EFFECTS OF DAUNORUBICIN AND DOXORUBICIN, FREE AND ASSOCIATED WITH DNA, ON HEMATOPOIETIC STEM-CELLS

Abstract

Daunorubicin (DNR)-DNA with free DNR and doxorubicin [antitumor agents] (DOX)-DNA with free DOX were compared for their effects in vivo in mice on pluripotent stem cells and granulocytic committed stem cells. Dose-survival, time-survival, and recovery curves were obtained after 1 i.v. injection of either drug. The dose-survival curves of colony-forming units-spleen (CFU-S) and colony-forming units-committed stem cells (CFU-C) were exponential in shape with both agents. DNR-DNA appeared more toxic to the hemopoietic precursor cells than did free DNR. In contrast, DOX-DNA was less toxic toward CFU-S and as toxic as DOX toward CFU-C. Time-survival curves indicated a minimum level of CFU-S and CFU-C at about 33 h. After that, the recovery of CFU-S was rapid for DNR-treated mice but remained below 50% of the controls on Day 12 for the DNR-DNA-treated group. In mice previously given injections of DOX or DOX-DNA, the recovery of the CFU-S was more protracted in time with a better recovery in mice treated with DOX-DNA. Both DNR and DNR-DNA induced an initial CFU-C decrease followed by a rapid but transient rise with a maximum on day 4 after chemotherapy. On day 12, the CFU-C recovery was still incomplete in both DNR- and DNR-DNA-treated mice. In the groups treated with DOX, the CFU-C recovery was more important after DOX-DNA complex than after free DOX. The results are discussed in view of the lysosomotropic chemotherapy hypothesis.