Swainsonine, an indolizidine alkaloid, stimulates the proliferative capacity of murine bone marrow, as manifested by increased colony forming activity and engraftment efficiency. Animals treated with swainsonine exhibit 5- to 10-fold increases in each of these parameters. It was also observed that swainsonine increased the survival of mice given 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 used C57BL/6 mice to examine hematological variables and bone marrow stem cell proliferation in mice given AZT by oral gavage. Mice were given an AZT dose known to depress hematologic function, along with 0 or 20 g of swainsonine per day. After 23 days of treatment, there were 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 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 then examined the effect of swainsonine on human bone marrow in vitro. The results indicate that swainsonine has a protective effect on these cells in vitro.
