Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor spread involves degradation of various components of the extracellular matrix and blood vessel wall. Among these is heparan sulfate proteoglycan, which plays a key role in the self-assembly, insolubility and barrier properties of basement membranes and extracellular matrices. Expression of an endoglycosidase (heparanase) which degrades heparan sulfate correlates with the metastatic potential of tumor cells, and treatment with heparanase inhibitors markedly reduces the incidence of metastasis in experimental animals. Heparin-binding angiogenic proteins are stored as a complex with heparan sulfate in the microenvironment of tumors. These proteins are released and can induce new capillary growth when heparan sulfate is degraded by heparanase. Here, we describe the molecular properties, expression and involvement in tumor progression of a human heparanase. The enzyme is synthesized as a latent approximately 65 kDa protein that is processed at the N-terminus into a highly active approximately 50 kDa form. The heparanase mRNA and protein are preferentially expressed in metastatic human cell lines and in tumor biopsy specimens, including breast carcinoma. Overexpression of the heparanase cDNA in low-metastatic tumor cells conferred a high metastatic potential in experimental animals, resulting in an increased rate of mortality. The heparanase enzyme also released ECM-resident bFGF in vitro, and its overexpression elicited an angiogenic response in vivo. Heparanase may thus facilitate both tumor cell invasion and neovascularization, two critical steps in tumor progression. Mammary glands of transgenic mice overexpressing the heparanase enzyme exhibit precocious branching of ducts and alveolar development, suggesting that the enzyme promotes normal morphogenesis and possibly pre-malignant changes in the mammary gland.
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PMID:Molecular properties and involvement of heparanase in cancer progression and mammary gland morphogenesis. 1154

Heparin and heparin-like compounds appear to possess anticancer properties apart from their anticoagulant activities. This paper reviews recent data on heparins in experimental models of tumor growth and metastasis and discusses various mechanisms by which heparins may inhibit cancer progression. The growing body of evidence supporting the antineoplastic activity of heparins provides the rationale for their widespread testing in cancer patients for the purpose of improving cancer-related survival. Their improved safety, convenience and ease of outpatient administration compared to unfractionated heparin, as well as the suggestion of superior anticancer activity, make the low molecular weight heparins the preferred agents to test in prospective cancer trials.
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PMID:Activity of heparins in experimental models of malignancy: Possible explanations for anticancer effects in humans. 1190 69

Activation of coagulation appears to play a role in tumor progression. This report describes the preliminary results of a phase II study using docetaxel plus enoxaparin in 15 patients with stage IV non-small cell lung cancer (NSCLC). Time to progression was the primary endpoint. Several surrogate markers of coagulation and angiogenesis were evaluated. Enoxaparin was administered at a daily dose of 1 mg/kg (subcutaneously). The initial dose of docetaxel was 100 mg/m2, given as a 60 min infusion every 21 days with prophylactic dexamethasone. Eight patients achieved an objective response (53%) and four had stable disease, with a median duration of 3.5 months. The median time to progression was 5 months (range, 2 to >15 months). The median survival was 11 months. The most frequent toxicities were neutropenia and asthenia. No significant bleeding or thrombotic events were observed. Eleven patients had elevated D-dimer plasma levels prior to therapy, and seven of these patients with a response or stable disease had a significant decline of the D-dimer during therapy. There were no consistent changes of the plasma levels of the angiogenic factors, except for transforming growth factor-beta-1 (TGF-beta1). The median baseline level of TGF-beta1 prior to therapy was 34,867 pg/ml. Twelve out of 13 patients who achieved a response or stable disease had a significant reduction of the TGF-beta1 levels during therapy. Enoxaparin in combination with chemotherapy was safe and well tolerated in patients with advanced NSCLC. This preliminary data suggests that enoxaparin may prolong the time to progression, and therefore justify the continuation of this trial.
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PMID:Phase II study of docetaxel plus enoxaparin in chemotherapy-naive patients with metastatic non-small cell lung cancer: preliminary results. 1456 92

Heparin/heparan sulfate-like glycosaminoglycans (HSGAGs) have been implicated in clinically relevant processes such as hemostasis, infection, development, and cancer progression, through their interactions with proteins. Electrospray ionization mass spectrometry (ESI-MS) and tandem mass spectrometry (MSn) were combined to identify and quantify 12 HSGAG disaccharides that can be generated by enzymatic depolymerization with heparin lyases. This technique includes free amine-containing disaccharides that had previously been observed in MSn but not quantified. Our methods use diagnostic product ions from MSn spectra of up to three isomeric disaccharides at once, and up to three sequential stages of MSn in tandem, for the quantitative analysis of the relative percentage of each of these isomers. The isomer quantification was validated using mock mixtures and showed acceptable accuracy and precision. These methods may be applied to the quantification of other isomers by MSn. While each of the 12 disaccharides alone had a linear response to an internal standard in the MS1 spectra, the individual response factors did not remain constant when the concentrations of the other 11 disaccharides in the mixtures fluctuated, due to competition for electrospray ionization. The absolute concentration of one fluctuating isomer was determined out of a constant mixture of the other disaccharides. The rapid, accurate, and sensitive quantification of all isomeric disaccharides may contribute to the eventual sequencing of longer saccharides by MSn, enabling the elucidation of the structure-function relationships of HSGAGs.
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PMID:Quantification of isomers from a mixture of twelve heparin and heparan sulfate disaccharides using tandem mass spectrometry. 1612 39

Heparin, a potent inhibitor of blood coagulation, exhibits antitumoral action in tumor progression such as in angiogenesis and metastasis but is not orally absorbed in the body, making it an attractive candidate as an oral drug for antiangiogenic cancer therapy. We generated LHD or orally active heparin using low molecular weight heparin (LMWH) and deoxycholic acid that is effectively absorbed in the gastrointestinal tract. Using the in vitro endothelial tubular formation and chicken chorioallantoic membrane angiogenesis assay, we found that antiangiogenic activity of this LHD was similar to that of LMWH. From the in vivo Matrigel plugs assay, LHD treated orally could effectively inhibit angiogenesis into the plugs induced by basic fibroblast growth factor, whereas LMWH treated orally could not due to no oral absorption. In addition, when this LHD was orally administered into the tumor bearing mice, it significantly inhibited tumor growth by its antiangiogenic therapeutic mechanism, and when accompanied with doxorubicin, it appeared to have an additive effect. Collectively, LHD having antiangiogenic activity could be orally absorbable and inhibit tumor growth via inhibiting angiogenesis. These findings demonstrate the therapeutic potential of LHD in the clinical trials, which is suggested as a new oral therapeutic remedy for cancer therapy.
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PMID:Suppression of angiogenesis and tumor growth by orally active deoxycholic acid-heparin conjugate. 1729 20

Coagulation activation appears to play a role in tumor progression. Low-molecular-weight heparin (LMWH) may influence tumor growth and LMWHs have been shown to beneficially influence tumor response to chemotherapy. In a phase II study using docetaxel plus enoxaparin in 25 patients with advanced breast cancer, fibrin monomer, transforming growth factor-beta 1 (TGF-beta(1)) and response rates were evaluated. Enoxaparin was administered at a daily dose of 0, 5 or 1.0 mg/kg and docetaxel at 35-45 mg/m(2) once weekly. Nine patients achieved a partial response (36%) and nine patients (36%) had stable disease. The median time to progression was 11.5 weeks (range 5-51 weeks), and 16 weeks combining patients with partial remission and stable disease. One major bleed occurred. Patients with partial remission had a significant decrease of TGF-beta(1) and fibrin (P < 0.05). A significant correlation between TGF-beta(1) and fibrin monomer was also seen in all subgroups independent of clinical response. The most frequent toxicities were granulocytopenia, asthenia, transient peripheral edema and temporary hot flushes. In conclusion, docetaxel plus enoxaparin was quite active and well tolerated in patients with advanced breast cancer. These preliminary data suggest further clinical research using chemotherapy plus enoxaparin as an antitumor therapy in advanced breast cancer is warranted.
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PMID:Combining chemotherapy and low-molecular-weight heparin for the treatment of advanced breast cancer: results on clinical response, transforming growth factor-beta 1 and fibrin monomer in a phase II study. 1758 15

Virus infection and oncogenesis are two tightly linked processes. Some viruses are endowed with a direct transforming capability and infection activates inflammation that, in turn, favours tumor progression. Also, both inflammation and tumor trigger (and are strongly dependent from) angiogenesis. Finally, some oncogenic viruses release "virokines" that contribute to the development of virus-associated tumors. At a molecular level, viral proteins, cytokines, receptors and adhesion molecules "cross-contribute" to the different processes and, amazingly, many of them bind to heparin and to heparan sulfate proteoglycans to exert their functions. Heparin-like polysulfated (PS) or polysulfonated (PSN) compounds are an heterogeneous group of natural or synthetic molecules whose prototypes are PS heparin and PSN suramin. They vary in their backbone structure, length, number/disposition of sulfated/sulfonated groups. Different combinations of these features confer to PS/PSN the capacity to bind with variable specificity to those heparin-binding proteins that "cross-contribute" to virus infection and tumor progression. Taken together, these considerations suggest that heparin-like PS/PSN antagonists may act as multitarget drugs that may control at once virus infection and tumor progression by targeting different proteins simultaneously. Here we discuss the possibility to exploit PS/PSN compounds for the development of drugs at the cross-road of viral infection and oncogenesis, taking in consideration the past efforts, possible drawbacks and future perspectives.
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PMID:Polysulfated/sulfonated compounds for the development of drugs at the crossroad of viral infection and oncogenesis. 1975 71

Heparin is commonly used for prevention or treatment of cancer-associated thromboembolism. Recent clinical evidence indicates that heparin, and low-molecular weight heparin improves survival of cancer patients. Experimental evidence from various animal models consistently supports the ability of heparin to attenuate metastasis. Heparin, apart from its anticoagulant activity contains a variety of biological activities possibly affecting cancer progression, including: inhibition of heparanase, blocking of P- and L-selectin mediated cell adhesion, and inhibition of angiogenesis. The delineation of antimetastatic activity of heparin is in the focus of several ongoing investigations. This review summarizes the current experimental evidence on the biology of heparin as a potential treatment cancer progression.
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PMID:Antimetastatic activities of heparins and modified heparins. Experimental evidence. 2043 9

Heparin is frequently used in the treatment of cancer-associated thromboembolism. Accumulating clinical evidence indicates that cancer patients treated with unfractionated and low-molecular weight heparin (LMWH) survive longer than patients treated by other anticoagulants, especially patients in the early stage of the disease. Experimental analysis from a number of animal models constantly provides evidence for the ability of heparin to attenuate metastasis. The non-anticoagulant activity of heparin on metastasis includes the ability to inhibit cell-cell-interaction through blocking of P- and L-selectin, to inhibit extracellular matrix protease heparanase, and to inhibit angiogenesis. This chapter summarizes current experimental evidence on the biology of heparin during cancer progression, with the focus on potential mechanism of heparin antimetastatic activity.
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PMID:Heparin as an inhibitor of cancer progression. 2080 51

Heparin, an anticoagulant that is widely used clinically, is also known to bind to several kinds of proteins through electrostatic interactions because of its polyanionic character. These interactions are mediated by the physicochemical properties of heparin such as sequence composition, sulfation patterns, charge distribution, overall charge density, and molecular size. Although this electrostatic character mediates its binding to many proteins related with tumor progression, thereby providing its antiangiogenic property, the administration of heparin for treating cancer is limited in clinical applications due to several drawbacks, such as its low oral absorption, unsatisfactory therapeutic effects, and strong anticoagulant activity which induces hemorrhaging. Here, we evaluated novel, orally active, low molecular weight heparin (LMWH) derivatives (LHD) conjugated with deoxycholic acid (DOCA) that show reduced anticoagulant activity and enhanced antiangiogenic activity. The chemical conjugate of LMWH and DOCA was synthesized by conjugating the amine group of N-deoxycholylethylamine (EtDOCA) with the carboxylic groups of heparin at various DOCA conjugation ratios. The LMWH-DOCA conjugate series (LHD1, LHD1.5, LHD2, and LHD4) were further formulated with poloxamer 407 as a solubilizer for oral administration. An in vitro endothelial tubular formation and in vivo Matrigel plug assay were performed to verify the antiangiogenic potential of LHD. Finally, we evaluated tumor growth inhibition of oral LHD administration in a SCC7 model as well as in A549 human cancer cell lines in a mouse xenograft model. Increasing DOCA conjugation ratios showed decreased anticoagulant activity, eventually to zero. LHD could block angiogenesis in the tubular formation assay and the Matrigel plug assay. In particular, oral administration of LHD4, which has 4 molecules of DOCA per mole of LMWH, inhibited tumor growth in SCC7 mice model as well as A549 mice xenograft model. LHD4 was orally absorbable, showed minimal anticoagulant activity and inhibits tumor growth via antiangiogenesis. These findings demonstrate the therapeutic potential of LHD4 as a new oral anti-cancer drug.
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PMID:High antiangiogenic and low anticoagulant efficacy of orally active low molecular weight heparin derivatives. 2086 8


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