Is there a field of wound pharmacology?
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Cicatrix↗
Biomedical subjects
J Folkman
Publications and source records attributed to J Folkman.
The role of angiogenesis in tumor growth.
Experimental and clinical evidence is here assembled in support of the concept that the development of a solid tumor progresses from a prevascular phase to a vascular phase. The prevascular tumor does not induce angiogenesis, is limited in size, and rarely metastasizes. The vascularized tumor induces host microvessels to undergo angiogenesis, has the potential to rapidly expand its cell population, and has a propensity to metastasize. Thus, angiogenesis is necessary but not sufficient for tumor growth and metastasis. Neovascularization of a tumor requires that a critical number of its cells have switched to the angiogenic phenotype. The mechanisms by which tumor cells become angiogenic, subjects of current study, are reviewed here. At least two general categories are recognized: (i) angiogenic activity arises from the tumor cell itself in the form of the release of angiogenic molecules such as basic fibroblast growth factor; (ii) angiogenic activity arises from host cells recruited by the tumor (e.g. macrophages), or is mobilized from the extracellular matrix, or requires concomitant loss of physiological inhibition of endothelial cell proliferation. Accumulating evidence indicates that for most tumors, the switch to the angiogenic phenotype depends upon the outcome of a balance between angiogenic stimulators and angiogenic inhibitors, both of which may be produced by tumor cells and perhaps by certain host cells.
Angiogenesis Inducing Agents↗
Inhibition of angiogenesis.
The concept of antiangiogenic therapy was first proposed in the early 1970s as a method of restricting tumor growth by inhibiting angiogenesis. In subsequent years sufficient knowledge about the process of angiogenesis itself was obtained so that it is now possible to begin to develop antiangiogenic therapy for clinical use. At least three strategies are feasible: (i) inhibition of release of angiogenic molecules from tumor cells; (ii) neutralization of angiogenic molecules that have already been released; and (iii) inhibition of vascular endothelial cells from responding to angiogenic stimulation. Most of the angiogenic inhibitors that have been discovered at the time of writing, directly interfere with the ability of endothelial cells to form new capillary blood vessels. Antiangiogenic activity is a newly found property of alpha-interferon. Although alpha-interferon is a relatively weak angiogenesis inhibitor in comparison to others, it has been very successful in the treatment of life-threatening hemangiomas in children. Early clinical experience with this first angiogenesis inhibitor to reach clinical trial, indicates that optimal antiangiogenic therapy in the future is likely to be based on the long-term use of inhibitors with low toxicity, and with little chance of inducing drug-resistance. It is apparent that different types of angiogenesis inhibitor may be administered together and that these compounds may also be administered to cancer patients as adjuncts to conventional chemotherapy. It is important to recognize that tumor vasculature has other properties besides angiogenesis, which make it a potential specific target for anti-cancer therapy.
Animals↗
Neovascularization is associated with a switch to the export of bFGF in the multistep development of fibrosarcoma.
In a transgenic mouse model, dermal fibrosarcomas develop in a pathway comprised of at least three stages: mild fibromatosis, aggressive fibromatosis, and fibrosarcoma. The latter two stages are highly vascularized when compared with both the normal dermis and the initial mild lesion. Analysis of cell cultures derived from biopsies of these lesions has revealed that basic fibroblast growth factor (bFGF) is synthesized in all three stages and in normal dermal fibroblasts derived from the same mice. Unexpectedly, there is a change in the localization of bFGF from its normal cell-associated state to extracellular release in the latter two stages, which is concomitant both with the neovascularization seen in vivo and with the tumorigenicity of these cell lines. Thus, in this multistep tumorigenesis pathway there appears to be a discrete switch to the angiogenic phenotype that correlates with the export of bFGF, a known angiogenic factor.
Animals↗
Role of vascular factors, including angiogenesis, in the mechanisms of action of sucralfate.
This brief overview of our recent results implicates vascular factors in the mechanisms of acute and chronic actions of sucralfate. Pretreatment of rats with sucralfate and its components, such as SOS and sodium sulfate, prevented the ethanol-induced microvascular injury and maintained blood flow in the gastric mucosa. Thus, preservation of microvascular integrity seems to be one of the mechanisms of acute gastroprotection by sucralfate. Chronic experiments with subcutaneously implanted sponges containing sucralfate or SOS revealed that both compounds stimulated angiogenesis, whereas only sucralfate enhanced the area of granulation tissue. These processes may have a role in the ulcer-healing action of sucralfate.
Animals↗
Potent anti-angiogenic action of AGM-1470: comparison to the fumagillin parent.
The anti-angiogenic activity of AGM-1470, a new synthetic analog of fumagillin isolated from Aspergillus fumigatus, was extensively examined both in vitro and in vivo using four different types of assay and compared to that of the fumagillin parent. Locally administered AGM-1470 inhibited the angiogenesis in the chick embryo chorioallantoic membrane assay and the rat corneal assay. In the rat sponge implantation assay, systemically administered AGM-1470 inhibited angiogenesis induced by basic fibroblast growth factor. Furthermore, in the rat blood vessel organ culture assay, AGM-1470 (1-1,000 ng/ml) was found to selectively inhibit the capillary-like tube formation of endothelial cells with a minimal effect on the non-endothelial cell growth. AGM-1470 showed more potent anti-angiogenic activity and less toxicity than the fumagillin parent. Therefore, AGM-1470 is much better than the fumagillin parent as anti-angiogenic compound.
Animals↗
Tumor angiogenesis and metastasis--correlation in invasive breast carcinoma.
BACKGROUND: Experimental evidence suggests that the growth of a tumor beyond a certain size requires angiogenesis, which may also permit metastasis. To investigate how tumor angiogenesis correlates with metastases in breast carcinoma, we counted microvessels (capillaries and venules) and graded the density of microvessels within the initial invasive carcinomas of 49 patients (30 with metastases and 19 without). METHODS: Using light microscopy, we highlighted the vessels by staining their endothelial cells immunocytochemically for factor VIII. The microvessels were carefully counted (per 200x field), and their density was graded (1 to 4+), in the most active areas of neovascularization, without knowledge of the outcome in the patient, the presence or absence of metastases, or any other pertinent variable. RESULTS: Both microvessel counts and density grades correlated with metastatic disease. The mean (+/- SD) count and grade in the patients with metastases were 101 +/- 49.3 and 2.95 +/- 1.00 vessels, respectively. The corresponding values in the patients without metastases were significantly lower--45 +/- 21.1 and 1.38 +/- 0.82 (P = 0.003 and P less than or equal to 0.001, respectively). For each 10-microvessel increase in the count per 200x field, there was a 1.59-fold increase in the risk of metastasis (95 percent confidence interval, 1.19 to 2.12; P = 0.003). The microvessel count and density grade also correlated with distant metastases. For each 10-microvessel increase in the vessel count per 200x field, there was a 1.17-fold increase in the risk of distant metastasis (95 percent confidence interval, 1.02 to 1.34; P = 0.029). CONCLUSIONS: The number of microvessels per 200x field in the areas of most intensive neovascularization in an invasive breast carcinoma may be an independent predictor of metastatic disease either in axillary lymph nodes or at distant sites (or both). Assessment of tumor angiogenesis may therefore prove valuable in selecting patients with early breast carcinoma for aggressive therapy.
Adult↗
Transcriptional regulation of basic fibroblast growth factor gene expression in capillary endothelial cells.
The growth of capillary endothelial cells (BCE) is an important regulatory step in the formation of capillary blood vessels. In vivo, the proliferation of these cells is stringently controlled. In vitro they can be stimulated by polypeptide growth factors, such as acidic fibroblast growth factor (aFGF) and basic fibroblast growth factor (bFGF). Since bFGF is synthesized and stored by vascular endothelial cells, this mitogen may play an important role in an autocrine growth regulation during angiogenesis. Here, evidence is presented for induction of the mRNA of bFGF by bFGF itself. A similar increase of bFGF mRNA was observed in response to thrombin and after treatment with phorbol ester. These results suggest that an autocrine loop may exist that may serve to modulate the mitogenic response in BCE under various physiological conditions, (e.g., wound healing and new capillary formation).
Animals↗
Human intestine matures as nude mouse xenograft.
This report describes a novel system for the study of the development and function of human intestine. Human fetal bowel transplanted into a subcutaneous tunnel on the back of athymic nude (nu/nu) mice develops a new microcirculation within 4 weeks. Tissues undergo morphological development, become similar to adult human bowel tissue, and may survive for 6 months after transplantation. Monoclonal antibody immunoperoxidase staining shows that the epithelial and some endothelial elements are of human phenotype, but the circulating blood cells and migrating mucosal lymphocytes are of mouse origin.
Animals↗
Duodenal ulcer. Discovery of a new mechanism and development of angiogenic therapy that accelerates healing.
The complete purification of the first angiogenic molecule, basic fibroblast growth factor (bFGF), was carried out in the authors' laboratory in 1983. Application of this peptide to chronic wounds enhances angiogenesis and accelerates wound healing. The authors showed that an acid-stable form of bFGF (i.e., bFGF-CS23) could be administered orally to rats with duodenal ulcers. The peptide promoted a ninefold increase of angiogenesis in the ulcer bed and accelerated ulcer healing more potently than cimetidine. Basic fibroblast growth factor did not reduce gastric acid. The authors now show that bFGF exists as a naturally occurring peptide in rat and human gastric and duodenal mucosa. This endogenous bFGF is present also in the bed of chronic ulcers in rats. Sucralfate binds bFGF and protects it from acid degradation. The sucralfate is angiogenic, based on its affinity for bFGF. When sucralfate is administered orally to rats, it significantly elevates the level of bFGF in the ulcer bed. Cimetidine, by its capacity to reduce gastric acid, also elevates bFGF in the ulcer bed. A hypothetical model is proposed in which prevention of ulcer formation or accelerated healing of ulcers by conventional therapies may be FGF dependent. Acid-stable bFGF-CS23 may be considered as a form of replacement therapy in the treatment of duodenal ulcers.
Aluminum Hydroxide↗
Interferon alpha therapy of haemangiomas in newborns and infants.
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Drug Resistance↗
Switch to the angiogenic phenotype during tumorigenesis.
Tumor growth and metastasis are angiogenesis-dependent. Virtually all solid tumors are neovascularized by the time they are detected. However, there is a prevascular phase during early tumor development where few or no tumor cells are angiogenic and expansion of the tumor is restricted to a few mm3. When enough tumor cells become angiogenic, the tumor can expand progressively and shed metastatic cells. This angiogenic switch has recently been quantitated for human breast cancer, as well as for prostate cancer. We have studied the problem of how tumors switch to the angiogenic phenotype by using transgenic mice in which tumors develop at a predictable time and in discrete prevascular and vascular stages. When the transgene is the bovine papilloma virus (BPV) genome, angiogenic fibrosarcomas develop from non-angiogenic precursors called fibromatoses. The fibrosarcomas secrete growth factors for capillary endothelial cells. In contrast, the fibromatoses do not secrete endothelial cell growth factors. When the transgene consists of the large "T" antigen of SV40 under the control of the rat insulin promoter, 70% of pancreatic islets become hyperplastic and 4-10% of these become angiogenic at 6-7 weeks. Tumors arise from these neovascularized hyperplastic islets and reach > 1000 x the volume of the preangiogenic islets. The onset of angiogenic activity coincides with the secretion of acidic fibroblast growth factor (aFGF) and other growth factors not fully identified at this writing. These studies help to explain the switch to the angiogenic phenotype during tumorigenesis and provide models to discover antiangiogenic therapies directed at the source of angiogenic activity. Such therapy, when developed, may be co-administered with currently available angiogenesis inhibitors which are directed at the target of angiogenic activity, vascular endothelial cells.
Animals↗
Angiostatic steroids potentiated by sulfated cyclodextrins inhibit corneal neovascularization.
It is known that hydrocortisone can be converted to a potent angiogenesis inhibitor by coadministration with heparin or with a sulfated cyclodextrin. The activity of tetrahydrocortisol-S, a purely angiostatic corticosteroid, can be potentiated by beta-cyclodextrin tetradecasulfate as shown in this study. This drug "pair" and other pairs of corticosteroids and beta-cyclodextrin tetradecasulfate can be applied topically to inhibit corneal neovascularization. Endotoxin-induced corneal neovascularization in rabbits was treated with beta-cyclodextrin tetradecasulfate coadministered with either: hydrocortisone, tetrahydrocortisol-S, or 6-alpha-fluoro-17,21-dihydroxy-16-beta-methyl-pregna-4,9(11),diene,3, 20-dione. When optimal ratios of steroid and cyclodextrin were used, neovascularization was reduced to 13%, 26%, and 28% of untreated controls for the three steroids, respectively. Hydrocortisone-cyclodextrin drug pairs suppressed virtually all inflammatory cell infiltration (induced by endotoxin), whereas tetrahydrocortisol-cyclodextrin pairs only partially reduced inflammation. These results demonstrate that corneal neovascularization and corneal inflammation are separable processes and that the neovascularization may be treated specifically using angiostatic steroids without inflammatory activity.
Administration, Topical↗
Sustained-release endotoxin. A model for inducing corneal neovascularization.
The rabbit corneal pocket assay is one of the most frequently used systems for the study of angiogenesis. This model particularly is useful to identify stimulators of new blood vessel formation. More recently, however, interest in inhibitors of angiogenesis has grown, and several antiangiogenic agents have been identified. Investigations of angiogenesis inhibitors require a reliable model for the stimulation of neovascularization. One method was modified to produce corneal neovascularization by implanting into the rabbit cornea a sustained-release polymer containing endotoxin (Escherichia coli lipopolysaccharide). The implant was prepared by mixing weighed quantities of endotoxin with ethylene vinyl acetate copolymer (Elvax) and forming 1-mm3 pellets containing 1%, 7.5%, 15%, 20%, 30%, and 40% (w/w) of endotoxin. Pure Elvax pellets were implanted as controls. Intrastromal corneal pockets were created in 92 eyes of male, albino New Zealand rabbits (n = 80), and sterilized endotoxin-copolymer implants were introduced. The growth rate of new vessels was measured by slit-lamp biomicroscopy. Endotoxin loads of 15% (n = 40) produced a strong neovascularization response with minimal stromal edema, with a mean growth rate of 0.21 +/- 0.12 mm/day. Loads of 1%, 7.5%, and 20% yielded 0.1 +/- 0.03 mm/day, 0.27 +/- 0.05 mm/day, 0.30 +/- 0.06 mm/day, respectively (n = 8, each group). Higher loads (30% and 40%; n = 8, each group) produced intense neovascularization, accompanied by severe corneal edema that obscured accurate measurement of the vessels. Corneal pockets that did not contain polymer implants were avascular. When endotoxin-Elvax pellets were removed, the new vessels regressed within 2 weeks.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Reduction of smooth muscle hyperplasia in vein grafts in athymic rats.
While developing an animal model of a vascular malformation, we found that two doses of cyclosporin A significantly reduced the smooth muscle cell hyperplasia observed in vein-arterial interposition grafts in Sprague-Dawley rats. Therefore, we hypothesized that T cells may either produce or augment a mitogen for vascular smooth muscle cells. To further investigate this, we quantitated the extent of smooth muscle cell hyperplasia in the vein grafts of athymic nude rats that lack mature, functioning T cells. Male Sprague-Dawley rats (275 to 350 gm) and athymic nude rats were anesthetized, and a segment of the superficial epigastric vein was placed into the transected femoral artery using microsurgical techniques. Sprague-Dawley rats (N = 9) and athymic nude rats (N = 5) undergoing vein grafting received 30 mg/kg cyclosporin A intraperitoneally, intraoperatively and 24 hours later. Sprague-Dawley rats (N = 7) and athymic nude rats (N = 6) that had vein grafts were not treated with cyclosporin A. Animals were killed at either 3 weeks or 6 weeks and histologic sections were taken from the middle of the graft to avoid clamp-induced trauma. At 3 weeks, untreated vein grafts in Sprague-Dawley rats exposed to arterial pressure exhibited a nine-fold increase in smooth muscle hyperplasia compared with the preoperative vein. Treatment of Sprague-Dawley rats with cyclosporin A resulted in a 57% reduction of smooth muscle hyperplasia (p less than 0.05). Vein grafts from athymic nude rats exhibited a 51% reduction in smooth muscle hyperplasia (p less than 0.05). Sprague-Dawley rats killed at 6 weeks revealed a recovery of smooth muscle hyperplasia equivalent to an untreated Sprague-Dawley vein graft at 3 weeks. Inhibition of smooth muscle hyperplasia persisted for 6 weeks in the athymic nude rats. Cyclosporin A administration or T cell deficiency in athymic nude rats decreases the smooth muscle hyperplasia observed in venous grafts exposed to arterial pressure. This finding provides evidence for a possible role of T cells in the regulation of cell growth in the vascular wall.
Animals↗
Synthetic analogues of fumagillin that inhibit angiogenesis and suppress tumour growth.
Neovascularization is critical for the growth of tumours and is a dominant feature in a variety of angiogenic diseases such as diabetic retinopathy, haemangiomas, arthritis and psoriasis. Recognition of the potential therapeutic benefit of controlling unabated capillary growth has led to a search for safe and effective angiogenesis inhibitors. We report here the synthesis of a family of novel inhibitors that are analogues of fumagillin, a naturally secreted antibiotic of Aspergillus fumigatus fresenius. We first isolated this fungus from a contaminated culture of capillary endothelial cells. Purified fumagillin inhibited endothelial cell proliferation in vitro and tumour-induced angiogenesis in vivo; it also inhibited tumour growth in mice, but prolonged administration was limited because it caused severe weight loss. Synthesis of fumagillin analogues yielded potent angiogenesis inhibitors ('angioinhibins') which suppress the growth of a wide variety of tumours with relatively few side-effects.
Animals↗
Affinity of fibroblast growth factors for beta-cyclodextrin tetradecasulfate.
beta-Cyclodextrin tetradecasulfate was found to have a very strong affinity for fibroblast growth factor (FGF) and could substitute for heparin in FGF purification. Basic FGF was purified about 200,000-fold from a rat chondrosarcoma using a method of biaffinity chromatography in which the beta-cyclodextrin tetradecasulfate polymer was mixed with copper-Sepharose. This method takes advantage of the strong affinity of FGF for both beta-cyclodextrin tetradecasulfate and copper.
Animals↗
What is the evidence that tumors are angiogenesis dependent?
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Animals↗