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In the metastasis study, the tumors were large at the time when the treatment was started, whereas smaller tumors were treated in the present study.Our results indicate that the inhibitoryef fect of anastellin and the fibronectin and fibrinogen polymers is mediated by an antiangiogen ic activ ity of these compounds.This ef fect seems to be dif ferent from the Dextrorphan tartrate antimetastatic activ ity we obser ved earlier, where only sFN was clearly active.Here, anastellin was approx imately as ef fective as sFN in suppressing tumor grow th and tumor angiogenesis.The antiangiogen ic ef fects of anastellin, sFN, and sFBG are likely to have been primarily Flibanserin responsible for the inhibition of tumor grow th that we have demonstrated here.The blood vessel density in the tumors of the treated mice was only about of that in control tumors.As vascularization is a prerequisite of tumor grow th, the low number of blood vessels must have been a major impediment to tumor grow th in the treated mice.Inhibition of angiogenesiswith its suppressive ef fect on tumorgrow th possibly underlies the antimet ast atic ef fect of anastellin and the polymers we obser ved in this study.First, we found that the number of met ast ases correlatedwith the size of the primarytumor and the number of blood vessels in it.The reduced vasculature in the tumor could make it more dif ficult for tumor cells to enter the circulation.Another possible contributing factor is the reduced abilityof tumor cells that have gained ac cess to the circulation to est ablish met ast atic colon ies.Earlier studies have shown that sFN inhibits lung colon ization by tumor cells injected into the circulation. As anastellin exhibited this activ it y, or did so weakly, this inhibitoryactiv itycould explain why sFN might be somewhat more active in reducing met ast asis than is anastellin, at leastwith the C tumors.Anastellin also did not inhibit spont aneous met ast asis in the prev ious study, suggesting that the antimet ast atic activ ities of sFN obser ved in the prev ious study depended on a mechan ism other than antiangiogen ic activ it y.As is the casewith these substances, the mechan ism of the antiangiogen ic activ ity of anastellin is unknown.However, we do know that each of these substances binds to one or more adhesion proteins.Angiostatin and its parent protein plasminogen can bindvitronectin, and the antiangiogen ic form of antithrombin is similar to the modified antithrombin that binds tovitronectin, it polymerizes these proteins in vitro and likely in vivo.Fibronectin and fibrinogen, and each of the other ligands for the various antiangiogen ic substances we have listed, are adhesion proteins contain ing the argin ine glycine aspartic acid cell adhesion sequence. Moreover, they all bind to the avb integrin, which is expressed at high levels in angiogen ic endothelial cells and which plays an important role in angiogenesis. On the basis of these considerations, we propose a common mechan ism of action in vivo for the known antiangiogen ic protein fragments: they polymerize an argin ine glycine aspartic acid contain ing protein, the resulting polymers bind to the avb integrin on angiogen ic endothelial cells, and the polymers inhibit cell proliferation and cause apoptosis.

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