Abstract
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.
Highlights
Tumors are angiogenesis dependent and vascular endothelial growth factor-A (VEGF-A), a heparinbinding protein, is a key angiogenic factor
Effect on physiologic body weight gain of dalteparin and epirubicin treatment Continuous infusion of dalteparin at 27, 80, and 240 IU ⁄ kg ⁄ day for 14 days did not affect body weight gain compared with vehicle controls
Treatment with dalteparin (80 IU ⁄ kg ⁄ day) + vehicle, using two s.c. pumps per animal, increased overall angiogenesis total microvascular length (TMVL) by 31%, as compared with the controls that were treated with vehicle + vehicle using two s.c. pumps (Table 2)
Summary
Tumors are angiogenesis dependent and vascular endothelial growth factor-A (VEGF-A), a heparinbinding 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. Cancer patients undergoing surgery or suffering from acute thrombosis and receiving conventional chemotherapy in combination with s.c. administration of various low-molecular-weight heparins (LMWHs) display significantly improved survival times, as compared with patients who are treated either subcutaneously with unfractionated heparin (UFH) or orally with the anticoagulant warfarin, or those who do not receive any anticoagulant treatment [3,4,5,6,7,8,9]. Definitive conclusions regarding the true anti-neoplastic effects of LMWHs cannot be drawn from the data of clinical trials given the current methodologic limitations
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