Non-anti-coagulant heparins: a promising approach for prevention of tumor metastasis (review).
The metastatic spread of solid tumors is responsible for most cancer-related deaths, and unfortunately no specific anti-metastatic therapy exists. Heparin is widely used in the clinic today as an anti-coagulant therapy for cancer patients at risk for venous thrombo-embolism. Recent clinical trials with low molecular weight heparin and meta-analyses of earlier clinical trials with unfractionated heparin indicate that heparin has an anti-metastatic activity. Animal studies using non-anti-coagulant heparin (NAC heparin) suggest that it is possible to separate the anti-metastatic and anti-coagulant activities of heparin. The use of heparin as an anti-metastatic agent is limited due to its potent anti-coagulant activity. NAC heparins have clinical potential because they could be administered at a higher dose, thereby fully exploiting the anti-metastatic component of heparin activity, and because they could be used with cancer patients with bleeding complications, where the use of heparin is currently precluded. The mechanism by which NAC heparin inhibits metastasis is not yet fully understood. Possible mechanisms include the inhibition of selectin-mediated cell-cell interactions, heparanase and angiogenesis, and stimulation of tissue factor pathway inhibitor release. The promising results from clinical trials and animal studies clearly warrant further investigation of NAC heparin as a therapeutic for the prevention of tumor metastasis.
Kragh
Michael
M
Department of Pharmacology, Novo Nordisk A/S, DK-2760 Måløv, Denmark. mick@novonordisk.com
Loechel
Frosty
F
D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D002450:Cell Communication; D002986:Clinical Trials as Topic; D004195:Disease Models, Animal; D005966:Glucuronidase / Q000378:metabolism; D006493:Heparin / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008956:Models, Chemical; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy*; D009389:Neovascularization, Pathologic; D000099175:Heparanase
D000925:Anticoagulants; D000970:Antineoplastic Agents; D005966:Glucuronidase; D006493:Heparin; D000099175:Heparanase