Thalidomide is an inhibitor of angiogenesis.
26 Apr 1994-Proceedings of the National Academy of Sciences of the United States of America (National Academy of Sciences)-Vol. 91, Iss: 9, pp 4082-4085
TL;DR: 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 Thalidomid-treated embryos.
Abstract: 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.
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TL;DR: Think of the switch to the angiogenic phenotype as a net balance of positive and negative regulators of blood vessel growth, which may dictate whether a primary tumour grows rapidly or slowly and whether metastases grow at all.
Abstract: Recent discoveries of endogenous negative regulators of angiogenesis, thrombospondin, angiostatin and glioma-derived angiogenesis inhibitory factor, all associated with neovascularized tumours, suggest a new paradigm of tumorigenesis. It is now helpful to think of the switch to the angiogenic phenotype as a net balance of positive and negative regulators of blood vessel growth. The extent to which the negative regulators are decreased during this switch may dictate whether a primary tumour grows rapidly or slowly and whether metastases grow at all.
7,916 citations
TL;DR: The unexpected finding that loss of a single VEGF allele is lethal in the mouse embryo between days 11 and 12 was reported, and angiogenesis and blood-island formation were impaired, resulting in several developmental anomalies.
Abstract: ANGIOGENESIS is required for a wide variety of physiological and pathological processes1. The endothelial cell-specific mitogen vascular endothelial growth factor (VEGF)2,3 is a major mediator of pathological angiogenesis4–6. Also, the expression of VEGF and its two receptors, Flt-1 and Flk-1/KDR, is related to the formation of blood vessels in mouse and rat embryos7–10. Mice homozygous for mutations that inactivate either receptor die in utero between days 8.5 and 9.5 (refs 11,12). However, ligand(s) other than VEGF might activate such receptors13,14. To assess the role of VEGF directly, we disrupted the VEGF gene in embryonic stem cells. Here we report the unexpected finding that loss of a single VEGF allele is lethal in the mouse embryo between days 11 and 12. Angiogenesis and blood-island formation were impaired, resulting in several developmental anomalies. Furthermore, VEGF-null embryonic stem cells exhibit a dramatically reduced ability to form tumours in nude mice.
3,733 citations
TL;DR: Thalidomide can induce marked and durable responses in some patients with multiple myeloma, including those who relapse after high-dose chemotherapy, and is active against advancedMyeloma.
Abstract: Background Patients with myeloma who relapse after high-dose chemotherapy have few therapeutic options. Since increased bone marrow vascularity imparts a poor prognosis in myeloma, we evaluated the efficacy of thalidomide, which has antiangiogenic properties, in patients with refractory disease. Methods Eighty-four previously treated patients with refractory myeloma (76 with a relapse after high-dose chemotherapy) received oral thalidomide as a single agent for a median of 80 days (range, 2 to 465). The starting dose was 200 mg daily, and the dose was increased by 200 mg every two weeks until it reached 800 mg per day. Response was assessed on the basis of a reduction of the myeloma protein in serum or Bence Jones protein in urine that lasted for at least six weeks. Results The serum or urine levels of paraprotein were reduced by at least 90 percent in eight patients (two had a complete remission), at least 75 percent in six patients, at least 50 percent in seven patients, and at least 25 percent in six p...
2,497 citations
TL;DR: Repositioning existing drugs for new indications could deliver the productivity increases that the industry needs while shifting the locus of production to biotechnology companies.
Abstract: Biopharmaceutical companies attempting to increase productivity through novel discovery technologies have fallen short of achieving the desired results. Repositioning existing drugs for new indications could deliver the productivity increases that the industry needs while shifting the locus of production to biotechnology companies. More and more companies are scanning the existing pharmacopoeia for repositioning candidates, and the number of repositioning success stories is increasing.
2,484 citations
TL;DR: The realization that tumor growth requires new blood vessels and the identification of chemical factors that mediate angiogenesis have broadened the understanding of pathologic processes and opened new avenues to the diagnosis and treatment of these diseases.
Abstract: Angiogenesis is fundamental to reproduction, development, and repair. All these processes depend on the tightly regulated growth of blood vessels that can “turn on” and “turn off” within a brief period. When blood vessels grow unabated, angiogenesis becomes pathologic and sustains the progression of many neoplastic and non-neoplastic diseases. The realization that tumor growth requires new blood vessels and the identification of chemical factors that mediate angiogenesis have broadened our understanding of pathologic processes and opened new avenues to the diagnosis and treatment of these diseases. Tumor hypervascularity was initially thought to reflect inflammatory vasodilation of preexisting host vessels, a . . .
2,246 citations
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TL;DR: Thalidomide selectively inhibits the production of human monocyte tumor necrosis factor alpha when these cells are triggered with lipopolysaccharide and other agonists in culture, and may be useful in determining the role of TNF-alpha in vivo and modulating its toxic effects in a clinical setting.
Abstract: Thalidomide selectively inhibits the production of human monocyte tumor necrosis factor alpha (TNF-alpha) when these cells are triggered with lipopolysaccharide and other agonists in culture. 40% inhibition occurs at the clinically achievable dose of the drug of 1 micrograms/ml. In contrast, the amount of total protein and individual proteins labeled with [35S]methionine and expressed on SDS-PAGE are not influenced. The amounts of interleukin 1 beta (IL-1 beta), IL-6, and granulocyte/macrophage colony-stimulating factor produced by monocytes remain unaltered. The selectivity of this drug may be useful in determining the role of TNF-alpha in vivo and modulating its toxic effects in a clinical setting.
1,201 citations
TL;DR: The inflammatory response that is seen in the cornea after TNF-alpha implantation suggests that the angiogenic properties of this agent may be a consequence of leukocyte infiltration.
Abstract: Tumor necrosis factor type alpha (TNF-alpha) inhibits endothelial cell proliferation in vitro. Basal cell growth (in the absence of exogenously added growth factor) and fibroblast growth factor (FGF)-stimulated cell proliferation are inhibited in a dose-dependent manner from 0.1 to 10 ng/ml with half-maximal inhibition occurring at 0.5-1.0 ng of TNF-alpha per ml. Bovine aortic and brain capillary endothelial and smooth muscle cells are similarly affected. TNF-alpha is a noncompetitive antagonist of FGF-stimulated cell proliferation. Its action on endothelial cells is reversible and noncytotoxic. Surprisingly, TNF-alpha does not seem to inhibit endothelial cell proliferation in vivo. In the rabbit cornea, even a high dose of TNF-alpha (10 micrograms) does not suppress angiogenesis induced by basic FGF. On the contrary, in this model system TNF-alpha stimulates neovascularization. The inflammatory response that is seen in the cornea after TNF-alpha implantation suggests that the angiogenic properties of this agent may be a consequence of leukocyte infiltration.
732 citations
TL;DR: This newly discovered steroid function appears to be governed by distinct structural configurations of the pregnane nucleus that inhibit angiogenesis in the presence of heparin or specific Heparin fragments.
Abstract: Steroids that lack glucocorticoid or mineralocorticoid activity were found to inhibit angiogenesis in the presence of heparin or specific heparin fragments. This newly discovered steroid function appears to be governed by distinct structural configurations of the pregnane nucleus. These compounds are here named angiostatic steroids.
555 citations
TL;DR: In 6 consecutive cases of lepromatous leprosy, acute severe lepra reactions were qUickly resolved with disappearance of symptoms as well as signs after the use of thalidomide as a sedative.
Abstract: In 6 consecutive cases of lepromatous leprosy, acute severe lepra reactions were qUickly resolved with disappearance of symptoms as well as signs after the use of thalidomide as a sedative. No exceptions were noted. Concurrent therapy with sulfones and arsenicals did not appear to be involved. The cases are reported at this early stage because of the obvious importance of corroborating these findings.
481 citations
TL;DR: A method is described which permits the growth of chicken embryos in petri dishes from the third to the 20th day of incubation, providing ready access to the embryo and its membranes for tissue grafting, for introduction of teratogenic agents, and for microscopic observation of morphogenesis and growth.
446 citations