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PurposeSome authors observed increased carboplatin-associated myelotoxicity in obese patients which was exclusively attributed to elevated AUC. To investigate the potential contribution of functional changes of cells primarily responsible for myelopoiesis, granulocyte-macrophage progenitors (CFU-GM) were studied in obesity-associated diabetes mellitus (DMT2). MethodsThe most frequently used animal model of human obesity with DMT2 is db/db mouse. Cellularity, frequency of CFU-GM and total CFU-GM content of femoral bone marrow was measured after 100 mg/kg dose of carboplatin in vivo. To exclude influence of pharmacokinetic changes direct toxicity of carboplatin on CFU-GM was also determined in vitro and was compared with other anticancer agents, namely doxorubicin, 5-fluorouracil and 4-thiouridylate. ResultsAfter intraperitoneal administration of carboplatin, each measured characteristics of bone marrow function were more significantly suppressed and the induced neutropenia were more serious in db/db mice than in the controls. The increased myelotoxicity seemed to be a direct effect on myeloid progenitor cells since their increased in vitro sensitivity was found in db/db mice. This was not specific for carboplatin, a similar double to 5-fold increase in myelotoxicity of each cytotoxic drug with different mechanism of action was observed. Four-thiouridylate, a promising antileukemic molecule with good therapeutic index, was by far the least toxic for CFU-GM of db/db mice.Conclusions A serious disorder of CFU-GM progenitors was suggested in obese mice with DMT2, which eventually might lead to more severe myelotoxicity and neutropenia. Weight loss and normalization of glucose homeostasis may be important before chemotherapy of malignant diseases in obesity with DMT2.

The effect of granulocyte colony-stimulating factor (G-CSF) was investigated in P-selectin glycoprotein ligand-1 (PSGL-1) deficient (PSGL-1(-/-)) and wild-type (PSGL-1(+/+)) mice to establish the role of this mucin in myeloid cell mobilization. G-CSF activates tissue proteases that cleave adhesion molecules, thus enhances the mobilization of myeloid cells and haematopoietic stem cells. Cytopenia was induced with a single dose of cyclophosphamide. In PSGL-1(-/-) animals, we observed a delayed extravasation of mature myeloid cells from the peripheral vessels into the tissue compartments and their faster mobilization from the bone marrow. Subsequently, animals received G-CSF twice a day for 4 days. Neutrophil and monocyte counts increased upon completion of G-CSF treatment and both values were significantly higher in PSGL-1(-/-) mice; 47.7 versus 28.3 G/l for neutrophils and 4.1 versus 2.0 G/l for monocytes. The ratio of atypical myeloid cells was also elevated. Analyzing the causes of the above differences, we identified a 4-fold increase in the colony-forming unit (CFU-GM) counts of the peripheral blood in PSGL-1(-/-) mice, compared to wild-type animals. A significantly elevated number of CFU-GM was detected also in the femurs of PSGL-1(-/-) mice, 4 and 5 days after cyclophosphamide treatment and these values paralleled with the elevation of CD34+/CD117+ stem cell counts in the peripheral blood. Our data suggest, that in the absence of PSGL-1, G-CSF was more potent in elevating absolute myeloid cell numbers by acting on cell release from the bone marrow, maturation from circulating precursor cells in the peripheral blood and prolonged retainment in the circulation.

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