A comparison of the effects of unfractionated heparin, dalteparin and danaparoid on vascular endothelial growth factor-induced tumour angiogenesis and heparanase activity.
Disseminated intravascular coagulation (DIC) is the most common complication of solid tumours. In this study, the effectiveness of three polysaccharide anticoagulants (PSAs), at therapeutic doses, at inhibiting solid tumour growth was investigated. Mice with tumour xenografts were subcutaneously injected with either unfractionated heparin (UFH; 200 units kg(-1) day(-1)), dalteparin (75 units kg(-1) day(-1)) or danaparoid (50 units kg(-1) day(-1)). At these concentrations, these PSAs are equieffective at inhibiting blood coagulation activated factor X. In mice with Lewis lung carcinoma (LLC) tumours dalteparin and, to a lesser extent, UFH inhibited both tumour growth and angiogenesis, whereas danaparoid did not. In contrast, in mice with KLN205 tumours, all the PSAs inhibited tumour growth and angiogenesis. All the PSAs significantly inhibited proliferation, migration of endothelial cells and vessel formation in matrigel plugs containing vascular endothelial growth factor (VEGF) and there were no significant differences between these effects of the PSAs. The PSAs had no effect on endothelial cell tubular formation in vitro. Although all the PSAs inhibited VEGF production in KLN205 tumours in vivo and cells in vitro, in LLC tumours and cells only UFH and dalteparin inhibited VEGF production, whereas danaparoid did not. In both LLC and KLN205 tumours in vivo, heparanase activity was inhibited by UFH and dalteparin, but not by danaparoid. Hence, UFH and dalteparin may be more effective than danaparoid at inhibiting cancer progression in DIC patients with solid tumours, due at least in part to their ability to suppress VEGF and heparanase in tumours.
Takahashi
Hidenori
H
Department of Geriatric and Respiratory Medicine, Tohoku University School of Medicine, Aoba-ku, Sendai, Japan.
Ebihara
Satoru
S
Okazaki
Tatsuma
T
Asada
Masanori
M
Sasaki
Hidetada
H
Yamaya
Mutsuo
M
D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D001760:Bleeding Time; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002809:Chondroitin Sulfates / Q000494:pharmacology*; D017985:Dalteparin / Q000494:pharmacology*; D003871:Dermatan Sulfate / Q000494:pharmacology*; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D005170:Factor X / Q000032:analysis / Q000037:antagonists & inhibitors; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism*; D006493:Heparin / Q000494:pharmacology*; D006497:Heparan Sulfate / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A; D000099175:Heparanase
D000925:Anticoagulants; D002809:Chondroitin Sulfates; D017985:Dalteparin; D003871:Dermatan Sulfate; D005170:Factor X; D005966:Glucuronidase; D006493:Heparin; D006497:Heparan Sulfate; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D000099175:Heparanase; C035838:danaparoid