In vitro Procoagulant Activity Induced in Endothelial Cells by Chemotherapy and Antiangiogenic Drug Combinations: Modulation by Lower-Dose Chemotherapy

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Abstract
One of the emerging problems concerning the use of antiangiogenic drugs, when used in combination with certain chemotherapy regimens, is enhanced rates and severity of adverse clotting events. For as yet unknown reasons, certain drugs and particular combinations can induce an elevated incidence of thromboembolic events in treated cancer patients [e.g., SU5416, a vascular endothelial cell growth factor receptor-2 (VEGFR-2) antagonist, when combined with gemcitabine and cisplatin (CDDP)]. Such results highlight the need to develop assays capturing the essence of enhanced clot formation under such combination treatment and which may have predictive potential as well. Here, we report the possibility of such an assay (i.e., the ratio of tissue factor over tissue factor pathway inhibitor expression or activity in cultured human endothelial cells calculated as a coagulation index). A marked increase in coagulation index was observed after exposure to SU5416 and the CDDP/gemcitabine chemotherapy combination in contrast to either of these treatments used alone. Substitution of SU5416 with any one of ZD6474, SU6668, IMC-1121, a monoclonal antibody to VEGFR-2, or an antibody to VEGF (bevacizumab) did not cause a marked increase in the coagulation index, nor did the combination of SU5416 with 5-fluorouracil and leucovorin. Finally, we noted that reducing the concentrations of gemcitabine and CDDP (i.e., use of “metronomic dosing” in vitro) significantly attenuated the coagulation index increase induced by these drugs, suggesting that use of low-dose chemotherapy regimens might be an approach to consider for reducing the incidence of adverse clotting events associated with chemotherapy alone or in conjunction with antiangiogenic drug combination therapies.