progenitor cells. In the absence of AZT, but in the presence of growth factors, the addition of swainsonine stimulated the growth of several classes of progenitor cells. This stimulatory effect helped to overcome the toxicity of AZT on murine bone marrow progenitor cells grown in semisolid media. We are currently using in vitro model systems with hematopoietic cell lines to eludicate the mechanism of swainsonine action and are looking at the ability of swainsonine to stimulate progenitor cells ex vivo for use in bone marrow transplantation.
