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Biomedical subjects

J Folkman

Publications and source records attributed to J Folkman.

At least 127 records · Page 7Linked to original sources
PubMed1994

Thalidomide is an inhibitor of angiogenesis.

Thalidomide is a potent teratogen causing dysmelia (stunted limb growth) in humans. We have demonstrated that orally administered thalidomide is an inhibitor of angiogenesis induced by basic fibroblast growth factor in a rabbit cornea micropocket assay. Experiments including the analysis of thalidomide analogs revealed that the antiangiogenic activity correlated with the teratogenicity but not with the sedative or the mild immunosuppressive properties of thalidomide. Electron microscopic examination of the corneal neovascularization of thalidomide-treated rabbits revealed specific ultrastructural changes similar to those seen in the deformed limb bud vasculature of thalidomide-treated embryos. These experiments shed light on the mechanism of thalidomide's teratogenicity and hold promise for the potential use of thalidomide as an orally administered drug for the treatment of many diverse diseases dependent on angiogenesis.

Animals↗
PubMed1994

Recombinant human betacellulin. Molecular structure, biological activities, and receptor interaction.

Soluble forms of human betacellulin (BTC) were purified to homogeneity from the conditioned medium of mouse A9 cells transfected with the BTC precursor cDNA. Three types of soluble BTC, designated BTC-1a, BTC-1b and BTC-2, were resolved by cation-exchange and size-exclusion column chromatography. Physicochemical analysis has revealed that BTC-1a represents the glycosylated, intact molecule composed of 80 amino acid residues (Asp32 to Tyr111 of the precursor molecule). BTC-1b appears to be a truncated molecule lacking 12 amino acid residues from the amino terminus of BTC-1a. BTC-2 was found to be a 50-amino acid molecule (Arg62 to Tyr111) that corresponds to the epidermal growth factor (EGF) structural unit. The biological activities of these BTC molecules were essentially identical as judged by their mitogenicity on Balb/c 3T3 fibroblasts. BTC and EGF were equipotent in stimulating Balb/c 3T3 cell proliferation and rat mesangial cell Ca2+ mobilization as well as in inhibiting the growth of human epidermoid carcinoma A431 cells. BTC and EGF antagonized each other with similar dose dependence for binding to A431 cells, indicating that these factors bind the same receptor molecules with equivalent avidity. The Kd value of EGF receptor (EGFR) and BTC is 0.5 nM as determined on Balb/c 3T3 cells. In addition, human mammary carcinoma MDA-MB-453 cells, which express multiple members of the EGFR family, were found to possess 2.7 x 10(3) BTC binding sites/cell, and the binding was readily quenched by EGF. These results suggest that the primary receptor for BTC is EGFR.

3T3 Cells↗
PubMed1994

Elevated levels of an angiogenic peptide, basic fibroblast growth factor, in the urine of patients with a wide spectrum of cancers.

BACKGROUND: Experimental evidence supports the hypothesis that the development of blood vessels is fundamental to the growth and metastasis of solid tumors. Elevated levels of the angiogenic peptide basic fibroblast growth factor (bFGF) have been significantly correlated with the status and extent of disease in bladder cancer. PURPOSE: We measured the bFGF levels in patients with cancer in organs other than the bladder to determine whether elevated levels accompany these cancers. METHODS: Urine samples were collected from 950 patients having a wide variety of solid tumors, leukemia, or lymphoma and from a control group of 87 healthy volunteers and 198 patients with non-cancer-related diseases. Levels of bFGF in samples prepared from the urine were measured using an enzyme bioassay. RESULTS: Male control subjects had a median bFGF level of 151 pg/g and female control subjects a median of 237 pg/g, with a combined 90th percentile of 619 pg/g. An elevated level of bFGF was found in the urine of some of the patients with every type of tumor studied except cervical carcinoma. For example, patients with active local cancers had a median level of 312 pg/g. Those with active, metastatic cancers had a median level of 479 pg/g and a 90th percentile level of 14143 pg/g. After "elevated" was defined to mean higher than the 90th percentile level for controls, 31% of patients with local active and 47% of patients with metastatic active cancers showed elevated bFGF levels. Survival among cancer patients at the median follow-up time was 85%-88% for those with "normal" and 71%-72% for those with "elevated" urine bFGF levels. IMPLICATIONS: Our results suggest that bFGF in urine deserves further evaluation of its potential use as a monitor of therapy or as a predictor of outcome once a cancer has been diagnosed.

Analysis of Variance↗
PubMed1994

Elevated basic fibroblast growth factor in the serum of patients with Duchenne muscular dystrophy.

The mechanism whereby dystrophin deficiency leads to excessive fibrosis and muscle degeneration is not known. The absence of dystrophin in skeletal muscle is associated with reduced plasma membrane stability as evidenced by elevated serum levels of the cytoplasmic enzyme creatine kinase. Basic fibroblast growth factor, a cytoplasmic polypeptide growth regulator that stimulates connective tissue synthesis, induces satellite cell proliferation, and suppresses myogenic differentiation, is made by skeletal muscle. We hypothesize that dystrophin deficiency leads to the constant release of basic fibroblast growth factor, which in turn contributes to fibrosis and muscle weakness by stimulating connective tissue and suppressing skeletal muscle differentiation. As an initial step in testing this hypothesis, we measured basic fibroblast growth factor in the serum of Duchenne muscular dystrophy patients. We found that whereas basic fibroblast growth factor was undetectable in the serum of normal individuals (n = 200), levels were elevated in 11 of 18 patients with Duchenne muscular dystrophy.

Adolescent↗
PubMed1994

Purification and characterization of two collagenase inhibitors from mouse sarcoma 180 conditioned medium.

We have previously shown that mouse sarcoma 180 cells produce vascular endothelial growth factor [VEGF; Rosenthal et al., 1990, Growth Factors, 4: 53-59], an endothelial mitogen that stimulates angiogenesis. Recent reports have implicated metalloproteinases and their inhibitors in the regulation of vascular morphogenesis, tumor invasion, and metastasis. We report here that mouse sarcoma 180 cells produce two collagenase inhibitors. These inhibitors were purified by heparin-Sepharose affinity chromatography, gel filtration, and C4 reverse phase h.p.l.c. Analytical gel electrophoresis of the purified inhibitors (MS-22 and MS-31) revealed molecular masses of 22,000 and 31,000 Da under reducing conditions, and 20,000 and 30,000 Da under nonreducing conditions, respectively. The NH2-terminal amino acid sequence of MS-22 was identical to that of tissue inhibitor of metalloproteinases type 2 (TIMP-2) produced by human melanoma cells [Stetler-Stevenson et al., 1989, J. Biol. Chem. 264: 17374-17378) over the first 30 amino acids. The NH2-terminal amino acid sequence of MS-31 was identical to that of murine TIMP-1 [Gewert et al., 1989, EMBO J 6:651-657]. Statistical analysis of the amino acid composition data of these two mouse sarcoma 180-derived collagenase inhibitors confirms the identification of MS-22 as TIMP-2 and MS-31 as TIMP-1.

Amino Acid Sequence↗
PubMed1994

Quantitation of angiogenesis and antiangiogenesis in the chick embryo chorioallantoic membrane.

A novel method for quantitating angiogenesis and its inhibition has been developed for the chick embryo. The method is based on the vertical growth of new capillary blood vessels into a collagen gel through two parallel nylon meshes which align the capillaries for counting. Angiogenesis is induced by basic fibroblast growth factor contained within the gel and slowly released by aluminum sucrose octasulfate (sucralfate) or by tumor cells implanted on the gel. The potency of four different angiogenesis inhibitors was compared at concentrations of 0.6 to 600 nmole. This technique may facilitate the discovery and development of angiogenesis inhibitors for clinical application.

Allantois↗
PubMed1994

Accelerated healing of duodenal ulcers by oral administration of a mutein of basic fibroblast growth factor in rats.

BACKGROUND/AIMS: Human basic fibroblast growth factor (bFGF) is an endothelial mitogen that stimulates angiogenesis and proliferation of other cells such as fibroblasts and smooth muscle cells. After this peptide was stabilized to acid and pepsin by site-specific mutagenesis, it was tested whether bFGF might accelerate the healing of experimental duodenal ulcers. METHODS: This mutein peptide (bFGF-CS23) was administered orally in comparison with cimetidine to rats with chronic duodenal ulcers previously induced by cysteamine. RESULTS: Oral bFGF-CS23 therapy maintained for 21 days at 100 ng/100 g twice daily resulted in (1) significant acceleration of healing of duodenal ulcers, i.e., reduction of mean ulcer area by 83% in the bFGF-CS23-treated rats compared with only 61% for cimetidine therapy and 40% for untreated controls; (2) complete healing with no residual ulcer in 62% of the bFGF-CS23-treated rats compared with only 7% of untreated rats; and (3) a ninefold increase in angiogenesis in the ulcer bed compared with untreated controls. A single dose of the bFGF-CS23 mutein had no effect on gastric output of hydrochloric acid or pepsin, but daily treatment for 2 or 3 weeks resulted in enhanced acid and pepsin outputs. CONCLUSIONS: Chronic duodenal ulcers can be healed rapidly by stimulating angiogenesis and other wound-healing processes in the ulcer bed without reduction of gastric acid.

Administration, Oral↗
PubMed1994

Splenosis is regulated by a circulating factor.

Splenic rupture may result in splenosis, the growth of splenic fragments. We used a parabiotic model to test the hypothesis that splenotic growth is governed by a circulating mediator(s). Pairs of C57B1/6 mice underwent side-to-side anastomosis. After 2 weeks, each of four groups underwent a second operation in which one or both of the partners had a sham operation or a splenectomy, or had splenic fragments transplanted into their peritoneums, or some combination thereof. Six weeks later, splenotic fragments were excised and weighed. Spleen fragments involuted when inserted into the pairs that had two intact spleens. In contrast, in pairs with one intact spleen and one set of fragments, multiple splenules developed, whose aggregate mass was approximately half (ratio, 0.53 +/- 0.04 [mean +/- SE]) that of the original transplanted fragments. Significantly more splenosis (P < .01) developed in pairs with no intact spleens and one set of fragments (0.82 +/- 0.04). The pairs with no intact spleens and twice as many fragments had an intermediate amount of splenosis (0.66 +/- 0.08). The authors conclude that (1) splenosis is inhibited by a factor (or factors) that circulates across the capillary network in a parabiotic pair of mice, and (2) the level of inhibition of splenosis appears to be directly proportional to total splenic mass. The authors speculate that spleen-saving operations, even if partial, may decrease the incidence of splenosis in the patient with a shattered spleen.

Animals↗
PubMed1994

Cytostatic inhibition of endothelial cell growth by the angiogenesis inhibitor TNP-470 (AGM-1470).

Recently, we reported the anti-angiogenic action along with anti-tumour activity of TNP-470 (AGM-1470). In this study, the effect of TNP-470 on the growth of human umbilical vein endothelial (HUVE) cells was examined. TNP-470 inhibited the growth of HUVE cells in a biphasic manner. The inhibition was cytostatic in the first phase (complete inhibition at 300 pg ml-1 to 3 micrograms ml-1 with an IC50 of 15 pg ml-1) and cytotoxic in the second phase (> or = 30 micrograms ml-1). The cytostatic inhibition of HUVE cell growth by TNP-470 was durable after washing out TNP-470 in culture. Incorporation of thymidine but not uridine and leucine by HUVE cells was inhibited in the first phase, while that of all three compounds was inhibited in the second phase. Human and rat endothelial cells among various types of cells were the most sensitive to the cytostatic inhibition, while differences in the cytotoxic inhibition were minimal. These results suggest that TNP-470 exerts its specific anti-angiogenic action by inhibiting cytostatically growth of endothelial cells in a relatively specific manner.

Antibiotics, Antineoplastic↗
PubMed1994

Cellular markers that distinguish the phases of hemangioma during infancy and childhood.

Hemangiomas, localized tumors of blood vessels, appear in approximately 10-12% of Caucasian infants. These lesions are characterized by a rapid proliferation of capillaries for the first year (proliferating phase), followed by slow, inevitable, regression of the tumor over the ensuing 1-5 yr (involuting phase), and continual improvement until 6-12 yr of age (involuted phase). To delineate the clinically observed growth phases of hemangiomas at a cellular level, we undertook an immunohistochemical analysis using nine independent markers. The proliferating phase was defined by high expression of proliferating cell nuclear antigen, type IV collagenase, and vascular endothelial growth factor. Elevated expression of the tissue inhibitor of metalloproteinase, TIMP 1, an inhibitor of new blood vessel formation, was observed exclusively in the involuting phase. High expression of basic fibroblast growth factor (bFGF) and urokinase was present in the proliferating and involuting phases. There was coexpression of bFGF and endothelial phenotypic markers CD31 and von Willebrand factor in the proliferating phase. These results provide an objective basis for staging hemangiomas and may be used to evaluate pharmacological agents, such as corticosteroids and interferon alfa-2a, which accelerate regression of hemangiomas. By contrast, vascular malformations do not express proliferating cell nuclear antigen, vascular endothelial growth factor, bFGF, type IV collagenase, and urokinase. These data demonstrate immunohistochemical differences between proliferating hemangiomas and vascular malformations which reflect the biological distinctions between these vascular lesions.

Adolescent↗
PubMed1994

Vascular endothelial growth factor/vascular permeability factor is temporally and spatially correlated with ocular angiogenesis in a primate model.

Ischemia often precedes neovascularization. In ocular neovascularization, such as occurs in diabetic retinopathy, a diffusible angiogenic factor has been postulated to be produced by ischemic retina and to lead to neovascularization of the retina, optic nerve, or iris. However, no angiogenic factor has been conclusively identified that satisfies this hypothesis. Vascular endothelial growth factor/vascular permeability factor, hereafter referred to as VEGF, is a likely candidate for an ocular angiogenic factor because it is a secreted mitogen, specific for endothelial cells, and is upregulated by hypoxia. We investigated the association of VEGF with the development of experimental iris neovascularization in the cynomolgus monkey. Following the production of retinal ischemia by laser occlusion of all branch retinal veins, VEGF was increased in the aqueous fluid, and the aqueous VEGF levels changed synchronously and proportionally with the severity of iris neovascularization. Northern analysis and in situ hybridization revealed that VEGF messenger RNA is upregulated in the ischemic retina. These observations support the hypothesis that ocular neovascularization is regulated by a diffusible factor and identify VEGF as a likely candidate for a retina-derived vascular permeability and angiogenesis factor in vivo.

Animals↗
PubMed1993

Basic fibroblast growth factor secreted by an animal tumor is detectable in urine.

Basic fibroblast growth factor (bFGF or FGF-2) is abnormally elevated in the serum and urine of patients with many types of cancer. However, the source of the bFGF is unclear. We developed a model that could distinguish between tumor-derived and host-derived bFGF. We gave athymic mice s.c. injections of cells of the murine K1000 tumor, which secretes a bFGF mutein (bFGF CS23) as its dominant angiogenic factor. Controls were given injections of Lewis lung carcinoma or saline. Urine was collected for 9 weeks, and bFGF was quantitated using two immunoassays which can discriminate between tumor bFGF CS23 and native bFGF. None of the mice had detectable urinary native bFGF, and no control mice had detectable urinary bFGF CS23. In contrast, urine from mice bearing the K1000 tumor revealed detectable bFGF CS23 by 2 weeks, and bFGF CS23 increased with increasing tumor volume throughout the study. Because bFGF CS23 is not produced by other cells, the bFGF CS23 in the urine most likely came from the K1000 tumor and not from the host. These results suggest that the source of elevated bFGF in the urine of human cancer patients is, at least in part, the tumor itself.

3T3 Cells↗
PubMed1993

Synthesis and secretion of vascular permeability factor/vascular endothelial growth factor by human retinal pigment epithelial cells.

The presence of the secreted angiogenic molecule, vascular permeability factor/vascular endothelial growth factor, was investigated in human retinal pigment epithelial cells. Northern and in situ hybridization analysis of cultured cells identified vascular permeability factor/vascular endothelial growth factor mRNA. Western analysis of cell lysates identified a 42 kD protein that comigrated with human recombinant vascular permeability factor/vascular endothelial growth factor. Immunoassay measurements detected vascular permeability factor/vascular endothelial growth factor protein in cell lysates and conditioned media in vitro and in cell lysates isolated directly from post-mortem eyes. These data demonstrate that human retinal pigment epithelial cells can synthesize the secreted angiogenic peptide vascular permeability factor/vascular endothelial growth factor in vitro and in situ. The production and secretion of this factor by human retinal pigment epithelial cells may be important in the pathogenesis of ocular neovascularization.

Antisense Elements (Genetics)↗
PubMed1993

Betacellulin: a mitogen from pancreatic beta cell tumors.

Betacellulin, a member of the epidermal growth factor family, has been identified in the conditioned medium of cell lines derived from mouse pancreatic beta cell tumors. Betacellulin is a 32-kilodalton glycoprotein that appears to be processed from a larger transmembrane precursor by proteolytic cleavage. The carboxyl-terminal domain of betacellulin has 50 percent sequence similarity with that of rat transforming growth factor alpha. Betacellulin is a potent mitogen for retinal pigment epithelial cells and vascular smooth muscle cells.

3T3 Cells↗
PubMed1993

Cloning and expression of cDNA encoding human betacellulin, a new member of the EGF family.

Betacellulin (BTC) is a novel growth factor purified from the conditioned media of mouse pancreatic beta tumor cells and has been found to be a new member of the epidermal growth factor (EGF) family. The cDNA encoding human BTC has been cloned from a cDNA library prepared from human breast adenocarcinoma cell line MCF-7. The nucleotide sequence encodes a polypeptide which consists of 178 amino acid residues including a putative signal sequence, indicating that the structural organization of human BTC is similar to that of mouse BTC. The amino acid sequence of the human BTC precursor protein exhibits 79% similarity with that of the mouse precursor protein. The BTC gene was found to be expressed in several mouse tissues including kidney and liver as well as in a mouse beta tumor cell line and MCF-7 cells, suggesting that BTC might play a physiological role in normal tissues.

Amino Acid Sequence↗