Diethyldithiocarbamate (DDTC) is a biochemical modulating agent that protects murine bone marrow progenitor cells from the cytotoxicity of a variety of
cancer chemotherapeutic agents. However, the mechanism of this protection is not well understood. Long-term human bone marrow cultures (LTBMC) were established and at day 17 treated with 30 mumol/L DDTC for 1 hour, after which DDTC was removed and replaced with complete medium.
Conditioned medium was then collected 6, 12, 24, and 48 hours later and analyzed for the presence of
cytokines. A time-dependent increase in
granulocyte-macrophage colony-stimulating factor (
GM-CSF) (12-fold), granulocyte-CSF (
G-CSF) (66-fold),
interleukin (IL)-6, (three-fold),
IL-1 beta (161-fold), and
tumor necrosis factor (
TNF)-alpha (25-fold) was observed. The maximum increase for the factors other than
TNF-alpha was at 24 to 48 hours posttreatment. However,
TNF-alpha peaked as early
as 6 hours post-DDTC. When
conditioned medium from these cultures was tested in a granulocyte-macrophage progenitor cell (GM-CFC) assay, an increase in colony formation was observed that correlated with the increased levels of
cytokines in the medium. The specificity of this effect was confirmed by the fact that the closely related congener bis(hydroxyethyl)dithiocarbamate was devoid of colony-stimulating activity. The addition of
antibodies for
TNF-alpha and/or
IL-1 alpha following DDTC treatment did not inhibit the release of
GM-CSF,
G-CSF, or
IL-6 from the LTBMC. These results suggest that DDTC accelerates bone marrow recovery following myelotoxic
drug treatment via increased production of
cytokines that are known to be essential for hematopoiesis.