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)

Heparin, cortisone, and combination of these two drugs were used for treatment of solitary tumors and artificial lung metastases of the fibrosarcoma NFSA and the mammary carcinoma MCA-K in C3Hf/Kam mice. Heparin reduced the number of artificial metastases of both tumors, but it did not affect the s.c. growth of these tumors. Conversely, cortisone reduced both the number of artificial metastases and the growth rate of s.c. tumors. The effect of cortisone was not further influenced by heparin. Cortisone showed a tendency for causing enhancement of spontaneous metastases. In addition, two heparin analogs, hexuronyl hexoaminoglycan sulfates were studied against MCA-K solitary tumors and their spontaneous metastases. They were ineffective when given alone, and they did not influence the effect of cortisone on the s.c. tumor growth. However, they slightly reduced the cortisone-induced enhancement of spontaneous metastases.
Clin Exp Metastasis
PMID:Treatment with cortisone plus heparin or hexuronyl hexoaminoglycan sulfates of murine tumors and their lung deposits. 407 12

Heparin or a heparin fragment administered with cortisone inhibited angiogenesis, caused regression of large tumor masses, and prevented metastases. Oral administration of heparin resulted in the release of non-anticoagulant heparin fragments in the serum which, in the presence of cortisone, had similar anti-angiogenic and antitumor effects. Of all the heparin fragments tested, the most potent inhibition of angiogenesis in the presence of cortisone was provided by a hexasaccharide with a molecular weight of about 1600.
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PMID:Angiogenesis inhibition and tumor regression caused by heparin or a heparin fragment in the presence of cortisone. 619 98

These studies provide the following evidence: (1) Angiogenesis is a multistep process. (2) The steps necessary to construct a capillary must occur in correct sequence, a motif that seems to be expressed entirely by vascular endothelial cells. (3) Primary tumors and their metastases are angiogenesis dependent, and angiogenesis may be a critical control point in tumor growth. (4) Heparin potentiates angiogenesis. (5) Heparin or its nonanticoagulant fragments, administered with cortisone, inhibit angiogenesis. (6) Heparin is degraded in the gastrointestinal tract and yields low molecular weight fragments, some of which are absorbed into the circulation. (7) There is a group of corticosteroids that inhibit angiogenesis in the presence of a heparin fragment, but have no glucocorticoid or mineralocorticoid activity. The compounds to which this new biologic activity has been assigned have been named "angiotropic" steroids. (8) There is a potential future role for angiogenesis inhibitors as a new class of pharmacologic agents.
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PMID:Toward a new understanding of vascular proliferative disease in children. 620 29

The Nb rat prostatic adenocarcinoma model has served as an animal model for testing various chemotherapeutic agents. This model has two tumor types: androgen-sensitive and androgen-insensitive. Herein, the androgen-insensitive tumor A.I.-II was evaluated in 52 animals, with heparin, heparan, 5-Fu, and cis-platinum for their effects on incidence of metastatic disease. Multiple experiments were previously carried out utilizing this tumor, which consistently has had an incidence of metastatic disease in 40-50% of the animals so implanted. Heparin at both doses and heparan significantly reduced metastasis in this study; however, they were not significant in reducing final tumor volumes as compared to the controls. 5-Fluorouracil at the dose evaluated neither significantly altered tumor volume nor altered metastatic disease. On the other hand, cis-platinum was significantly effective in lowering both metastatic disease and tumor volume (p less than 0.05).
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PMID:The evaluation of heparin in control of metastasis of Nb rat androgen-insensitive prostate carcinoma. 654 May 44

Five cancer patients (three with lesions in the lung and one each with breast and head and neck cancer) with multiple metastases developed "migratory thrombophlebitis." These patients were not ambulatory. None of the patients showed a picture of "consumptive coagulopathy," although a "hypercoagulable state" was observed. Fibrinogen levels were normal or increased, FDP were slightly increased, and AT-III was decreased. Prior to heparin therapy, values for PT and PTT were within normal range. Sodium heparin, 30,000 to 36,000 units per day, was administered by continuous intravenous infusion. Despite prolongation of the PTT to twice the baseline levels, signs and symptoms of thrombophlebitis persisted for several days. When thrombophlebitis was controlled with heparin, Coumadin therapy was instituted, but thrombophlebitis recurred at the original site and at new sites, even though the prothrombin time was in the therapeutic range (2 to 2 1/2 times the normal value). The antithrombotic action of heparin depends on a normal quantity of plasma AT-III. Long-term use of heparin is feasible, but the optimal time for discontinuation of heparin treatment has not been established. Heparin is superior to oral anticoagulation therapy to control thrombophlebitis associated with advanced cancer.
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PMID:Thrombophlebitis in cancer patients. 694 57

Heparanase activity correlates with the metastatic potential of lymphoma, melanoma and mammary adenocarcinoma cell lines. We investigated the ability of various modified species of heparin and size-homogeneous oligosaccharides derived from depolymerized heparin to inhibit (1) heparanase-mediated degradation of heparan sulfate in a naturally produced subendothelial extracellular matrix (ECM), and (2) lung colonization of B16-BL6 melanoma cells in C57BL mice. Inhibition of heparanase was best achieved by heparin species containing 16 or more sugar units and having sulfate groups at both the N and O positions. Low-sulfate oligosaccharides were less effective heparanase inhibitors than medium- and high-sulfate fractions of the same-size saccharide. While O-desulfation abolished the heparanase-inhibiting effect of heparin, O-sulfated, N-substituted (e.g. N-acetyl or N-hexanoyl) species of heparin retained high inhibitory activity. Potent inhibitors of heparanase activity were also efficient inhibitors of tumor invasion and lung colonization. Heparin fractions with high and low anticoagulant activity expressed similar high antiheparanase and antimetastatic activities. Structural requirement for the inhibition of melanoma cell heparanase and lung colonization by species of heparin were different from those identified for (1) release of ECM-bound basic fibroblast growth factor (b-FGF) and (2) stimulation of b-FGF receptor binding and mitogenic activity. These results indicate that various nonanticoagulant species of heparin and other polyanionic molecules differing in size, sulfation and substituted groups can be designed to elicit specific effects resulting in the inhibition of cell invasion in tumor metastasis and autoimmunity, or stimulation of neovascularization and wound healing.
Invasion Metastasis
PMID:Inhibition of tumor metastasis by heparanase inhibiting species of heparin. 765 22

Three cases of lower limb, deep venous thrombosis that progressed to ischemia in patients with advanced ovarian cancer are reported. One patient developed frank gangrene of the extremity. Venous stasis, secondary to venous compression from metastatic disease, was the predisposing factor in all cases. Heparin therapy was uniformly unsuccessful in halting progression of thrombosis. Ischemic thrombosis originating from extrinsic venous compression is unlikely to respond to conventional therapy alone. Local external radiation to metastatic sites, given early and possibly in conjunction with conventional treatment methods, may achieve a clinical response by causing a reduction in tumor size and thus relief of venous compression.
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PMID:Lower limb ischemic venous thrombosis in patients with advanced ovarian carcinoma. 850 98

Oral glucosamine has anti-inflammatory activity in rodents, and anecdotal evidence suggests that it may be clinically useful in inflammatory bowel disorders. A possible explanation is that supplemental glucosamine increases production of heparan sulfate (HS) proteoglycans by the vascular endothelium, thereby improving the endothelium's barrier function. Extravasation of leukocytes and metastatic cancer cells requires degradation of HS. Heparin can inhibit neutrophil activation, adhesion, and chemotaxis, and--like glucosamine--has been reported effective for managing inflammatory bowel syndromes. Cytokine-mediated loss of endothelial HS may be a key factor in the coordinated inflammatory response. These considerations suggest that glucosamine may have clinical utility in a range of inflammatory disorders, and should be assessed with regard to its impact on cancer metastasis and peripheral ischemic disease. In inflammatory bowel disease, fish oil, ginkgolides, and enteric-coated 5-aminosalicylic acid may safely complement the efficacy of glucosamine.
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PMID:Vascular heparan sulfates may limit the ability of leukocytes to penetrate the endothelial barrier--implications for use of glucosamine in inflammatory disorders. 988 30

Classic studies indicate that the formation of tumor cell-platelet complexes in the blood stream is important in facilitating the metastatic process. Metastasis in animal models can be inhibited by heparin, and retrospective analyses of heparin use in human cancer have shown promise. However, most follow-up human studies using vitamin K antagonists have failed, and conclusive proof for other previously proposed mechanisms of heparin action is lacking. Carcinoma progression and metastasis are associated with overexpression of sialylated fucosylated mucins. Structurally similar molecules happen to be natural ligands for vascular adhesion molecules called the selectins. Heparin also happens to be a good inhibitor of P-selectin, which is expressed on activated platelets or endothelial cells. We have found that heparin blocks P-selectin-mediated interactions of endogenous platelets with sialylated fucosylated mucins on circulating carcinoma cells and that this reduces tumor cell survival. The use of more specific and selective P-selectin inhibitors will some day help to dissect the relative importance of this mechanism of heparin action in cancer. Meanwhile, we suggest that the failure of vitamin K antagonists to improve cancer prognosis should be ignored and that heparin therapy should be immediately revisited under this new paradigm. Unlike the suggestions in most previous studies, we propose that heparin use should be reexplored specifically during the interval from initial visualization of a primary tumor until just after its definitive surgical removal. A suggested clinical trial is outlined.
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PMID:Heparin inhibition of selectin-mediated interactions during the hematogenous phase of carcinoma metastasis: rationale for clinical studies in humans. 1188 26

Angiogenesis is a critical determinant of tumor growth and the development of metastases. Heparin, steroids, and heparin/steroid combinations have been used in a variety of in vitro models and in vivo in animal models as effective inhibitors of angiogenesis. We tested heparin, steroid and heparin/steroid combinations at a variety of concentrations to determine their effect on the human 'angiogenic switch' from a resting to a proliferative endothelium in vessels from three placentas (initiation), and the effect of these compounds on the subsequent growth of a human angiogenic response (promotion). Using full-thickness human placental vein discs cultured in three-dimensional fibrin-thrombin clots, we demonstrated that heparin (300, 3000 micrograms/ml), steroid (350, 3500 micrograms/ml), and combinations of heparin/steroid at these doses effectively blocked both initiation and promotion of a human angiogenic response in a dose-dependent fashion. We also demonstrated that high-dose steroid or heparin/steroid treatment for 15 days resulted in disruption of vessel integrity, while treatment with heparin alone produced a suppressed growth rate but had intact vessel architecture. High-dose heparin/steroid treatment could also disrupt a developed angiogenic response and retard further development of an angiogenic response following the cessation of treatment.
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PMID:Inhibition of human angiogenesis with heparin and hydrocortisone. 1191 Oct 15


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