Alok A Khorana1, Abha Sahni, Owen D Altland, Charles W Francis. 1. James P. Wilmot Cancer Center and Hematology/Oncology Unit, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY14642, USA.
Abstract
OBJECTIVE: Studies have shown improved survival in cancer patients treated with low molecular weight heparins (LMWHs). Tumors depend on an expanding vasculature, and heparins may affect vessel growth and function. We investigated the effect of heparins differing in Mr on selected endothelial cell properties. METHODS AND RESULTS: Human umbilical vein endothelial cells were cultured with fibroblast growth factor-2 and heparins differing in Mr. Cell proliferation was assessed by [3H]thymidine incorporation, and vascular organization was assessed by in vitro assays. Maximum inhibition of 94+/-2% was observed with 6-kDa LMWH, greater than the inhibition seen with unfractionated heparin (58+/-8%) or 3-kDa LMWH (60+/-9%, P=0.02 for both). No inhibition of proliferation was observed with heparin tetrasaccharide, octasaccharide, or pentasaccharide (fondaparinux). Three- and 6-kDa fractions decreased endothelial tube formation in Matrigel to 58+/-15% and 67+/-9% (P<0.05), respectively, of that with fibroblast growth factor-2, whereas no inhibition was observed with unfractionated heparin, tetrasaccharide, pentasaccharide, or octasaccharide. LMWH (6 kDa) also inhibited vessel formation in a placental explant. CONCLUSIONS: Heparin inhibition of endothelial cell proliferation and organization requires a chain length of >8 saccharide units, with maximal inhibition at Mr of 6 kDa. This Mr dependence differs from that required for anticoagulant activity.
OBJECTIVE: Studies have shown improved survival in cancerpatients treated with low molecular weight heparins (LMWHs). Tumors depend on an expanding vasculature, and heparins may affect vessel growth and function. We investigated the effect of heparins differing in Mr on selected endothelial cell properties. METHODS AND RESULTS:Human umbilical vein endothelial cells were cultured with fibroblast growth factor-2 and heparins differing in Mr. Cell proliferation was assessed by [3H]thymidine incorporation, and vascular organization was assessed by in vitro assays. Maximum inhibition of 94+/-2% was observed with 6-kDa LMWH, greater than the inhibition seen with unfractionated heparin (58+/-8%) or 3-kDa LMWH (60+/-9%, P=0.02 for both). No inhibition of proliferation was observed with heparin tetrasaccharide, octasaccharide, or pentasaccharide (fondaparinux). Three- and 6-kDa fractions decreased endothelial tube formation in Matrigel to 58+/-15% and 67+/-9% (P<0.05), respectively, of that with fibroblast growth factor-2, whereas no inhibition was observed with unfractionated heparin, tetrasaccharide, pentasaccharide, or octasaccharide. LMWH (6 kDa) also inhibited vessel formation in a placental explant. CONCLUSIONS:Heparin inhibition of endothelial cell proliferation and organization requires a chain length of >8 saccharide units, with maximal inhibition at Mr of 6 kDa. This Mr dependence differs from that required for anticoagulant activity.
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