Search

: ObjectiveUnresponsiveness to chemotherapy is a major problem in the treatment of leukemia, which can be caused by unresponsiveness of noncycling cells to cell cycle-dependent cytotoxic agents. Targeted toxins consisting of a targeting and activating cytokine (granulocyte-macrophage colony-stimulating factor [GM-CSF]) and diphtheria toxin (DT) can be used to overcome this kind of resistance of leukemic cells. In this study we manipulated the cell cycle and proliferative status of leukemic cells, explored the effect on sensitivity to DT, and determined the ability of DT388GMCSF fusion proteins to activate and subsequently kill leukemic cells.: Materials and MethodsWe used the GM-CSF–dependent myeloid leukemic cell line AML-193 as a model. GM-CSF or granulocyte colony-stimulating factor (G-CSF) was used to manipulate the cell cycle and proliferative state of AML-193 cells. Cell death was quantified by 51Cr release assays. The results obtained in the AML-193 cell line model were confirmed using primary leukemic blasts.: ResultsSimilar to treatment with chemotherapy and immunotherapy, leukemic cells in resting G0 phase were relatively resistant to DT-induced cell death. Synchronized recruitment of leukemic cells into activated phases of the cell cycle by low concentrations of GM-CSF or G-CSF resulted in significant increased DT sensitivity. DT388GMCSF fusion proteins specifically targeted GM-CSF receptor-expressing cells, resulting in recruitment of leukemic cells from G0 phase of the cell cycle and subsequent kill of these cells.: ConclusionLeukemic cells in G0 phase, which are resistant to conventional chemotherapy, Fas-induced immunotherapy, and DT alone, can be synchronically activated and subsequently killed by DT388GMCSF fusion proteins. [Copyright &y& Elsevier]

Patients with a central venous catheter (CVC) who receive intensive chemotherapy or a stem cell transplantation for haematological disease are at risk for developing CVC-related thrombosis. To study the incidence of thrombosis, 105 consecutive patients underwent serial Doppler-ultrasound and we evaluated whether clinically manifest thrombosis could be predicted by screening with Doppler-ultrasound. Patients with subclavian or jugular inserted CVCs were clinically assessed each day for signs and symptoms of thrombosis. Additional Doppler-ultrasound screens were performed weekly by an independent physician in all patients until CVC removal. Doppler-ultrasound recordings were assessed by two blinded observers. In cases of clinically suspected thrombosis, the attending physicians followed routine diagnostic and therapeutic procedures. The overall cumulative incidence of CVC-related thrombosis was 28·6% (30 of 105 patients). Of the 30 patients with thrombosis, 26 had subclinical thrombosis by Doppler-ultrasound, nine of whom developed clinically manifest thrombosis later. Four patients had clinically manifest thrombosis without prior abnormal Doppler-ultrasound. In cases of subclinical thrombosis the risk of developing symptomatic disease increased sevenfold (34·6% vs. 5·1%). Doppler-ultrasound screening may be useful to identify those patients that are at high and low risk for clinically manifest CVC-related thrombosis. [ABSTRACT FROM AUTHOR]