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Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There is now considerable direct evidence that tumor growth is angiogenesis-dependent. The most compelling evidence is based on the discovery of angiostatin, an angiogenesis inhibitor that selectively instructs endothelium to become refractory to angiogenic stimuli. Angiostatin, which specifically inhibits endothelial proliferation, induced dormancy of metastases defined by a balance of apoptosis and proliferation. We now show that systemic administration of human angiostatin potently inhibits the growth of three human and three murine primary carcinomas in mice. An almost complete inhibition of tumor growth was observed without detectable toxicity or resistance. The human carcinomas regressed to microscopic dormant foci in which tumor cell proliferation was balanced by apoptosis in the presence of blocked angiogenesis. This regression of primary tumors without toxicity has not been previously described. This is also the first demonstration of dormancy therapy, a novel anticancer strategy in which malignant tumors are regressed by prolonged blockade of angiogenesis.
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PMID:Angiostatin induces and sustains dormancy of human primary tumors in mice. 864 May 62

Angiostatin, an internal fragment of plasminogen, is a potent inhibitor of angiogenesis, which selectively inhibits endothelial cell proliferation. When given systemically, angiostatin potently inhibits tumor growth and can maintain metastatic and primary tumors in a dormant state defined by a balance of proliferation and apoptosis of the tumor cells. We identified angiostatin while studying the phenomenon of inhibition of tumor growth by tumor mass and have elucidated one mechanism for this phenomenon. In our animal model, a primary tumor almost completely suppresses the growth of its remote metastases. However, after tumor removal, the previously dormant metastases neovascularize and grow. When the primary tumor is present, metastatic growth is suppressed by a circulating angiogenesis inhibitor. Serum and urine from tumor-bearing mice, but not from controls, specifically inhibit endothelial cell proliferation. The activity copurifies with a 38 kD plasminogen fragment which we have sequenced and named angiostatin. Human angiostatin, obtained from a limited proteolytic digest of human plasminogen, has similar activities. Systemic administration of angiostatin, but not intact plasminogen, potently blocks neovascularization and growth of metastases and primary tumors. We here show that the inhibition of metastases by a primary mouse tumor is mediated, at least in part, by the angiogenesis inhibitor angiostatin.
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PMID:Angiostatin: an endogenous inhibitor of angiogenesis and of tumor growth. 900 23

Extracellular manipulation of protein disulfide bonds has been implied in diverse biological processes, including penetration of viruses and endotoxin into cells and activation of certain cytokine receptors. We now demonstrate reduction of one or more disulfide bonds in the serine proteinase, plasmin, by a reductase secreted by Chinese hamster ovary or HT1080 cells. Reduction of plasmin disulfide bond(s) triggered proteolysis of the enzyme, generating fragments with the domain structure of the angiogenesis inhibitor, angiostatin. Two of the known reductases secreted by cultured cells are protein disulfide isomerase and thioredoxin, and incubation of plasmin with these purified reductases resulted in angiostatin fragments comparable with those generated from plasmin in cell culture. Thioredoxin-derived angiostatin inhibited proliferation of human dermal microvascular endothelial cells with half-maximal effect at approximately 0.2 microg/ml. Angiostatin made by cells and by purified reductases contained free sulfhydryl group(s), and S-carbamidomethylation of these thiol group(s) ablated biological activity. Neither protein disulfide isomerase nor thioredoxin were the reductases used by cultured cells, because immunodepletion of conditioned medium of these proteins did not affect angiostatin generating activity. The plasmin reductase secreted by HT1080 cells required a small cofactor for activity, and physiologically relevant concentrations of reduced glutathione fulfilled this role. These results have consequences for plasmin activity and angiogenesis, particularly in the context of tumor growth and metastasis. Moreover, this is the first demonstration of extracellular reduction of a protein disulfide bond, which has general implications for cell biology.
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PMID:Generation of angiostatin by reduction and proteolysis of plasmin. Catalysis by a plasmin reductase secreted by cultured cells. 925 80

Angiostatin inhibits angiogenesis and metastatic tumor growth; however, its usefulness in treating primary nonmetastasizing tumors is less well understood. We now report the effectiveness of human angiostatin administration in a mouse hemangioendothelioma model. Human angiostatin was administered to mice with s.c. hemangioendothelioma and associated disseminated intravascular coagulopathy (Kasabach-Merritt syndrome). Angiostatin significantly reduced tumor volume in comparison to nontreated controls, increased survival, and prevented the profound thrombocytopenia and anemia of Kasabach-Merritt syndrome. Apoptosis of tumor cells was induced by angiostatin, but tumor cell proliferation was not inhibited. These data suggest angiostatin as a novel treatment for nonmetastasizing vascular tumors and for Kasabach-Merritt syndrome.
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PMID:Human angiostatin inhibits murine hemangioendothelioma tumor growth in vivo. 939 49

Angiostatin, a 38 kilodalton fragment of plasminogen, is a potent inhibitor of angiogenesis. However, little is known about how angiostatin affects endothelial gene expression. To learn more about its effect on endothelial-specific genes implicated in angiogenesis, we examined E-selectin expression and function in bovine capillary endothelial cells treated with recombinant angiostatin. Angiostatin caused a four to five-fold increase in E-selection polypeptide levels in proliferating endothelial cells but little or no increase in confluent cells. P-selection polypeptide levels were unaffected by angiostatin in either proliferating or confluent cells. E-selectin mRNA and adhesion activity in proliferating endothelial cells were also increased by angiostatin. Angiostatin had little effect on the distribution of endothelial cells in G0/G1, S, and G2/M, indicating angiostatin does not alter cell cycle progression significantly. These data demonstrate that angiostatin selectively upregulates E-selectin in proliferating endothelial cells in vitro. This selectivity may provide insights into the mechanism by which angiostatin inhibits tumor growth in vivo without apparent effects on quiescent endothelium.
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PMID:Angiostatin upregulates E-selectin in proliferating endothelial cells. 958 13

The antitumoral effects that follow the local delivery of the N-terminal fragment of human plasminogen (angiostatin K3) have been studied in two xenograft murine models. Angiostatin delivery was achieved by a defective adenovirus expressing a secretable angiostatin K3 molecule from the cytomegalovirus promoter (AdK3). In in vitro studies, AdK3 selectively inhibited endothelial cell proliferation and disrupted the G2/M transition induced by M-phase-promoting factors. AdK3-infected endothelial cells showed a marked mitosis arrest that correlated with the down-regulation of the M-phase phosphoproteins. A single intratumoral injection of AdK3 into preestablished rat C6 glioma or human MDA-MB-231 breast carcinoma grown in athymic mice was followed by a significant arrest of tumor growth, which was associated with a suppression of neovascularization within and at the vicinity of the tumors. AdK3 therapy also induced a 10-fold increase in apoptotic tumor cells as compared with a control adenovirus. Furthermore, we showed that systemic injection of AdK3 delayed C6 tumor establishment and growth, confirming that angiostatin can function in a paracrin manner. Our data support the concept that targeted antiangiogenesis, using adenovirus-mediated gene transfer, represents a promising alternative strategy for delivering antiangiogenic factors as their bolus injections present unsolved pharmacological problems.
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PMID:Angiostatin gene transfer: inhibition of tumor growth in vivo by blockage of endothelial cell proliferation associated with a mitosis arrest. 960 Sep 71

Despite recent advances in neurosurgery, radiation, and chemotherapy, the prognosis of patients with malignant gliomas remains dismal. Based on the observation that solid tumor growth is angiogenic dependent, and gliomas are among the most angiogenic of all tumors, therapeutic strategies aimed at inhibiting angiogenesis are theoretically attractive. Angiostatin, an internal peptide fragment of plasminogen, has recently been shown to potently inhibit endothelial proliferation in vitro and tumor growth in vivo. Long-term systemic delivery of proteins, however, poses a number of difficult logistic and pharmacological problems and may not be necessary or optimal for treating locally aggressive tumors such as gliomas. We now demonstrate that retroviral and adenoviral vectors that transduce the angiostatin cDNA can be used to inhibit endothelial cell growth in vitro and angiogenesis in vivo. Vector-mediated inhibition of tumor-associated angiogenesis results in increased apoptotic tumor cell death, leading to inhibition of tumor growth. These studies support a potential role of vector-mediated transduction of the cDNA encoding angiostatin as a potential novel therapeutic strategy for the treatment of malignant brain tumors and confirm the antitumor activity of angiostatin and the concept of dormancy therapy.
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PMID:Viral vector-targeted antiangiogenic gene therapy utilizing an angiostatin complementary DNA. 969 67

Human malignant gliomas are among the most malignant and most intensely vascularized solid tumors. Angiostatin, an internal fragment of plasminogen, was recently discovered as an endogenous inhibitor of tumor-related angiogenesis by selective inhibition of endothelial cell growth. Using xenograft transplants of rat and primary human glioma cells in immunodeficient mice we investigated the effects of systemic administration of angiostatin purified from human plasma on tumor growth. The rat C6 and 9L glioma and the human U87 glioma cell lines implanted either s.c. or intracranially in Swiss nude mice responded to angiostatin in a dose-dependent fashion with growth inhibition to 11% of controls (P < 0.01), without detectable signs of toxicity. The inhibition of treated tumors was accompanied by a marked reduction of vascularity to 38% of controls (P < 0.01) in the presence of an up to 6-fold increased apoptotic index (P < 0.01), consistent with the hypothesis that angiostatin acts tumoristatic by inhibiting tumor-induced endothelial cell proliferation. Expression analysis of growth factors in angiostatin-treated tumors revealed an up to 3-fold decrease in vascular endothelial growth factor-mRNA and an up to 4-fold increase in basic fibroblast growth factor-mRNA, as compared with untreated controls in rat gliomas (P < 0.01). This suggests that inhibition of the tumorigenic phenotype may be mediated in part by a downregulation of vascular endothelial growth factor expression within the tumor. Our data demonstrate that systemic administration of angiostatin efficiently suppresses malignant glioma growth in vivo. The tumoristatic activity against intracranial tumors independent of the blood brain barrier suggests that targeting the vascular compartment may offer novel therapeutic strategies against malignant gliomas.
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PMID:Angiostatin suppresses malignant glioma growth in vivo. 978 18

Although the therapeutic value of angiostatin, a proteolytic fragment of plasminogen, has been recognized for the treatment of cancer, the production of bioactive angiostatin remains a difficult task. Here we report that expression of a cDNA encoding a secreted, four-kringle human angiostatin inhibited tumor growth of B16F10 melanoma cells in mice but did not suppress tumor cell growth in culture. After transfection and selection, stable expression of the angiostatin cDNA was demonstrated in several B16F10 clones by quantitative mRNA analysis using the Taqman method. Cells that expressed angiostatin at either a low, medium, or high level were injected into C57BL/6 mice. s.c. Growth of B16F10 tumors was diminished by the angiostatin transgene, and the inhibition was directly proportional to the expression level of angiostatin in the transfected cells. However, suppression of s.c. tumor growth was transient, and eventually, tumors emerged with a strongly decreased expression of the transgene. Angiostatin expression also reduced lung metastasis from i.v.-injected B16F10 cells. Our data indicate that a cDNA encoding bioactive human angiostatin is potentially useful for gene therapy of human cancers, but the delivery of the transgene may require repeated dosing to achieve sustained dormancy of primary tumors and cancer metastases.
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PMID:Inhibition of tumor growth correlates with the expression level of a human angiostatin transgene in transfected B16F10 melanoma cells. 1058 98

Angiostatin is an endogenous inhibitor of tumor neovascularization that inhibits the proliferation of endothelial cells. Production of sufficient quantities of biologically active angiostatin by the enzymatic cleavage of plasminogen has proven difficult in that it has delayed clinical testing. We have cloned, expressed, and purified a recombinant human angiostatin derivative (K1-3) using a mammalian expression system. Through the addition of a secretory signal and polyhistidine sequence tag, K1-3 can be purified from post-culture medium by simple column chromatography. Purified K1-3 protein is apparently folded in an active conformation, as evidenced by its ability to bind to lysine-Sepharose. In vitro, recombinant K1-3 significantly suppressed endothelial cell proliferation in a dose-dependent manner with an IC50 of 50 nM. Using an animal model of intracranial brain tumors in immune-competent rats, systemic administration of purified recombinant K1-3 resulted in up to 85% suppression of tumor growth (P = 0.011). Growth suppression was accompanied by a 32% decrease (P = 0.01) in tumor neovascularization. This study demonstrates a simple method to produce a biologically active recombinant angiostatin derivative. The ability to suppress intracerebral tumor growth after systemic administration suggests that K1-3 is likely to have therapeutic value in the treatment of malignant glial tumors.
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PMID:Simplified production of a recombinant human angiostatin derivative that suppresses intracerebral glial tumor growth. 1058 88


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