Elevated levels of the angiogenic peptide basic fibroblast growth factor in urine of bladder cancer patients.
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Angiogenesis Inducing Agents↗
Biomedical subjects
J Folkman
Publications and source records attributed to J Folkman.
Analysis of experimental antiangiogenic therapy.
Angiogenesis is a fundamental process by which new blood vessels are formed. Progressive tumor growth necessitates the continuous induction of new capillary blood vessels which converge upon the tumor. Suppression of tumor growth can be accomplished with the use of antiangiogenesis agents. AGM-1470 is a potent angiogenesis inhibitor in vitro and in vivo. In mouse studies, AGM-1470 has suppressed the growth and neovascularization induced by four murine tumors resulting in a 55% to 77% decrease in tumor growth. In these mice significant toxicity did not result from AGM-1470 therapy. AGM-1470 administered systemically to C57BI/6 male mice for 20 to 28 days inhibited the growth of: (1) Lewis lung carcinoma resulting in a T/C (treatment/control = mean tumor volume of treated/mean tumor volume of control) of 0.38 +/- 0.03 (P < .001); (2) colon adenocarcinoma 38 resulting in a T/C of 0.23 +/- 0.02 (P < .001); and (3) fibrosarcoma 105 resulting in a T/C of 0.31 +/- 0.05 (P < .001). To determine if antiangiogenic therapy was equally effective in mice of both sexes and in immunodeficient animals, we tested AGM-1470 in the treatment of fibrosarcoma 105 in both female mice and nude mice. For female mice T/C was 0.24 +/- 0.06 (P < .001). For nude mice T/C was 0.27 +/- 0.06 (P < .001). These results demonstrate that AGM-1470 suppresses the growth of a variety of different tumors. Furthermore, the antitumor effect of AGM-1470 therapy is independent of the immune system and sex.
Adenocarcinoma↗
The combination of antiangiogenic agents to inhibit primary tumor growth and metastasis.
Neovascularization is a critical component for the growth of tumors and is a dominant feature in diseases such as diabetic retinopathy and hemangiomas in infancy. Angiogenesis inhibition is a potentially important therapeutic modality. We have previously reported that AGM-1470 is a fungal-derived angiogenesis inhibitor that suppresses primary tumor growth and metastases and is also nontoxic. alpha-Interferon, an angiogenesis inhibitor, is effective in the treatment of life-threatening hemangiomas. We therefore attempted to treat murine primary tumors and metastases with a combination of AGM-1470 and alpha/beta-interferon. Treatment began after solid tumors formed. Six-week-old syngeneic C57BI/6 mice were treated for 21 days with either AGM-1470, or alpha/beta-interferon or AGM-1470 + alpha/beta-interferon. The combination of the angiogenesis inhibitors AGM-1470 and alpha/beta-interferon suppressed tumor growth by 80% compared with controls (P < or = .001). AGM-1470 and alpha/beta-interferon inhibited pulmonary metastatic tumor growth greater than sevenfold (P < or = .001) compared with controls. These effects were better than either inhibitor alone, and the combined effect was additive. Combination of angiogenesis inhibitors may be useful in the treatment of tumors and other angiogenesis-dependent diseases.
Animals↗
Regression of experimental iris neovascularization with systemic alpha-interferon.
BACKGROUND: Intraocular neovascularization leads to visual loss in many eye diseases, including diabetic retinopathy, age-related macular degeneration, and neovascular glaucoma. Current treatment relies on laser photocoagulation, involving the destruction of functional retinal tissue. A pharmacologic treatment directed at the newly growing vessels would represent a major advance. METHODS: The authors investigated the effect of systemic alpha-interferon in an experimental model of iris neovascularization in cynomolgus monkeys. Alpha-interferon was administered systemically to animals with angiographically documented iris neovascularization. RESULTS: Animals in the treatment group showed regression of neovascularization angiographically and histologically in eight of eight eyes. Control animals with documented iris neovascularization, followed without drug treatment, showed progression of the neovascularization in three of three eyes. CONCLUSION: Systemic alpha-interferon led to inhibition of neovascularization and regression of new vessels in an experimental model of iris neovascularization. This represents the first successful, controlled treatment of experimental neovascularization in the eye using a systemic drug directed specifically at the neovascular tissue.
Animals↗
Diagnostic and therapeutic applications of angiogenesis research.
Certain principles of the angiogenic process elucidated in the laboratory over the past 3 decades have now been translated to clinical application. These applications are in the areas of prognosis, inhibition of angiogenesis, and acceleration of angiogenesis. As more experience is gained from these studies we may begin to see the development of therapies for many other angiogenic diseases, including diabetic retinopathy, rheumatoid arthritis, and psoriasis. It may be possible to increase the rate of neovascularization of a myocardial infarction and perhaps even to stimulate the growth of coronary collateral vessels. From these laboratory and clinical studies it has become clear that angiogenesis is a fundamental process that dominates diseases in many different branches of medicine and surgery. A clear understanding of the biological and molecular aspects of this process will be critical to the successful treatment of a wide spectrum of "angiogenic diseases" [53].
Humans↗
Tumor angiogenesis correlates with metastasis in invasive prostate carcinoma.
Tumor growth and metastasis require angiogenesis; and microvessel density, a measure of tumor angiogenesis, correlates with metastasis in breast and lung carcinoma. To determine how microvessel density correlated with metastasis in prostate carcinoma, we counted microvessels within the initial invasive carcinomas of 74 patients (29 with metastasis, 45 without). Microvessels were highlighted by immunostaining endothelial cells for factor VIII-related antigen. Without knowledge of the patient's cancer stage, microvessels were counted in a 200 field (0.739 mm2) in the most active areas of neovascularization. The mean microvessel count in tumors from patients with metastases was 76.8 microvessels per 200 field (median, 66; standard deviation, 44.6). The counts within carcinomas from patients without metastasis were significantly lower, 39.2 (median, 36; standard deviation, 18.6) (P < 0.0001). Microvessel counts increased with increasing Gleason's score (P < 0.0001), but this increase was present predominantly in the poorly differentiated tumors. Although Gleason's score also correlated with metastasis (P = 0.01), multivariate analysis showed that Gleason's score added no additional information to that provided by microvessel count alone. Assay of microvessel density within invasive tumors may prove valuable in selecting patients for aggressive adjuvant therapies in early prostate carcinoma.
Adult↗
Synergistic effects of vascular endothelial growth factor and basic fibroblast growth factor on the proliferation and cord formation of bovine capillary endothelial cells within collagen gels.
BACKGROUND: Angiogenesis occurs within the interstitial matrix. We therefore cultured endothelial cells within collagen gels rather than on the surface of culture dishes. We measured the effect of a human glioblastoma-derived factor, and the combined effect of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), on both the proliferative and morphologic changes exhibited by endothelial cells. EXPERIMENTAL DESIGN: Bovine capillary endothelial (BCE) cells were cultured in a gel of type I collagen. Effects of growth factors were evaluated by the cell recovery from the gel and the morphologic changes of cells. The glioblastoma-derived factor was characterized by column chromatography, immunoblotting, and immunoadsorption with an anti-VEGF antibody. RESULTS: After 4 days of culture in the collagen gel with 10% calf serum Dulbecco's minimum essential medium, most of the BCE cells died. Addition of glioblastoma-conditioned medium resulted in a change in morphology from a round shape to an elongated spindle shape; moreover, the number of BCE cells was enhanced. The major activity in the conditioned medium was VEGF. In the 3-dimensional gel, we found a higher activity associated with VEGF, compared with bFGF when the growth factors were added 24 hours after seeding. In this assay, the response to bFGF diminished within 24 hours, but that to VEGF continued for 48 hours. When the two factors were added to the culture simultaneously, the cell number was greater than the sum of those stimulated with either growth factor alone. In the presence of both bFGF and VEGF, cord-like structures became prominent in the BCE cell cultures. CONCLUSIONS: A human glioblastoma cell line produced VEGF, which enhanced the proliferation of BCE cells and induced an elongated shape in collagen gels. VEGF and bFGF increased the rate of proliferation and the number of cord-like structures in a synergistic manner.
Animals↗
1-Deoxymannojirimycin inhibits capillary tube formation in vitro. Analysis of N-linked oligosaccharides in bovine capillary endothelial cells.
Capillary endothelial cells can be induced to form capillary-like structures in vitro by plating on fibronectin-coated dishes (Ingber, D. E., and Folkman, J. (1989) J. Cell Biol. 109, 317-330), thereby mimicking angiogenesis. To assess the role of glycoproteins bearing asparagine-linked oligosaccharides in this process, we tested the effect of oligosaccharide processing inhibitors on the formation of capillary tubes. Deoxymannojirimycin, a compound that prevents synthesis of hybrid and complex-type oligosaccharides, inhibited the formation of capillary tubes. In contrast, swainsonine, an inhibitor that blocks synthesis of complex- but not hybrid-type oligosaccharides, did not inhibit tube formation. Lectin affinity chromatography of 2-[3H] mannose-labeled glycopeptides from endothelial cells induced to form tubes did not reveal a striking difference in the spectrum of oligosaccharides compared to uninduced cells. Since endothelial cells formed tubes normally in the presence of swainsonine, we analyzed glycopeptides from swainsonine-treated induced and uninduced cells. Cells induced to form tubes were enriched in monosialylated hybrid-type oligosaccharides sensitive to alpha-fucosidase, beta-galactosidase, and beta-N-acetylhexosaminidase, suggestive of sialyl Lewis-X determinants. We used an enzyme-linked immunoassay to measure sialyl Lewis-X epitopes on capillary endothelial cells and found that both induced and uninduced cells expressed sialyl Lewis-X epitopes. Deoxymannojirimycin and, to a lesser extent, swainsonine reduced the level of sialyl Lewis-X epitopes in cells induced to form capillary tubes, but neither compound affected the level of epitopes in cell monolayers. We conclude that synthesis of at least hybrid-type oligosaccharides is required for capillary tube formation in vitro and that an increase in monosialylated, fucosylated glycans on asparagine-linked oligosaccharides occurs during this process.
1-Deoxynojirimycin↗
Tumor angiogenesis: a new significant and independent prognostic indicator in early-stage breast carcinoma.
BACKGROUND: Axillary lymph node status has been the most important prognostic factor in operable breast carcinoma, but it does not fully account for the varied disease outcome. More accurate prognostic indicators would help in selection of patients at high risk for disease recurrence and death who are candidates for systemic adjuvant therapy. Our recent findings indicated that microvessel density (count or grade) in invasive breast carcinoma (a measure of tumor angiogenesis) is associated with metastasis and thus may be a prognostic indicator. PURPOSE: This study was designed to further define the relationship of microvessel density with overall and relapse-free survival and with other reported prognostic indicators in breast carcinoma. METHODS: In a prospective, blinded study of 165 consecutive patients, the microvessels within primary invasive breast carcinoma were highlighted by immunocytochemical staining to detect factor VIII-related antigen. Using light microscopy, we counted microvessels per 200x field in the most active areas of neovascularization and graded microvessel density. These findings were correlated, by univariate and multivariate analyses, with overall and relapse-free survival, axillary node status, and other prognostic indicators (median follow-up, 51 months). RESULTS: There was a highly significant (P < or = .001) association of microvessel density with overall survival and relapse-free survival in all patients, including node-negative and node-positive subsets. All patients with breast carcinomas having more than 100 microvessels per 200x field experienced tumor recurrence within 33 months of diagnosis, compared with less than 5% of the patients with breast carcinoma having 33 or fewer microvessels per 200x field. Moreover, microvessel density was the only statistically significant predictor of overall survival among node-negative women (P < .001). Only microvessel density (P < .001) and histologic grade (P = .04) showed statistically significant correlations with relapse-free survival in the node-negative subset. CONCLUSIONS: Microvessel density in the area of the most intense neovascularization in invasive breast carcinoma is an independent and highly significant prognostic indicator for overall and relapse-free survival in patients with early-stage breast carcinoma (I or II by International Union Against Cancer criteria). IMPLICATIONS: Such an indicator would be useful in selection of those node-negative patients with breast carcinoma who are at high risk for having occult metastasis at presentation. These patients could then be given systemic adjuvant therapy.
Adult↗
Isolation and characterization of human heparin.
Heparin was isolated from an unusually large human hemangioma that contained an elevated level of mast cells. Purification of multimilligram quantities of heparin from this tissue sample permitted a thorough examination of its structure and activity. Characterization of this human heparin included the following: one-dimensional and two-dimensional 1H-nuclear magnetic resonance spectral analysis; oligosaccharide mapping; saccharide compositional analysis; and in vitro assessment and anticoagulant activity. Oligosaccharide mapping and nuclear magnetic resonance spectroscopy showed that this human heparin is structurally similar to porcine intestinal mucosal heparin but distinctly different from bovine lung heparin. This human heparin also has substantially more in vitro anticoagulant activity than either of these pharmaceutical heparins.
Animals↗
Basic fibroblast growth factor modulates the mitogenic potency of the platelet-derived growth factor (PDGF) isoforms by specific upregulation of the PDGF alpha receptor in vascular smooth muscle cells.
Platelet-derived growth factor AA (PDGF AA), in contrast to PDGF AB and BB, is a poor mitogen for smooth muscle cells (SMC). However, together with basic fibroblast growth factor (bFGF) it acts synergistically on DNA synthesis of these cells. Northern blot analysis revealed that bFGF selectively increases the PDGF-receptor alpha subtype (PDGF-R alpha) mRNA level without a significant effect on the PDGF-R beta mRNA level. The amount of PDGF-R alpha protein is also selectively increased after stimulating SMC with bFGF as shown by immunoprecipitation of lysates from SMC with anti-PDGF-R alpha antibodies. The number of binding sites for 125I-PDGF AA is more than doubled after bFGF-treatment, whereas the specific binding for PDGF AB and BB increased only by approximately 30 and 20%, respectively. The increase in the number of PDGF-R alpha renders the SMC responsive for PDGF AA as demonstrated by the induction of the proto-oncogene c-fos as well as by an increased cell proliferation. The enhanced PDGF binding after bFGF treatment may in fact explain the observed synergistic behavior. These data are discussed with regard to a possible role of growth factor-induced transmodulation of receptor expression during atherogenesis.
Animals↗
Interferon alfa-2a therapy for life-threatening hemangiomas of infancy.
BACKGROUND AND METHODS: Most hemangiomas are small, harmless birthmarks that appear soon after birth, proliferate for 8 to 18 months, and then slowly regress over the next 5 to 8 years, leaving normal or slightly blemished skin. In rare cases, hemangiomas can endanger vital structures, with a mortality of up to 60 percent. About a third of these life-threatening hemangiomas respond to treatment with corticosteroids, but for the others there is no safe and effective treatment. We evaluated the effects of daily subcutaneous injections of interferon alfa-2a (up to 3 million units per square meter of body-surface area) in 20 neonates and infants with life-threatening or vision-threatening hemangiomas that failed to respond to corticosteroid therapy. RESULTS: In 18 of the 20 patients the hemangiomas regressed by 50 percent or more after an average of 7.8 months of treatment (range, 2 to 13). One infant died of refractory proliferation of a lesion and consumptive coagulopathy. The condition of three other patients who had large hemangiomas associated with consumptive coagulopathies that were unresponsive to conventional therapies stabilized after seven days of treatment with interferon alfa-2a alone. Transient side effects of treatment with interferon alfa-2a included fever, neutropenia (one patient), and skin necrosis (one patient). No long-term toxicity has been observed after a mean follow-up of 16 months. CONCLUSIONS: Interferon alfa-2a appears to induce the early regression of life-threatening corticosteroid-resistant hemangiomas of infancy.
Disseminated Intravascular Coagulation↗
Systemic antiangiogenic therapy for choroidal neovascularization. What is the role of interferon alfa?
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Choroid↗
Control of angiogenesis by heparin and other sulfated polysaccharides.
Heparin and its related polysaccharides are revealed to have important new functions as regulators of blood vessel growth and regression. This regulatory activity may be explained in part by at least five mechanisms in which heparin and heparan sulfate interact with peptide growth factors: (1) Heparin and heparan sulfate have a high affinity for angiogenic growth factors such as the fibroblast growth factors and VEGF, as well as for angiogenic inhibitors such as thrombospondin and platelet factor 4. (2) Heparin and its related polysaccharides stabilize bFGF and other growth factors. (3) FGFs and thrombospondin are stored in the extracellular matrix bound to heparan sulfate; fragments of heparin or heparan sulfate may act as natural chaperones to shuttle bFGF or other growth factors to different cellular compartments. (5) Heparin-like low-affinity receptors on the surface of endothelial cells (and other cells), prepare FGFs for binding to their specific high affinity receptors; and (6) Heparin and its related polysaccharides potentiate angiostatic steroids. It is likely that future investigations will uncover even more fundamental regulatory roles for heparin as well as for other polysaccharides in the normal function of growth factors, especially in the complex process of angiogenesis.
Animals↗
Angiogenesis--retrospect and outlook.
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Angiogenesis Inducing Agents↗
Use of an animal model for the study of the role of human immunodeficiency virus 1 in the human intestine.
The gastrointestinal manifestations of human immunodeficiency virus (HIV)-1 disease have centered on identifiable causes of intestinal dysfunction such as parasitic and bacterial pathogens. The lamina propria of the intestine contains cell that harbor HIV-1, but the significance of this observation remains unknown. Because limited animal models are available to evaluate the gastrointestinal effects of this infection, a system that uses human fetal intestine transplanted subcutaneously onto the back of an immunodeficient mouse was developed. After 8 weeks, fetal tissues mature into an adult-appearing tissue with a lumen. Cell-free HIV-1 was inoculated into the explants, an evidence for infection was evaluated by histological evaluation, in situ hybridization, and polymerase chain reaction. No evidence for HIV-1 incorporation into epithelial cells could be found. It was concluded that this model provides a system in which intestinal HIV-1 interaction can be evaluated. In this model, cell-free HIV-1 does not appear to infect the epithelial cell.
Animals↗
Hirschsprung's disease: associated abnormalities and demography.
We here examine the demographic parameters of patients with Hirschsprung's disease. The study population includes all patients with histologically confirmed disease treated at the Children's Hospital Medical Center of Boston over the 25-year period extending from 1961 through the first quarter of 1986. There were 179 cases. Overall, children with Hirschsprung's disease were found less likely to be first born (P less than .01). This relationship was seen to persist irrespective of maternal age, maternal race, or type of disease. The implications of this finding are discussed. Overall, 22% of these children had one or more associated abnormalities involving the neurological, cardiovascular, urological, and gastrointestinal systems. Many of the disorders appeared to be related to neurocrestopathies. Frequent associations included Down's syndrome, defects in cardiac septation, tetralogy of Fallot, and Dandy-Walker syndrome. These conditions occurred more frequently than would have been predicted through chance alone. This study found no association between an increased maternal age and the occurrence of Hirschsprung's disease. This study also found that approximately 7% of the affected children had been born prematurely.
Abnormalities, Multiple↗