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...

Conclusions And Recommendations

Based on the phase I-II program described above, the following conclusions can be drawn 1. Marimastat has a favorable pharmacokinetic profile, with high systemic bioavailability, linear dose-plasma relationship, balanced excretion (75 hepatic, 25 renal), and an elimination half-life compatible with twice-daily dosing. 2. Musculoskeletal symptoms (by and large reversible upon drug discontinuation) have been identified as the primary dose-limiting toxicity. No other major toxicity has emerged. 3....

Extracellular Sequestration and Release of FGF2

Another major issue associated with the release pathway of FGF-1 and FGF-2 is the nature of their sequestration by HSPG in the extracellular matrix and basement membrane of endothelial cells from different sources (79,134-136). The model in which FGFs might be stored in a latent form that can be locally activated by heparin or heparanase, or by exposure to their high-affinity receptors, offers an attractive possibility for the regulation of FGF activities in normal and pathological situations....

Distribution in Tumors

Historically, neck nodes were the first tumors to be investigated with the KIMOC 6650. In 1990, Fleckenstein published results in seven patients (53). Most tumors were hypoxic, with recorded pO2 values below 10 mmHg. In 1993, results were published on patients treated at the IGR (51,52). Oxygen tension was measured in tumors of 35 patients (mean age 56 yr, range 36-79 yr) with a metastatic neck node from a primary squamous carcinoma of the head and neck (ENT). The site of the primary disease...

Effect Of pH On Angiogenesis

The vascular and perfusion insufficiencies in tumors may be incriminated, at least in part, for the development of acidic and hypoxic environment in the tumors. Conversely, such an adverse environment may greatly affect the vascularization, i.e., angiogenesis, and also affect the functional integrity of the tumor vasculature. In the early stage of tumor growth, the tumor cells evoke various pathological changes in the nearby host cells and tissues. These affected normal cells, as well as the...

Modulation of TSP1 Production During Tumor Development

TSP-1 is produced by a number of normal cells, and, as a result, their secretions inhibit angiogenesis (3). As such normal cells develop into malignant tumors whose growth and survival depends on vigorous neovascularization, they must develop an angiogenic phe-notype (94). Tumors developing in tissues that elaborate high levels of TSP-1 usually downregulate TSP-1 secretion. This is seen in glioblastoma multiforme (26), some fibrosarcomas (95), some breast carcinomas (96,97), and bladder...

Relevance Of Nutrition For Investigation Of Tumor Angiogenesis In The Laboratory And In Clinical Studies

Hypotheses concerning tumor angiogenesis are ultimately evaluated and characterized in animal models prior to moving into human intervention studies (5). All investigators working with animal models of tumor angiogenesis should be familiar with several basic concepts of diet and nutrition in rodent models of carcinogenesis. S imply expressed, each investigator should be confident that the diets employed in their studies are reportable and reproducible, in the same fashion that the animal model...

Interactions Between Food Energy Consumption Tumor Growth And Angiogenesis

A strong positive correlation between energy intake and the incidence or growth of tumors has been reported in virtually every animal model system evaluated (6,10,40,41). Many studies have shown that an imposed restriction of total food intake or energy inhibits tumorigenesis (Fig. 1 12). In addition, groups of mice or rats with free access to food, which is typical in most rodent studies, also show a striking positive correlation between self-selected energy intake and risk of cancer (Fig. 2...

Dietary Lipids And Fatty Acid Patterns

The role of dietary lipid concentration, sources of fat, and specific fatty acid patterns on the incidence and progression of many cancers has been the source of much specula tion and investigation (6,7,21). The human and laboratory evidence is most convincing for a stimulatory effect of dietary lipid concentration, particularly a diet rich in saturated fats, on cancers of the colon and rectum (6,7,21). Less certain, but supported by many studies, are the positive relationships between diets...

Intracellular pH In Tumors

There have been attempts to determined the intracellular pH (pHj) with glass micro-electrodes with a diameter as small as 1 m, but the results of these studies were inconclusive. In the late 1970s, magnetic resonance spectroscopy (MRS) was introduced as a means to determine pH in tumors in situ, or in normal tissues in animals and humans. Since then, there has been a marked improvement in the MRS technique, and it is now widely used to determine the pHj, as well as the metabolic state of...

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...

Role Of Organ Environment In Pathogenesis Of Metastasis

Clinical observations of cancer patients, and studies with experimental rodent tumors, have revealed that certain tumors produce metastasis to specific organs, independent of vascular anatomy, rate of blood flow, and number of tumor cells delivered to each organ. The distribution and fate of hematogenously disseminated, radiolabeled melanoma cells in experimental rodent systems amply demonstrate that tumor cells reach the microvas-culature of many organs (33-36). Extravasation into the organ...

References

M. (1994) The implications of angiogenesis for the biology and therapy of cancer metastasis. Cell 79, 185-188. 2. Weidner, N. (1995) Intratumor microvessel density as a prognostic factor in cancer. Am. J. Pathol. 147, 9-19. 3. Weidner, N., Semple, J. P., Welch, W. R., and Folkman, J. (1991) Tumor angiogenesis and metastasis correlation in invasive breast carcinoma. N. Engl. J Med. 324, 1-8. 4. Horak, E. R., Leek, R., Klenk, N., Lejeunde, S., Smith, K., Stuart, N.,...

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...

High Affinity FGF Receptors

The first receptor for FGF was purified and cloned as a high-affinity receptor for FGF-2 from chicken (41). This receptor, FGF receptor-1 (FGFR-1), was highly homologous to the flg tyrosine kinase previously cloned from human endothelial cells. Subsequently, FGFR-1 was shown to bind FGF-1, FGF-2, and FGF-4 (42). FGFR-2 was first identified by screening of a mouse liver expression library with antiphosphotyrosine antibodies, and was called bek (43). Subsequent molecular cloning of human, murine,...

Dietary Protein And Amino Acids

It is not possible to establish recommendations for cancer prevention based upon dietary protein level or source. Dietary protein can increase, decrease, or have no effect on tumorigenesis in various tumor models, suggesting that protein may exert very specific mechanisms of action that are unique to each target tissue and initiating agent (42,147-149). Very little research has focused on the role of dietary protein or amino acids in tumor angiogenesis. One mechanism whereby dietary protein...

Concluding Remarks

FGF-2, one of the first identified stimulators of angiogenesis, initially occupied a center stage in the angiogenesis field, but was edged out by VEGF. The lack of a characteristic signal sequence for secretion, and the low expression of FGF-2 receptors, raised doubts about its role as a major, direct acting angiogenic growth factor (149). Nevertheless, elevated levels of soluble FGF-2 have been detected in the serum and urine of many cancer patients, and FGF-2 has been shown to be a potent...

TSP1 Acts Directly on Endothelial Cells

TSP-1 Inhibits Most Proangiogenic Activities of Cultured Endothelial Cells TSP-1 acts directly on endothelial cells. Exogenous TSP-1, at concentrations from 1 to 10 nM inhibits the chemotactic migration of cultured capillary endothelial cells (see Fig. 2 and references therein). At 5-10-fold higher concentrations, it also inhibits mito-genesis and tube formation (Fig. 2). Although TGF- is an effective inhibitor of migration and mitogenesis in endothelial cells and is a frequent...

TSP1 Is a Potent Inhibitor In Vivo

TSP-1 Inhibits Neovascularization in Multiple Experimental Assays Purified TSP-1 protein, isolated from human platelets or from BHK hamster cells, has been tested in a variety of in vivo assays, in which, with a single exception, it has been a potent inhibitor of new blood vessel growth. When incorporated into Hydron pellets, along with an inducer, and implanted into the corneas of rats (14-16) or mice (19), TSP-1 is consistently inhibitory (concentrations from 0.65 to 2.5 g mL have been...

Mechanism Of Action For Squalamine

Steroid hormone function is well understood, including considerable knowledge that has accumulated in the past 20 yr on the interaction of steroid hormones and hormone Percent Decrease in Vmax for Rabbit or Human NHE-3 Transfected in Chinese Hamster Lung Cell Line PS120 (an NHE-Negative Cell Line) Percent Decrease in Vmax for Rabbit or Human NHE-3 Transfected in Chinese Hamster Lung Cell Line PS120 (an NHE-Negative Cell Line)

Mechanism Of Retinoid Action

Images Retinoid Mechanism Action

Retinoids are a class of chemical compounds that include active metabolites of vitamin A (retinol) as well as a diverse array of synthetic derivatives. Vitamin A is required for normal embryonic development, epithelial homeostasis, maintainance of reproductive capacity, and functioning of the visual cycle (1). Additionally, retinoids have been shown to modulate a wide variety of cellular processes, including proliferation, differentiation, homeostasis, and malignant transformation (for reviews...

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...

Human Angiostatin Protein Derived from Elastase Cleavage of Human Plasminogen

A corresponding fragment of human plasminogen, including K1-3 obtained by elastase cleavage of human plasminogen, was highly effective at inhibiting the bFGF-stimulated proliferation of BCE cells, in vivo reduction of metastases, and inhibition of growth of primary tumors. In fact, all in vivo studies reported with native human AP was with material derived from elastase-cleaved human plasminogen (6,8). There are several known and putative elastase sites within K1-4 of human plasminogen (Fig. 1)...

Info

22.2 28.6 30.9 21.8 21.2 15.5 aTumor tissue sections from paraffin-embedded blocks were deparaffinized and stained with monoclonal mouse anti-human endothelial cell antibody (CD31, DAKO, Carpinteria, CA) or monoclonal mouse antihuman von Willebrand factor (Cell Biology Boehringer Mannheim, Indianapolis, IN) using avidin-biotin complex (ABC) method (DAKO LSAB Kit, DAKO). For the counting of blood vessels, the most vascular area of the tumor was located at low magnification, and vessels were...

Other Effects Of Thalidomide

In addition to its antiangiogenic activity, other effects of thalidomide have been reported. Thalidomide has been used in the treatment of lepromatous reaction (51-54), graft-versus-host disease (55-60), lupus erythematosis, Behcet's syndrome (61), rheumatoid arthritis (62,63), and Crohn's disease (64,65). Thalidomide has been shown to prolong graft survival in rat cardiac transplants (66,67) and to inhibit HIV replication (68). Macrophages appear to be a cellular target of thalidomide, since...

Vitamin A

The role of vitamin A nutrition in the risk of human cancer is complex and does not warrant generalizations (7,163). S implistic conclusions and recommendations for intakes at specific dosages beyond the recommended daily intake is not possible. The possibility that vitamin A, its metabolites, and analogs may modulate angiogenesis is based on studies showing that molecular and functional properties of endothelial cells are influenced by these compounds. Both proliferation and shape of capillary...

Fragments of Plasminogen Generated by Elastase Digestion

The number of elastase sites between K3 and K4 of human plasminogen would yield several possible fragments upon elastase digestion K1-3 with the O sugar, K1-3 with the O and N sugar, K1-3 without sugars, and K1-3 with the N sugar (Fig. 1). The N-terminus of AP, generated by elastase digestion of human plasminogen, was defined as Lys78 or Tyr80 (6). Once formed, plasmin converts the circulating zymogen Glu-plasminogen (N-terminus is Glu1) to Lys-plasminogen (N-terminus is Lys78) by releasing a...

Introduction

Sodium pentosan polysulfate PPS xylanopolyhydrogensulfate, Fig. 1 is a semisynthetic sulfated heparinoid polysaccharide that has been used in Europe as an anticoagulant for nearly 30 yr 1-3 . It is obtained from extract of beechwood shavings, and consists of a mixture of polymers with mol wt ranging from 1.8 to 9 kDa mean 4.7 kDa 3 . This glycosaminoglycan is a highly negatively charged compound that contains 1.9 sulfate groups per monosaccharide unit. PPS's antitumor activity has been...

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...