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Dalteparin, a low‐molecular‐weight heparin, promotes angiogenesis mediated by heparin‐binding VEGF‐A in vivo
Author(s) -
NORRBY KLAS,
NORDENHEM ARVID
Publication year - 2010
Publication title -
apmis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.909
H-Index - 88
eISSN - 1600-0463
pISSN - 0903-4641
DOI - 10.1111/j.1600-0463.2010.02635.x
Subject(s) - angiogenesis , epirubicin , pharmacology , in vivo , heparin , low molecular weight heparin , medicine , chemotherapy , cancer research , cyclophosphamide , biology , microbiology and biotechnology
Norrby K, Nordenhem A. Dalteparin, a low‐molecular‐weight heparin, promotes angiogenesis mediated by heparin‐binding VEGF‐A in vivo . APMIS 2010; 118: 949–57. Tumors are angiogenesis dependent and vascular endothelial growth factor‐A (VEGF‐A), a heparin‐binding protein, is a key angiogenic factor. As chemotherapy and co‐treatment with anticoagulant low‐molecular‐weight heparin (LMWH) are common in cancer patients, we investigated whether angiogenesis in vivo mediated by VEGF‐A is modulated by metronomic‐type treatment with: (i) the LMWH dalteparin; (ii) low‐dosage cytostatic epirubicin; or (iii) a combination of these two drugs. Using the quantitative rat mesentery angiogenesis assay, in which angiogenesis was induced by intraperitoneal injection of very low doses of VEGF, dalteparin sodium (Fragmin ® ) and epirubicin (Farmorubicin ® ) were administered separately or in combination by continuous subcutaneous infusion at a constant rate for 14 consecutive days. Dalteparin was administered at 27, 80, or 240 IU/kg/day, i.e., doses that reflect the clinical usage of this drug, while epirubicin was given at the well‐tolerated dosage of 0.4 mg/kg/day. While dalteparin significantly stimulated angiogenesis in an inversely dose‐dependent manner, epirubicin did not significantly affect angiogenesis. However, concurrent treatment with dalteparin and epirubicin significantly inhibited angiogenesis. The effect of dalteparin is the first demonstration of a proangiogenic effect of any LMWH in vivo. The fact that co‐treatment with dalteparin and epirubicin significantly inhibited angiogenesis suggests a complex drug effect.