Eradication of chronic myeloid leukemia stem cells: a novel mathematical model predicts no therapeutic benefit of adding G-CSF to imatinib

Imatinib mesylate induces complete cytogenetic responses in patients with chronic myeloid leukemia (CML), yet many patients have detectable BCR-ABL transcripts in peripheral blood even after prolonged therapy. Bone marrow studies have shown that this residual disease resides within the stem cell compartment. Quiescence of leukemic stem cells has been suggested as a mechanism conferring insensitivity to imatinib, and exposure to the Granulocyte-Colony Stimulating Factor (G-CSF), together with imatinib, has led to a significant reduction in leukemic stem cells in vitro. In this paper, we design a novel mathematical model of stem cell quiescence to investigate the treatment response to imatinib and G-CSF. We find that the addition of G-CSF to an imatinib treatment protocol leads to observable effects only if the majority of leukemic stem cells are quiescent; otherwise it does not modulate the leukemic cell burden. The latter scenario is in agreement with clinical findings in a pilot study administering imatinib continuously or intermittently, with or without G-CSF (GIMI trial). Furthermore, our model predicts that the addition of G-CSF leads to a higher risk of resistance since it increases the production of cycling leukemic stem cells. Although the pilot study did not include enough patients to draw any conclusion with statistical significance, there were more cases of progression in the experimental arms as compared to continuous imatinib. Our results suggest that the additional use of G-CSF may be detrimental to patients in the clinic

Endocytosis of alpha 1-acid glycoprotein variants and of neoglycoproteins containing mannose derivatives by a mouse hybridoma cell line (2C11-12). Comparison with mouse peritoneal macrophages.

International audienceMacrophages from various origins are known to express membrane lectins that mediate the endocytosis of mannose-bearing glycoconjugates. Most macrophage tumor cell-lines lack such receptors. In this paper we show by flow cytometry analysis that a newly generated macrophage hybridoma (2C11-12), which displays several macrophage characteristics, also expresses mannose membrane lectins, resulting in the internalization of fluoresceinylated neoglycoproteins into acidic compartments. Thioglycolate elicited mouse peritoneal macrophages and the 2C11-12 hybridomas were compared by flow cytometry with regard to the binding and endocytosis of alpha 1-acid glycoprotein (AGP) variants separated by affinity chromatography on immobilized concanavalin A. AGP C eluted specifically with methyl alpha-mannopyranoside, which contains two bi-antennary oligosaccharides, was endocytosed as mannosylated serum albumin (Man-BSA). In both types of macrophages, the fluoresceinylated ligands were internalized in acidic compartments as demonstrated by the fluorescence intensity increase upon monensin post-incubation. However the behaviour of the internalized ligands was found to be quite different. AGP C and Man-BSA were rapidly degraded by thioglycolate elicited peritoneal macrophages and excreted in the medium as small peptide fragments; conversely they remained a longer time in the 2C11-12 hybridoma

Venous Thromboembolism During Treatment with Antipsychotics: A Review of Current Evidence

This article summarises the current evidence on the risk of venous thromboembolism (VTE) with the use of antipsychotics. An increasing number of observational studies indicate an elevated risk of VTE in antipsychotic drug users. Although the use of certain antipsychotics has been associated with VTE, current data can neither conclusively verify differences in occurrence rates of VTE between first- and second-generation antipsychotics or between individual compounds, nor identify which antipsychotic drugs have the lowest risk of VTE. The biological mechanisms involved in the pathogenesis of this adverse drug reaction are still to be clarified but hypotheses such as drug-induced sedation, obesity, increased levels of antiphospholipid antibodies, enhanced platelet aggregation, hyperhomocysteinaemia and hyperprolactinaemia have been suggested. Risk factors associated with the underlying psychiatric disorder may at least partly explain the increased risk. Physicians should be aware of this potentially serious and even sometimes fatal adverse drug reaction and should consider discontinuing or switching the antipsychotic treatment in patients experiencing a VTE. Even though supporting evidence is limited, prophylactic antithrombotic treatment should be considered in risk situations for VTE