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BACKGROUND Heparin has many actions that may affect the malignant process, especially metastasis. METHODS The author conducted an extensive review of the available medical literature about heparin activity that may apply to important factors involved in the malignant process. RESULTS Thrombin is generated by tumors, and the resultant fibrin formation impedes natural killer cell activity. Microthrombi arrest tumor cells in capillaries. Heparin prevents the formation of thrombin and neutralizes its activity. Angiogenesis has an important role in metastasis; heparin minimizes angiogenesis via the inhibition of vascular endothelial growth factor, tissue factor, and platelet activating factor. It decreases tumor cell adhesion to vascular endothelium as it inhibits selectin and chemokine actions, and it also decreases the replication and activity of some oncogenic viruses. Matrix metalloproteinases, serine proteases, and heparanases have an important role in metastasis. Heparin decreases their activation and limits their effects. It competitively inhibits tumor cell attachment to heparan sulfate proteoglycans. It blocks the oncogenic action of ornithine decarboxylase and enhances the antineoplastic effect of transforming growth factor‐β. Heparin inhibits activator protein‐1, which is the nuclear target of many oncogenic signal transduction pathways, and it potently inhibits casein kinase II, which has carcinogenic activity. Platelet‐derived growth factor, which has oncogenic effects, is also inhibited by heparin, as are reverse transcriptase, telomerase, and topoisomerase prooncogenic actions. CONCLUSIONS These various heparin actions justify clinical investigation of its possible beneficial effect on malignant disease. Cancer 1999;85:257–72. © 1999 American Cancer Society.

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With the technical assistance of Anne Dudley T HE DETERMINATION of the level of circulating endogenous heparin is important, since heparin may normally function to keep the blood in a fluid state, and it also probably plays a major role in the clearing of alimentary lipemia from the bloodstream. Unfortunately, methods for the extraction of native heparin are not only difficult and tedious, but the end-product includes other mucopolysaccharides that interfere with assays based upon metachromatic technics.' On the other hand, coagulation tests, such as the protamine titration and toluidine blue procedures, are not an index of the amount of heparin but rather indicators of the equilibrium between the systems of factors favoring or inhibiting blood clotting.2 A relatively simple procedures based upon thrombin neutralization is available, but it is only discriminating enough to disclose marked increases in heparin levels. There are excellent methods4 for measuring the levels of injected, free heparin, but these do not afford information about the quantity of endogenous plasma heparin, which. with rare exceptions, is always protein-bound.These various difficulties, and the failure to appreciate them, have led to marked discrepancies in the results reported in studies of circulating heparin. Some responsible investigators4 imply that heparin is not normally present in human plasma, whereas others5 have reported very high levels. It

Heparin, 200 mg. subcutaneously, was administered twice weekly to a group of 105 patients with known previous myocardial infarction. A comparable control group of 117 individuals received saline placebos. Over a two-year period, there were 21 deaths due to cardiovascular disease in the placebo group, 4 cardiovascular deaths in the heparin group. The observed differences in deaths between the two groups is statistically significant, p < .01. The results indicate that heparin, in the dosage and manner administered, retards the progress of atherosclerotic disease in patients with coronary atherosclerosis.