The Aminosterol Squalamine Chemical And Biological Properties
Squalamine was initially described by Moore et al. 58 as an antimicrobial substance isolated from the dogfish shark Squalus acanthias, and was successfully demonstrated to be a broad spectrum antibiotic. Squalamine is a 7,24-dihydroxylated 24-sulfated cholestane steroid conjugated to a spermidine at C-3 Fig. 1 . Key features of the chemical Percentage Inhibition of Angiogenesis in 3-d Chick Chorioallantoic Membrane CAM .Assay Scored in the Presence of Different Concentrations of Squalamine...
Conclusions
The authors' concept of wound angiogenesis, thus, is as follows Initiation of angio-genesis in wounds can be described as a response to a metabolic demand precipitated in an environment that has little oxygen and or a high level of lactate. These conditions limit the supply of NAD , and, therefore, ADPR and pADPR. In response to this deficit, macrophages and perhaps endothelial cells elicit VEGF, and keep it in an active form, which stimulates new vessel growth. Figure 3 shows how metabolic...
Ch2h5
Fig. 2. Structure of thalidomide and related parent compounds. The chiral carbon atom of thalidomide is shown with an asterisk . induced malformations in mice as well as rats 34,37 . Although PG acid was initially thought to be nonteratogenic in rabbits 38 , feeding experiments showed that PG acid was rapidly excreted and penetrated to such a limited extent that hardly any of the drug reached the embryo. Thalidomide is more hydrophobic than PG acid and showed greater penetration 35 . Thus,...
Interleukin12
In addition to small molecules, the search for antiangiogenic substances has led to the discovery of proteins that inhibit various steps in the breakdown of the basement membrane 55,56 . These include naturally occurring proteins, such as protamine 57 , interferon IFN -a 58,59 , IFN-y 60 , platelet factor 4 57,61 , tissue inhibitors of metalloproteinases TIMPs 62,63 , interleukin-12 IL-12 64-66 , angiostatin 67 , peptides derived from cartilages 68,69 , vitreous humor 70 , smooth muscle 71 ,...
Cd36 Mediates TSP1 Angioinhibitory Activity
CD36 glycoprotein IV is an 88-kDa transmembrane protein that binds several molecules, including TSP-1, and is involved primarily in adhesion and scavenging for reviews, see refs. 51 and 52 . A variety of experiments indicate that CD36 is necessary for the angioinhibitory activity of TSP-1 both in vitro 37 and in vivo 52a . First, CD36 fusion proteins block the inhibitory activity of whole TSP-1 and of TSP-1 peptides in endothelial cell migration assays, and the potency of TSP-1 angioinhibitory...
Nonhydroxamic Acid Nonpeptidic MMP Inhibitors
Bayer found that the known anti-inflammatory agent, fenbufen, possesses modest inhibitory activity against gelatinase-A, and has prepared more potent analogs, such as 18 46 . This compound features a carboxylic acid zinc binding group and a cyclic imide P1 substituent. A large P1' b iphenyl group ensures selectivity for the deep-pocket MMPs. A variety of nonpeptidic natural-product MMP inhibitors have been discovered by screening. These include pycnidione 19 Merck 89 , futoenone derivatives...
Role Of Lactate In Angiogenesis
Crucial evidence in support of this thesis is provided by the role of lactate in tissue repair. Wound spaces are also characterized by increased levels of lactate 5-15 mM 9 . However, hypoxia only partially accounts for this. The excess of lactate is primarily the result of the influx of fibroblasts and macrophages, both of which contain few mitochondria, rely on aerobic glycolysis as their normal source of energy, and, therefore, consume small amounts of oxygen and large amounts of glucose....
Tumor Pathophysiology Leading To Hypoxia
It is generally believed that hypoxia in tumors develops in two ways. The first form, referred to as chronic hypoxia, has classically been thought to result from long diffusion distances between tumor vessels 41 . The second form, known as perfusion limited, or acute, hypoxia, has been attributed to transient blockages in, or collapse of, tumor vessels 42 . This chapter will distinguish between these two forms of hypoxia in the following manner Cells that are chronically hypoxic exist in an...
Plasminogen and Plasminogen Activator Assembly on Endothelial Cell
Circulating Glu-plasminogen is converted to Lys-plasminogen upon high-affinity binding to its endothelial cell receptor annexin II 25,26 . Tissue plasminogen activator, which is synthesized and secreted be endothelial cells, can bind to Lys-plasminogen on the endothelial cell surface at a separate domain. S uch an assembly provides an efficient method of plasmin generation at the endothelial cell surface see review in ref. 35 . Lipoprotein a , a low-density lipoprotein with extensive homology...
Historical Perspective
A new drug application NDA 12-611 was originally submitted for thalidomide in September 1960 to the then Bureau of Medicine a precursor to the FDA 8 . It was being indicated for use in the treatment of somnolence and as a mild hypnotic. At that time thalidomide was widely used in Europe and was considered a safe and effective sedative. The application was found to have significant shortcomings by three reviewers and additional data was requested. In February 1961 reports emerged of peripheral...
FGF1 and FGF2 in Tumor Development
Extensive studies on the expression of FGF-1 and FGF-2 in tumor biopsies in vivo together with functional studies on tumor cell proliferation in vitro, provided a plethora of evidence for the involvement of FGF-1 and FGF-2 in tumor development. In some cases, expression of FGF-1 or FGF-2 correlated with malignancy, and interference with the activities of FGF-1 or FGF-2 diminished tumor growth and cell transformation 15 . FGF-1 and FGF-2 were significantly upregulated in human gliomas,...
References Blb
1. Folkman, J. 1971 Tumor angiogenesis therapeutic implications. New Eng. J. Med. 285,1182-1186. 2. Teicher, B. 1996 Systems approach to cancer therapy antiangiogenics standard cytotoxics' mechanism s of interaction . Cancer Metastasis Rev. 15, 247-272. 3. Teicher, B. A., Holden, S. A., Ara, G., Alvarez Sotomayor, E., Huang, Z. D., Chen, Y.-N., and Brem, H. 1994 Potentiation of cytotoxic cancer therapies by TNP-470 alone and with other antiangiogenic agents. Int. J. Cancer 57, 920-925. 4....
A Liquid Shark Cartilage Extract With Antiangiogenic Properties
-941 is a liquid shark cartilage extract prepared by washing and scrubbing fresh shark cartilage under water to remove any residual tissue. The cleaned cartilage is then homogenized in demineralized water and stirred for 1 h to allow extraction of water-soluble molecules. After centrifugation, the liquid fraction is ultrafiltrated and the fraction below 500 kDa is retained. The ultrafiltrate is further filtered through a 0.22- m membrane, dispensed into sterile glass vials, and stored at -20 C...
Intratumoral Microvascular Density
Intratumoral microvessel density MVD has been extensively studied in a variety of solid tumors and has been reported as a powerful independent prognostic factor in many tumor types 29 . Several clinical reports have suggested a strong correlation between intratumoral MVD and the development of metastases, primary tumor growth, and the expression of certain angiogenic peptides 30 . A variety of methods for assessing MVD have been reported 31 , but the most commonly used is that proposed by...
Antiangiogenic Activity Of Interferon
The IFN family consists of three major glycoproteins that exhibit species specificity leukocyte-derived IFN-a, fibroblast-derived IFN-p, and immune-cell-produced IFN-y. Although IFN-a and IFN-P share a common receptor the type I IFN receptor and induce a similar pattern of cellular responses, certain cellular reactions can be stimulated only by IFN-p, probably by the phosphorylation of a receptor-associated protein that is uniquely responsive to IFN-P 104 . Although IFNs originally captured...
References Qez
1. Beck, L., Jr. and D'Amore, P. A. 1997 Vascular development cellular and molecular regulation. 2. Bussolino, F., Mantovani, A., and Persico, G. 1997 Molecular mechanisms of blood vessel formation. 3. Hanahan, D. 1997 Signaling vascular morphogenesis and maintenance. Science 277, 48-50. 4. Billington, D. C. 1991 Angiogenesis and its inhibition potential new therapies in oncology and nonneoplastic diseases. Drug Design Discovery 8, 3-35. 5. Folkman, J. and Klagsbrun, M. 1987 Angiogenic factors....
Diane R Bielenberg and Isaiah J Fidler
Angiogenesis in the Pathogenesis of a Metastasis Role of Organ Environment in Pathogenesis of Metastasis Host Microenvironment-Dependent Expression of Angiogenesis Organ-Dependent Expression of Basic Fibroblast Growth Factor by Tumor Cells Organ-Specific Modulation of Il-8 Expression in Melanoma Cells Molecular Determinants of Angiogenesis in Cutaneous Hemangiomas Modulation of Angiogenesis by Host Lymphoid Cells Antiangiogenic Activity of Interferon-P
Side Effects
As discussed above, thalidomide has been used for the treatment of leprosy, graft versus host disease, rheumatoid arthritis, aphthous ulcers associated with AIDS, and various dermatologic disorders. The side effects of thalidomide have been well documented and they include drowsiness, constipation, peripheral sensory neuropathy, swelling of the limbs, erythema of the limbs, hair loss, fever, rash, and amenorrhea. Dizziness and mood changes occurred in 33-100 of all patients. Other frequent...
Mmp18
aThe principal substrates listed are only helpful as a guide in practice, the substrate specificity shown in vitro is broad with considerable overlap between MMPs. MT stands for membrane type. aThe principal substrates listed are only helpful as a guide in practice, the substrate specificity shown in vitro is broad with considerable overlap between MMPs. MT stands for membrane type. played by other MMPs, and supports the hypothesis that the metallo- and serine proteinase families act in an...
Distribution of VEGF Flk1KDR and Flt1 mRNA
The proliferation of blood vessels is crucial for a wide variety of physiological processes, such as embryonic development, normal growth and differentiation, wound healing, and reproductive functions. During embryonic development, VEGF expression is first detected within the first few days following implantation in the giant cells of the trophoblast 79,111 . At later devel opmental stages in mouse or rat embryos, the VEGF mRNA is expressed in several organs, including heart, vertebral column,...
Squalamine And Endothelial Cells
The specificity of squalamine for endothelial cells was evaluated in culture with bovine retina BREC and rat brain RBE-4 endothelial cells at different concentrations, and compared to results with rat 9L glioma , rabbit VX2 carcinoma , and human brain tumor H80 cells 66 . The endothelial cell lines were grown in DMEM media containing 10 fetal bovine serum, 1 L-glutamine, 25 mM HEPES, and genticine and 20 ng mL vascular endothelial growth factor VEGF in the presence or absence of squalamine. The...
Nonhydroxamic Acid Pseudopeptide Derivatives
The use of alternative ZBGs to the hydroxamic acid moiety has been driven by both intellectual property considerations 85 and unmet fears of potential toxic liability. A variety of different ZBGs carboxylate, aminocarboxylate, sulfhydryl, and derivatives of phosphorus acids have been identified 48,81 . A comparative study of different ZBGs has suggested the following preference in terms of inhibition of fibroblast collagenase hydroxamate gt gt formylhydroxylamine gt sulfhydryl gt phosphinate gt...
Disease Models Involving Neovascularization And Squalamine
To determine if squalamine, like the angiostatic steroids previously studied, was effective in disease models involving neovascularization in animals, squalamine was evaluated in two tumor models, the rat 9L glioma allograft and human lung tumor xenografts in mice, and in a neonatal mouse model for corneal neovascularization, which employs hyperoxic exposure 81 . The conditions of this model simulate the ocular condition of retinopathy of prematurity ROP . Although rare, ROP in premature human...