Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Blood coagulation is activated commonly in pancreatic carcinoma but the role of the tumor cell in this activation is undefined. Immunohistochemical procedures were applied to fixed sections of 22 cases of resected adenocarcinoma of the pancreas to determine the presence of components of coagulation and fibrinolysis pathways in situ. Tumor cell bodies stained for tissue factor: prothrombin: and factors VII, VIIIc, IX, X, XII, and subunit "a" of factor XIII. Fibrinogen existed throughout the tumor stroma, and tumor cells were surrounded by fibrin. Staining for tissue factor pathway inhibitor, and plasminogen activators was minimal and inconsistent. Plasminogen activator inhibitors -1, -2, and -3 were present in the tumor stroma, and on tumor cells and vascular endothelium. Extravascular coagulation activation exists associated with pancreatic carcinoma cells in situ that is apparently unopposed by naturally occurring inhibitors or the plasminogen activator-plasmin system. We postulate that such local coagulation activation may regulate growth of this malignancy. These findings provide a rationale for testing agents that modulate the blood coagulation/fibrinolytic system (that inhibit tumor growth in other settings) in pancreatic carcinoma.
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PMID:Localization of blood coagulation factors in situ in pancreatic carcinoma. 1177 8

Tumor cell migration and metastasis in cancer are facilitated by interaction of the serine protease urokinase type plasminogen activator (uPA) with its receptor uPAR (CD 87). Overexpression of uPA and uPAR in cancer tissues is associated with a high incidence of disease recurrence and early death. In agreement with these findings, disruption of the protein-protein interaction between uPAR present on tumor cells and its ligand uPA evolved as an attractive intervention strategy to impair tumor growth and metastasis. For this, the uPAR antagonist cyclo[19,31][D-Cys(19)]-uPA(19)(-)(31) was optimized to efficiently interrupt binding of uPA to cellular uPAR. First, the disulfide bridge of this lead compound was shifted and then the modified peptide was shortened from the amino and carboxy terminus to generate cyclo[21,29][Cys(21,29)]-uPA(21)(-)(30). Next, cyclo[21,29][D-Cys(21)Cys(29)]-uPA(21)(-)(30) was yielded by changing the chirality of Cys(21) to D-Cys(21). For analysis of uPAR binding activity, we employed competitive flow cytofluorometric receptor binding assays, using FITC-uPA as the ligand and U937 promyeloid leukemia cells as the cellular source of uPAR. As demonstrated for cyclo[21,29][D-Cys(21)Cys(29)]-uPA(21)(-)(30), the achieved peptide modifications maintained receptor binding activity (IC(50) = 0.04 microM), which is close in order to that of the parent protein ligand, uPA (IC(50) = 0.01 microM). A detailed NMR analysis with restrained and free molecular dynamics calculations in explicit H(2)O exhibits a well-defined structure with characteristic features such as an omega-loop with two betaI-turns about Lys(3), Tyr(4), Ser(6), and Asn(7). Hydrophobic clustering of the side chains of Tyr(4), Phe(5), Ile(8), and Trp(10) is observed. Side chain mobility is analyzed with time-dependent distance restraints. The NMR structure of cyclo[21,29][D-Cys(21)Cys(29)]-uPA(21)(-)(30) is very similar to the previously reported structure of the amino terminal fragment of uPA. Systematic point mutations led to cyclo[21,29][D-Cys(21)Nle(23)Cys(29)]-uPA(21)(-)(30), which still binds to uPAR but is resistant to proteolytic cleavage, e.g., by the tumor-associated serine proteases uPA and plasmin, and is stable in blood serum or plasma. In conclusion, small cyclic peptides were created, which mimic the structure and activity of the binding epitope of uPA to uPAR and which may serve as novel therapeutic agents in cancer metastasis.
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PMID:Synthesis, solution structure, and biological evaluation of urokinase type plasminogen activator (uPA)-derived receptor binding domain mimetics. 1240 9

The specific functions of plasminogen, stromal plasminogen activator, stromal plasminogen activator receptor, and stromal plasminogen activator inhibitor in the progression of the murine soft tissue sarcoma, T241 were investigated. Negation of plasminogen to the tumor blunted the orthotopic growth of the sarcoma in syngeneic mice. The reduced tumor growth was associated with a dramatic increase in tumor-infiltrating F4/80-positive macrophages and a diminution of vessel density, but not with obvious differences in fibrin and collagen deposition, or invasiveness of the tumor. Ablation of plasminogen activation by the tumor stroma only modestly impaired the prolonged growth of the sarcoma, suggesting that tumor cell-produced plasminogen activator is sufficient to mediate productive plasminogen activation. Plasminogen facilitated sarcoma progression, angiogenesis, and suppression of macrophage infiltration in the absence of either stromal urokinase plasminogen activator receptor or stromal plasminogen activator inhibitor. These data demonstrate that tumor cell-produced plasminogen activator and host plasminogen cooperate to facilitate soft tissue sarcoma growth and suppress the accumulation of tumor-infiltrating macrophages.
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PMID:Plasminogen promotes sarcoma growth and suppresses the accumulation of tumor-infiltrating macrophages. 1248 35

We have developed a parenteral delivery system for the administration of the highly promising pure antiestrogen RU 58668 (RU). Two types of nanoparticles (NP) made of biodegradable copolymers and coated with polyethylene-glycol (PEG) chains were prepared: nanospheres (NS) (diameter, approximately 110 nm) and nanocapsules (NC) with an oily core (diameter, approximately 250 nm). The amount of RU incorporated into NS and NC was approximately 33 vs. approximately 5 microg RU/mg of polymer, respectively. Coating with PEG chains prolonged the antiestrogenic potency of RU, as shown by a prolonged antiuterotrophic activity of encapsulated RU into PEG-poly(D,L lactic acid) (PLA) NS, as compared to that of conventional nonpegylated NS. In mice bearing MCF-7 estrogen-dependent tumors, free RU injected at 4.3 mg/kg/week by i.v. route slightly decreased the estradiol-promoted (0.5 mg/kg/week) tumor growth while RU-loaded PEG-PLA NS injected at the same dose strongly reduced it. Analysis of cell cycle parameters in tumors treated with RU indicated that RU-loaded PEG-PLA NS injected at 4.3 mg/kg/week in MCF-7 tumors decreased cyclin D(1) and cyclin E simultaneously, and increased p27. The antitumoral activity of RU encapsulated within pegylated NC was stronger than that of RU entrapped with pegylated NS loaded at an equivalent dose. Indeed, the former decreased the tumor size in nude mice transplanted with the estrogen receptor-positive but estrogen-independent MCF-7/Ras breast cancer cells at a concentration 2.5 times lower than that of the latter (0.4 mg/kg/week compared to 1 mg/kg/week). Empty PEG-PLA NS and NC were devoid of antiuterotrophic and antitumoral activities. Altogether, these results suggest that the incorporation of the pure antiestrogen RU into long-circulating NP could represent a novel antiestrogen drug delivery system for the parenteral route.
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PMID:In vitro and in vivo biologic evaluation of long-circulating biodegradable drug carriers loaded with the pure antiestrogen RU 58668. 1284 87

Plasminogen activator inhibitor-1 (PAI-1) is the principal inhibitor of urokinase type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA), and as such is thought to play an important role in the regulation of extracellular matrix remodeling. In blood, PAI-1 is bound to the adhesion protein vitronectin and is associated with vitronectin in fibrin clots and the provisional matrix. Elevated levels of PAI-1 are associated with atherosclerosis and an increased thrombotic tendency, while PAI-1 deficiency leads to increased fibrinolysis and bleeding. PAI-1 is also elevated in many solid tumors and is associated with a poor prognosis in cancer. PAI-1 has been shown to be a potent regulator of both vascular cell migration in vitro and of angiogenesis and tumor growth in vivo. PAI-1 can both promote and inhibit tumor growth and angiogenesis. Low concentrations of PAI-1 can stimulate tumor angiogenesis while treatment of animals with high doses of PAI-1 inhibits angiogenesis and tumor growth. Hence, PAI-1 appears to have a multifunctional role in regulating the migratory and fibrinolytic activity of vascular cells, and this, in turn, may help to explain the many varied actions of PAI-1.
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PMID:Plasminogen activator inhibitor-1 in tumor growth, angiogenesis and vascular remodeling. 1287 Oct 67

Proteolytic degradation of the extracellular matrix is essential to angiogenesis. Two families of proteases, the serine proteases of plasminogen activator/plasmin system and the matrix metalloproteinases (MMPs) are closely involved in these processes. The treatment of mice with a diet containing a new synthetic MMP inhibitor, OPB-3206: 3S-[4-(N-hydroxyamino)-2R-isobutylsuccinyl] amino-1methoxy-3, 4-dihydrocarbostyril, abrogated the development of new vessels in a rat corneal assay, and in a mouse Matrigel assay. In an in vitro angiogenesis model, OPB-3206 inhibited the migration and the tube formation of bovine aortic endothelial cells at 10-100 times lower concentrations than those required to inhibit the growth of these cells. OPB-3206 as well as other MMP inhibitory drugs, batimastat/BB-94 and marimastat/BB-2516, also selectively inhibited tubular morphogenesis in vitro. OPB-3206 reduced the activities of interstitial collagenase and type IV collagenase, but the concentrations of 50% inhibition against these MMPs were much higher than those of BB-94 and BB-2516. However, this new compound also inhibited urokinase type plasminogen activator activity on fibrin zymogram, while BB-94 and BB-2516 did not. Furthermore, the addition of urokinase type plasminogen activator reduced the inhibitory effect of the tubular morphogenesis of vascular endothelial cells by OPB-3206. The treatment of mice with a diet containing this new compound also reduced the growth of implanted mammary carcinomas as well as the lung metastasis of colon carcinoma. The anti-angiogenic effect of OPB-3206 appeared to be associated with its inhibition of tumor growth and metastasis.
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PMID:A new synthetic matrix metalloproteinase inhibitor modulates both angiogenesis and urokinase type plasminogen activator activity. 1451 52

Tumor growth requires proteolytic activity. As a consequence, protein breakdown products are present in the circulation of patients with cancer. Within the past decade a large number of proteolytic fragments have been identified that inhibit angiogenesis and tumor growth. The mechanism of action of these inhibitors is still poorly understood. We recently found that the effects of the angiogenesis inhibitor endostatin on endothelial cells is critically dependent on the presence of cross-beta structure, a structure also present in amyloidogenic polypeptides in plaques of patients with amyloidosis, such as Alzheimer disease. We also showed that cross-beta structure containing endostatin is a ligand for tissue-type plasminogen activator (tPA). We noted that many angiogenesis inhibitors stimulate tPA-mediated plasminogen activation. Because the presence of cross-beta structure is the common denominator in tPA-binding ligands, we hypothesize that these endogenous antiangiogenic proteolytic fragments share features with amyloidogenic polypeptides. We postulate that the cross-beta structural fold is present in these antiangiogenic polypeptide fragments and that this structure mediates the inhibitory effects. The hypothesis provides new insights in the potential mechanisms of these angiogenesis inhibitors and offers opportunities to improve their use.
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PMID:Do antiangiogenic protein fragments have amyloid properties? 1516 35

Angiostatin, a proteolytic fragment of plasminogen consisting of the first 3 or 4 kringle domains, reduces tumor growth by specifically inhibiting tumor angiogenesis. Angiostatin is generated in vitro in a 2-step process. First, plasminogen is converted to plasmin by plasminogen activators. Next, plasmin excises the angiostatin fragment from plasminogen, a process requiring molecules that are able to donate a free sulfhydryl group. In this study, we investigated whether stimulation of in vivo angiostatin generation by administration of plasminogen activator and a free sulfhydryl group donor (FSD) has anti-tumor activity. First, we determined the optimal conditions for in vitro angiostatin generation by incubating murine plasma with different concentrations of plasminogen activator and/or the FSD captopril. Angiostatin generation was monitored by western blot analysis. Our results were extrapolated to the in vivo situation by administering the optimal dose of tissue-type plasminogen activator (tPA, i.v. injection 3 times/week) and captopril (in drinking water) to mice and analyzing the presence of angiostatin in the circulation. Angiostatin was readily detectable in mice receiving both tPA and captopril, but not in mice receiving either one of the agents. Finally, the anti-tumor activity of the tPA/captopril treatment was tested in a human melanoma xenograft model. Administration of tPA alone had only a marginal effect on tumor growth. Captopril alone reduced tumor growth by about 60%, whereas treatment with both captopril and tPA resulted in 83% inhibition of tumor growth.
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PMID:Anti-tumor activity of a combination of plasminogen activator and captopril in a human melanoma xenograft model. 1535 48

Our previous studies demonstrated that a synthetic peptide encompassing residues 185-203 of the noncollagenous (NC1) domain of the alpha3 chain of type IV collagen, named tumstatin, inhibits in vitro melanoma cell proliferation and migration. In the present study, B16F1 melanoma cells were stably transfected to overexpress the complete tumstatin domain (Tum 1-232) or its C-terminal part, encompassing residues 185-203 (Tum 183-232). Tumstatin domain overexpression inhibited B16F1 in vitro cell proliferation, anchorage-independent growth, and invasive properties. For studying the in vivo effect of overexpression, representative clones were subcutaneously injected into the left side of C57BL6 mice. In vivo tumor growth was decreased by -60% and -56%, respectively, with B16F1 cells overexpressing Tum 1-232 or Tum 183-232 compared to control cells. This inhibitory effect was associated with a decrease of in vivo cyclin D1 expression. We also demonstrated that the overexpression of Tum 1-232 or Tum 183-232 induced an in vivo down-regulation of proteolytic cascades involving matrix metalloproteinases (MMPs), especially the production or activation of MMP-2, MMP-9, MMP-13, as well as MMP-14. The plasminogen activation system was also altered in tumors with a decrease of urokinase-type plasminogen activator (u-PA) and tissue-type plasminogen activator (t-PA) and a strong increase of plasminogen activator inhibitor-1 (PAI-1). Collectively, our results demonstrate that tumstatin or its C-terminal antitumor fragment, Tum 183-232, inhibits in vivo melanoma progression by triggering an intracellular transduction pathway, which involves a cyclic AMP (cAMP)-dependent mechanism.
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PMID:In vivo overexpression of tumstatin domains by tumor cells inhibits their invasive properties in a mouse melanoma model. 1553 Aug 61

The two-kringle domain of tissue-type plasminogen activator (t-PA) has previously been shown to contain anti-angiogenesis activity. In this study, we explored the potential in vivo anti-tumor effects of the recombinant kringle domain (TK1-2) of human t-PA. Anti-tumor effects of purified Pichia-driven TK1-2 were examined in nude mice models by subcutaneous implantation of human lung (A-549) and colon (DLD-1, HCT-116) cancer cell lines. Mice bearing the tumors were injected with PBS or purified TK1-2 (30 mg/kg) i.p. every day for 22 days. TK1-2 treatment suppressed the A-549, DLD-1, and HCT-116 tumor growth by 85.3%, 52.4%, and 62.5%, respectively. Immunohistological examination of the tumor tissues showed that TK1-2 treatment decreased the vessel density and also the expression of angiogenesis-related factors including angiogenin, VEGF, alpha-SMA, vWF, and TNF-alpha, and increased the apoptotic fraction of cells. TK1-2 neither inhibited in vitro growth of these cancer cells nor affected t-PA-mediated fibrin clot lysis. These results suggest that TK1-2 inhibits the tumor growth by suppression of angiogenesis without interfering with fibrinolysis.
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PMID:The kringle domain of tissue-type plasminogen activator inhibits in vivo tumor growth. 1565 16


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