Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of anticoagulant drugs on formation of experimental tumor metastases after i.v. inoculation of BL6 melanoma or Lewis lung carcinoma (3LL) cells was studied in mice with stimulated or depressed natural killer (NK) cell activity. When mice were treated with anticoagulants (warfarin or heparin) or when NK cell activity was stimulated by polyinosinic-polycytidylic acid, significant antimetastatic effects were observed; these effects were substantially augmented when the treatments were combined. However, when NK reactivity of mice was suppressed by anti-asialo GM1 serum or cyclophosphamide, the antimetastatic effects of warfarin and heparin were diminished or completely abrogated. In some experiments, the anticoagulants had a partial effect in mice treated with cyclophosphamide or anti-asialo GM1 serum and reduced at least to control levels the number of metastases in these mice. This limited antimetastatic effect of the anticoagulants was mostly due to the action of residual NK cells, since it was completely abrogated in mice whose NK cell activity was more completely suppressed by two injections of anti-asialo GM1 serum. In addition, the low NK reactivity of 3-week-old C57BL/6 or beige mice was sufficient to support the antimetastatic effects of the anticoagulants, effects that completely disappeared after these mice were treated with anti-asialo GM1 serum. Augmentation or abrogation of the antimetastatic effects of heparin after polyinosinic-polycytidylic acid or anti-asialo GM1 treatments, respectively, was observed in athymic nude and allogeneic BALB/c mice that received i.v. injections of B16F1 melanoma cells, indicating that the antimetastatic effects of anticoagulants depend on the presence of active NK rather than T-cells. Furthermore, adoptive transfer of NK-competent but not NK-depleted syngeneic spleen cells restored the antimetastatic effect of heparin in cyclophosphamide-treated mice. Warfarin treatment increased the elimination of radiolabeled BL6 melanoma cells from the lungs of normal mice, and the rate of tumor cell elimination was further potentiated when NK cell activity was stimulated by polyinosinic-polycytidylic acid. In contrast, after anti-asialo GM1 treatment, warfarin had no effect on the survival of i.v. administered tumor cells. Covering of YAC-1 or 3LL tumor cells with fibrin after in vitro exposure with fibrinogen and thrombin substantially protected them from the in vitro cytotoxic action of NK or lymphokine-activated killer cells.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Augmentation of the antimetastatic effect of anticoagulant drugs by immunostimulation in mice. 380 83

Platelet-aggregating and thrombin-generating activities of B16 and 3LL cells were inhibited by trypsin, phospholipase A2 and by heating, but not by neuraminidase. It was confirmed that the platelet aggregation effect of these cells is due to thrombin generation. The lung-colonizing ability of treated cells injected intravenously was directly proportional to the ability to generate thrombin and to aggregate platelets. These results suggest that B16 and 3LL cells aggregate platelets through thrombin generation probably via their heat-labile surface lipoprotein, and that emboli composed of platelets, fibrin, and tumor cells may aid further the metastatic process.
Invasion Metastasis 1986
PMID:Platelet-aggregating activities of metastasizing tumor cells. IV. Effects of cell surface modification on thrombin generation, platelet aggregation and subsequent lung colonization. 394 Oct 29

The PAIII rodent metastatic prostatic adenocarcinoma model was employed to evaluate the effects of dietary warfarin, a prototypic antagonist of thrombin generation on the lymphatic and pulmonary metastases of the tumor from the tail site of subcutaneous transplantation in male Lobund Wistar (LW) rats. In addition, the anticoagulant effects of warfarin were determined in the same animals. Warfarin, administered in the diet at concentrations equivalent to 0.063, 0.125 or 0.250 mg./kg. b.w. for 30 days had no effect on final body weight, gluteal or iliac lymph node weights. Significant (p less than 0.05) dose-dependent extensions of whole blood prothrombin (WBPT), activated partial thromboplastin (WBAPTT) and clotting times (WBCT) over control values were observed with warfarin treatment. Preliminary studies demonstrated that the 0.500 mg./kg. dose produced 50 per cent mortality at +14 days. Warfarin produced significant (p less than 0.05) dose-dependent decreases in the number of PAIII pulmonary metastases as indicated by reductions in dry lung weights and lung colony numbers when compared to untreated tumor-bearing controls. While the therapeutic index of warfarin is a limiting factor in clinical use as an antimetastatic agent, these results suggest that compounds capable of altering hemostatic mechanisms may be potential inhibitors of tumor metastasis. The PAIII prostatic adenocarcinoma model may be a useful system to quantitatively evaluate potential antimetastatic and cytotoxic agents.
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PMID:Inhibitory effect of warfarin on the metastasis of the PAIII prostatic adenocarcinoma in the rat. 394 58

Thrombin generated in the process of platelet aggregation induced by three metastasizing murine tumors was measured using a chromogenic substrate specific for thrombin. Addition of B16 cells or 3LL cells to the platelet-rich plasma induced the generation of a significant amount of thrombin during the lag period preceding aggregation, while that of MH134 cells did not. Thrombin generation was observed in both the presence and the absence of platelets, indicating that platelets are not necessarily required for thrombin generation by these tumor cells. This suggests that the adherence of platelets to tumor cells is not an essential step for the initiation of thrombin-mediated aggregation induced by B16 and 3LL cells. Furthermore, the results of a one-stage clotting assay using plasma deficient in coagulation factors indicated that B16 and 3LL cells generated thrombin through direct activation of factor X.
Invasion Metastasis 1985
PMID:Platelet-aggregating activities of metastasizing tumor cells. III. Platelet aggregation as resulting from thrombin generation by tumor cells. 398 Jan 64

Acquired dysfibrinogenemia has not been previously reported as a paraneoplastic marker for malignancy. This report describes the clinical course of a patient who at the time of diagnosis of nonmetastatic renal cell carcinoma had dysfibrinogenemia characterized by prolongation of the thrombin and Reptilase times and increased sialic acid content of the purified fibrinogen. The thrombin and Reptilase times returned toward normal values after nephrectomy but became abnormal with the development of nonhepatic metastases. It is concluded that acquired dysfibrinogenemia can be part of a paraneoplastic syndrome and is a sensitive plasma marker for tumor progression.
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PMID:Acquired dysfibrinogenemia. Paraneoplastic syndrome in renal cell carcinoma. 398 42

Because tumor-induced platelet aggregation appears to play a role in the development of certain experimental tumor metastases, we examined the mechanism(s) of tumor-induced platelet aggregation as well as the effect of various anti-platelets agents. Two mechanisms for tumor-induced platelets aggregation have been previously described: (1) a mechanism which requires complement, a stable plasma factor, divalent cation and a sialo-lipo-protein vesicular component of the tumor membrane for platelet aggregation; and (2) a mechanism which operates via the generation of thrombin and requires a phospholipid component of the tumor membrane. We now report a new mechanism of tumor-induced platelet aggregation which is shared by three different tumors: a spontaneously metastatic human melanoma, HM29, a murine melanoma, B16F10, and a carcinogen-induced metastatic murine colon carcinoma, CT26. These tumors do not require cell-surface sialic acid or serum complement as does the first mechanism. They do not require cell-surface phospholipid, as do the tumors representing the other two mechanism. They do not aggregate platelets via the generation of thrombin as do tumors representing the second mechanism. These tumors are unique in that they require a trypsin-sensitive surface protein for activity. The ability of the thrombin-generating tumors to aggregate platelets is uniquely sensitive to two highly specific, synthetic thrombin-competitive inhibitors: DAPA and No. 805. The other two groups of tumors are at least 10 times more sensitive to inhibition of platelet aggregation by elevation of cyclic AMP levels (prostacyclin, 6-keto-PGE1, dibutyryl cyclic AMP) and at least 10 times more sensitive to inhibition of prostaglandin synthesis (indomethacin, ibuprofen). Thus, tumor-induced platelet aggregation is heterogeneous with respect to mechanism of action as well as inhibition by anti-platelet pharmacologic agents. Sensitivity to anti-platelet agents correlates with the mechanism by which tumor cells aggregate platelets.
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PMID:A new mechanism for tumor induced platelet aggregation. Comparison with mechanisms shared by other tumor with possible pharmacologic strategy toward prevention of metastases. 629 77

This review studies interactions of tumor cells with a particular host system which is normally responsible for hemostasis and the physiological integrity of the blood vessel luminal surface. With malignancy components of this system are frequently activated, producing abnormalities of blood coagulation, increased platelet responses, and conditions favoring tumor growth and metastasis. Activation of the clotting cascade is mediated by tumor and macrophage procoagulants, acting via Factor X or VII. Thrombin and fibrin are formed. Thrombin also interacts with platelets and the endothelium, potentiating or decreasing coagulation. Generation of thrombin or other tumor mechanisms activate platelets, leading to direct aggregation or secretion of ADP, serotonin, and/or intermediates of the arachidonate metabolism. Vascular lesions caused by tumor attack, platelet secretion, or exogenous agents promoting metastasis may also activate the hemostatic system. It is not yet fully understood how activation of the clotting system, including platelets, contributes to metastasis. Secretion of platelet products appears, however, to be heavily involved. Based on putative mechanisms of action, anticoagulants, platelet inhibitors, thrombocytopenic or vascular repairing agents have been used to control tumor spread. Results depended on the agent and experimental model of metastasis used. Except for coumarin, which was beneficial even against spontaneous metastases, other anticoagulants and platelet inhibitors, excluding perhaps Nafazatrom, gave equivocal results. Thrombocytopenic agents, however, were effective in every tumor system and with any experimental model of metastasis, indicating that platelets play a role in this process. Also consistent were the inhibitory effects of leech salivary gland extract (probably a vascular repairing agent) against lung tumor colonization promoted by ionizing radiation, cyclophosphamide, and cortisone.
Cancer Metastasis Rev 1984
PMID:Role of plasma, platelets, and endothelial cells in tumor metastasis. 638 44

The mechanisms by which B16, 3LL and MH134 tumor cells induce platelet aggregation were studied. The B16 and 3LL tumors, which have high or moderate procoagulant activities, aggregated platelets only in the presence of Ca2+ and plasma factors. MH134, which had much lower procoagulant activity, aggregated platelets even in the absence of these factors. The induction of aggregation by B16 and 3LL could be prevented by thrombin inhibitors but not by the ADP scavenger, suggesting that thrombin, generated by procoagulant activities of tumor cells themselves, might play a major role in initiating aggregation. MH134-induced aggregation was not affected by any of the inhibitors, indicating that the mechanisms by which MH134 initiate platelet aggregation are independent of both thrombin and ADP.
Invasion Metastasis 1984
PMID:Platelet-aggregating activities of metastasizing tumor cells. II. Variety of the aggregation mechanisms. 648 Feb 87

The role of platelets in cancer metastasis was studied by investigating the effects of the antiplatelet agents ticlopidine, diltiazem, dipyridamole and trapidil on artificial and spontaneous pulmonary metastases in mice. These agents were tested at their optimal inhibitory doses on adenosine diphosphate-induced platelet aggregation; namely, 100 mg/kg for ticlopidine, 2 mg/kg for diltiazem, 180 mg/kg for trapidil and 60 mg/kg for dipyridamole. At these doses, trapidil caused moderate inhibition of thrombin-induced platelet aggregation in mice, but the other agents had only slight effects. Artificial pulmonary metastasis was produced by inoculation of Lewis lung carcinoma (LLC) or B16 melanoma (B16) cells into C57BL/6 mice. For induction of spontaneous pulmonary metastases, these tumor cells were implanted subcutaneously into the footpads of mice. The resulting primary tumors of LLC and B16 were removed 9-10 and 17 days later, respectively. Artificial pulmonary metastases were inhibited significantly by all the antiplatelet agents tested. Spontaneous pulmonary metastases were markedly reduced only when these agents were given after removal of the primary tumor. The role of platelets is discussed with respect to thrombus formation in the lodgement of tumor cells and the participation of platelet-derived growth factor in the growth of metastatic foci.
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PMID:Effects of antiplatelet agents on pulmonary metastases. 672 29

We performed coagulation studies in 16 patients with advanced neuroblastoma. Four of these patients had major hemorrhagic or thromboembolic complications. Abnormal coagulation screening tests were seen in all patients with active metastatic disease. We also measured plasma fibrinopeptide A, a sensitive measure of intravascular thrombin generation. Increased concentrations of fibrinopeptide A were found in each patient studied with active metastatic disease. Coagulopathy is a frequent finding in metastatic neuroblastoma and may cause severe morbidity. Laboratory studies suggesting either hyper- or hypocoagulability are frequent findings.
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PMID:Coagulopathy of disseminated neuroblastoma. 687 12


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