Studies on the anticoagulative activities of sulfated polysaccharides and inhibitory effect on experimental blood-borne tumor metastasis

Abstract

Blood coagulation plays a very important role for the attachment of tumor cells to the capillary endothelium at an early stage of hematogenous metastasis. Attempts were made to find more reliable antimetastatic agents by studying the effect of five sulfated polysaccharides having different molecular weight and sulfur content on intravenously induced blood-borne pulmonaly metastasis in rats. Xylan sulfate and dextran sulfate strongly inhibited the development of metastatic nodules on the pulmonary surface. Chondroitin polysulfate was less inhibitory, whereas chondroitin sulfate and glucose polysulfate were not inhibitory. Their antimeta-static effect depended on the dose and time of administration, being greatest when they were injected intraperitoneally 1hr. before intravenous inoculation of AH-109A cells.The mechanism of inhibition of blood-borne metastasis by these sulfated polysaccharides was studied in relation to the blood coagulation system. We examined the coagulative activity of three sulfated polysaccharides, xylan sulfate, chondroitin polysulfate and chondroitin sulfate which have strong, weak and no inhibitory effect on metastasis, respectively.The coagulative activity of blood was measured by determining whole blood clotting time, partial thromboplastin time, prothrombin time and thrombin time. Xylan sulfate had the strongest anticoagulative activity, and showed the dose dependence of it. Anticoagulative activity of chondroitin polysulfate was less than that of xylan sulfate. Chondroitin sulfate had no anticoagulative activity. These results indicated that the antimetastatic activity of sulfated polysaccharides were correlated with their anticoagulative activity.Subsequently, we investigated the effect of three compounds on blood coagulation factors. The surface contact factors, factor XI and XII in the plasma of rats injected with xylan sulfate were markedly inactivated. Moderate inactivations of factor II, V, VII, VIII, IX and X were noted in these plasma. Marked inactivations of factor XI and XII, and moderate inactivation of factor VIII were noted in the plasma of rats injected with chondroitin polysulfate. Chondroitin sulfate did not cause any inactivation of blood coagulation factors. The results indicated that the inactivation of surface contact factor was also closely related with inhibitory effects on blood-borne metastasis.Intravascular coagulation concerning mainly with the attachment of transported tumor cells to the endothelium of capillaries might be thought to be induced by 1) obstruction of blood flow by tumor cell emboli, 2) release of the tissue thromboplastin from injured endothelium, 3) activation of contact factors by injured endothelium due to tumor cells, 4) activation of the extrinsic coagulation factors by tumor cells. Xylan sulfate interfered with intrinsic thromboplastin formation due to in-activation of contact factors in intrinsic blood coagulation mechanism, and showed the antithrombin activity.