Doxorubicin toxicity in relation to the proliferative state of human hematopoietic cells

The relation between the proliferative state of normal human hematopoietic cells and their sensitivity to doxorubicin was studied. T-lymphocytes were stimulated with phytohaemagglutinin/interleukin 2 before or after a 2-h exposure to doxorubicin (range 0-2 microgram/ml). The doxorubicin concentration that inhibited DNA synthesis in 50% of the lymphocytes, measured qualitatively with 5-iodo-2'-deoxyuridine incorporation, was significantly lower (a factor of 2.5) in case of drug exposure of stimulated lymphocytes compared to nonstimulated lymphocytes. These proliferation-dependent differences were not related to differences in cellular drug concentrations, as was determined with flow cytometry. Bone marrow cells were stimulated for 2 days with human placenta-conditioned medium before or after exposure to doxorubicin (range 0-2 microgram/ml), after which they were cultured in a bone marrow clonogenic assay. In analogy with the lymphocyte experiments, proliferation-dependent differences in drug sensitivity were found. The drug concentration that inhibited the growth of granulocyte-macrophage colonies (granulocyte-macrophage colony-forming units, CFU-GM) to 50% appeared significantly lower (a factor of 3.4) with drug exposure of stimulated bone marrow cells compared to nonstimulated bone marrow cells. The relative insensitivity of quiescent, but potentially proliferative cells to doxorubicin might explain the recovery of hematopoiesis after doxorubicin-induced bone marrow hypoplasia.