Humoral factors influencing granulopoiesis have been evaluated using diffusion chambers (DC) implanted in the peritoneal cavity of mice challenged by an aseptic abscess produced by the subcutaneous implantation of copper rods. This resulted in an increase in peripheral blood neutrophils and an increase in tibial granulocytic elements. When DC loaded with bone-marrow cells were implanted into mice stimulated the day before by an aseptic abscess significantly more CFU-s, CFU-c, proliferative and non-proliferative granulocytes were produced, as compared to DC implanted into control hosts. When DC were implanted 4-6 d after the induction of inflammation in mice a significant depression of DC granulopoiesis was observed. Levels of serum and DC fluid CSF and serum inhibitors of in vitro colony growth showed no correlation with DC myelopoiesis. The data show that mice undergoing an inflammatory reaction elaborate first humoral substance(s) enhancing CFU-s and granulocytic growth in DC and next inhibitory factor(s) of DC granulopoiesis.
We have compared the toxicologic, pharmacologic, and therapeutic properties of the DNA complexes of daunorubicin and doxorubicin, after intravenous (IV) administration into mice. The overall toxicity of doxorubicin is significantly reduced after IV injection as a DNA complex while daunorubicin-DNA is as toxic as free daunorubicin. On hemopoietic stem cells, daunorubicin-DNA was found to be more cytotoxic than daunorubicin, while the opposite was observed with doxorubicin and doxorubicin-DNA. Both complexes are more effective than the corresponding free drugs on the L1210 murine leukemia, when given IV at equitoxic doses. The tissue uptake in mice, after IV administration, is generally lower when the drugs are given bound to DNA. The stability of the two DNA complexes is very different in the bloodstream: daunorubicin-DNA behaves more like a prodrug of daunorubicin, while doxorubicin-DNA, remaining stable in the bloodstream, meets much more the requirements of an ideal drug-macromoleculare carrier entity.
We compared the toxicity of detorubicin (DET) and of doxorubicin (DOX) on the hematopoietic stem cells in C57BL6J mice by means of the CFUS and CFUC assays. On an equimolar basis DET appears to be less toxic than DOX for both the pluripotent stem cells and the granulocytic progenitor cells. Moreover, the administration of these anthracyclines as DNA complexes leads to a decreased toxicity to the pluripotent stem cells, while no such attenuated toxic effect is observed in committed stem cells.
The diffusion chamber (DC) technique has been applied to the culture of L1210 cells in view of determining their sensitivity to chemotherapic agents. The surviving fraction of L1210 cells cultivated in DC's 4 d after i.v. injection o f the host mice with 10 mg/kg of daunorubicin or daunorubicin-DNA was 40 % and 9 %, respectively.The results suggest that the D C technique could be a useful in vivo predictive test for cancer chemotherapy.
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