Showing papers by "Rakesh K. Jain published in 1998"

Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis.

Abstract: As a result of deprivation of oxygen (hypoxia) and nutrients, the growth and viability of cells is reduced. Hypoxia-inducible factor (HIF)-1alpha helps to restore oxygen homeostasis by inducing glycolysis, erythropoiesis and angiogenesis. Here we show that hypoxia and hypoglycaemia reduce proliferation and increase apoptosis in wild-type (HIF-1alpha+/+) embryonic stem (ES) cells, but not in ES cells with inactivated HIF-1alpha genes (HIF-1alpha-/-); however, a deficiency of HIF-1alpha does not affect apoptosis induced by cytokines. We find that hypoxia/hypoglycaemia-regulated genes involved in controlling the cell cycle are either HIF-1alpha-dependent (those encoding the proteins p53, p21, Bcl-2) or HIF-1alpha-independent (p27, GADD153), suggesting that there are at least two different adaptive responses to being deprived of oxygen and nutrients. Loss of HIF-1alpha reduces hypoxia-induced expression of vascular endothelial growth factor, prevents formation of large vessels in ES-derived tumours, and impairs vascular function, resulting in hypoxic microenvironments within the tumour mass. However, growth of HIF-1alpha tumours was not retarded but was accelerated, owing to decreased hypoxia-induced apoptosis and increased stress-induced proliferation. As hypoxic stress contributes to many (patho)biological disorders, this new role for HIF-1alpha in hypoxic control of cell growth and death may be of general pathophysiological importance.

Regulation of transport pathways in tumor vessels: Role of tumor type and microenvironment

Abstract: Novel anti-neoplastic agents such as gene targeting vectors and encapsulated carriers are quite large (approximately 100–300 nm in diameter) An understanding of the functional size and physiological regulation of transvascular pathways is necessary to optimize delivery of these agents Here we analyze the functional limits of transvascular transport and its modulation by the microenvironment One human and five murine tumors including mammary and colorectal carcinomas, hepatoma, glioma, and sarcoma were implanted in the dorsal skin-fold chamber or cranial window, and the pore cutoff size, a functional measure of transvascular gap size, was determined The microenvironment was modulated: (i) spatially, by growing tumors in subcutaneous or cranial locations and (ii) temporally, by inducing vascular regression in hormone-dependent tumors Tumors grown subcutaneously exhibited a characteristic pore cutoff size ranging from 200 nm to 12 μm This pore cutoff size was reduced in tumors grown in the cranium or in regressing tumors after hormone withdrawal Vessels induced in basic fibroblast growth factor-containing gels had a pore cutoff size of 200 nm Albumin permeability was independent of pore cutoff size These results have three major implications for the delivery of therapeutic agents: (i) delivery may be less efficient in cranial tumors than in subcutaneous tumors, (ii) delivery may be reduced during tumor regression induced by hormonal ablation, and (iii) permeability to a molecule is independent of pore cutoff size as long as the diameter of the molecule is much less than the pore diameter

The next frontier of molecular medicine: delivery of therapeutics.

Abstract: Despite exciting progress in the biology underlying a variety of proposed molecular medicines, an unmet challenge Remains—delivery. This problem, how to better target the new generation of therapeutics, cuts across all diseases. The solution offers unprecedented opportunities for multidisciplinary teams of bioengineers to work with biological and medical scientists to realize the fruits of our nation's investment in molecular and cellular medicine.

Endothelial cell death, angiogenesis, and microvascular function after castration in an androgen-dependent tumor: Role of vascular endothelial growth factor (vascular regressionypermeabilityyvascular density)

Abstract: The sequence of events that leads to tumor vessel regression and the functional characteristics of these vessels during hormone-ablation therapy are not known. This is because of the lack of an appropriate animal model and monitoring technology. By using in vivo microscopy and in situ molecular analysis of the androgen-dependent Shionogi car- cinoma grown in severe combined immunodeficient mice, we show that castration of these mice leads to tumor regression and a concomitant decrease in vascular endothelial growth factor (VEGF) expression. Androgen withdrawal is known to induce apoptosis in Shionogi tumor cells. Surprisingly, tumor endothelial cells begin to undergo apoptosis before neoplastic cells, and rarefaction of tumor vessels precedes the decrease in tumor size. The regressing vessels begin to exhibit normal phenotype, i.e., lower diameter, tortuosity, vascular perme- ability, and leukocyte adhesion. Two weeks after castration, a second wave of angiogenesis and tumor growth begins with a concomitant increase in VEGF expression. Because human tumors often relapse following hormone-ablation therapy, our data suggest that these patients may benefit from com- bined anti-VEGF therapy. Nearly one-third of human tumors are hormone sensitive. Hormone-ablation therapy leads to regression of the hor- mone-dependent tumors. In addition, hormone withdrawal inhibits vascular endothelial growth factor (VEGF) expression as well as angiogenesis in prostate cancer in both patients and animals (1, 2), and induces apoptosis in these cells during the regression (3-5). Shionogi murine tumor is a male mammary carcinoma and androgen-dependent. Similar to human hor- mone-sensitive tumors, the depletion of androgen by castra- tion leads to regression of Shionogi tumors (3). Similar to human and murine hormone-dependent tumors, Shionogi tumor relapses after the regression following hormone abla- tion. A more effective treatment would require an understanding of molecular and physiological processes during tumor growth, regression, and relapse. The mechanisms of rapid vascular regression following hormone withdrawal, the function of regressing vessels, and the molecular determinants responsible for the second wave of angiogenesis and tumor growth are, however, not known. In an effort to dissect these processes and to assess their clinical implications, we investigated angiogen- esis, microvascular function, apoptosis, and VEGF expression during the initial growth, regression, and relapse of the Shionogi tumor. VEGF is expressed at a high level during the initial tumor growth and decreases to an almost undetectable level 1 week after castration. Strikingly, tumor endothelial cells begin to undergo apoptosis before neoplastic cells, the regress- ing vessels in the tumor begin to exhibit normal phenotype, and the dominant angiogenic factor in the relapsed tumor is VEGF.

Endothelial cell death, angiogenesis, and microvascular function after castration in an androgen-dependent tumor: Role of vascular endothelial growth factor

Abstract: The sequence of events that leads to tumor vessel regression and the functional characteristics of these vessels during hormone–ablation therapy are not known. This is because of the lack of an appropriate animal model and monitoring technology. By using in vivo microscopy and in situ molecular analysis of the androgen-dependent Shionogi carcinoma grown in severe combined immunodeficient mice, we show that castration of these mice leads to tumor regression and a concomitant decrease in vascular endothelial growth factor (VEGF) expression. Androgen withdrawal is known to induce apoptosis in Shionogi tumor cells. Surprisingly, tumor endothelial cells begin to undergo apoptosis before neoplastic cells, and rarefaction of tumor vessels precedes the decrease in tumor size. The regressing vessels begin to exhibit normal phenotype, i.e., lower diameter, tortuosity, vascular permeability, and leukocyte adhesion. Two weeks after castration, a second wave of angiogenesis and tumor growth begins with a concomitant increase in VEGF expression. Because human tumors often relapse following hormone–ablation therapy, our data suggest that these patients may benefit from combined anti-VEGF therapy.

Role of nitric oxide in angiogenesis and microcirculation in tumors.

Abstract: Nitric oxide (NO) is a free radical molecule with high reactivity, a short half life and a variety of physiological activities. The role of NO in tumor microcirculation, based on the data collected to date, can be summarized as follows: 1) NO may partially mediate tumor angiogenesis; 2) endogenous NO derived from tumor vascular endothelium and/or tumor cells increases and/or maintains tumor blood flow via dilatation of arteriolar vessels, decreases leukocyte-endothelial interaction, and increases vascular permeability; 3) exogenous NO can increase tumor blood flow via vessel dilatation, and reduce vessel tone; and 4) NO production rates and vascular response to NO are heterogeneous and tumor-dependent. Modulation of NO level in tumor vessels can alter tumor hemodynamics and thus augment oxygen, drug, gene vector and effector cell delivery to solid tumors.

Intracellular Magnetic Labeling of Lymphocytes for In Vivo Trafficking Studies

Abstract: Lymphocyte adhesion and trafficking is difficult to observe in vivo over time We used magnetic resonance imaging (MRI) to identify magnetically labeled lymphocytes in phantom experiments and in tissue A method of lymphocyte labeling was developed that is based on fluid-phase endocytosis of nanometer-sized biocompatible superparamagnetic particles The maximum cell uptake in culture was 011 ng Fe/cell corresponding to 5 × 106 particles/lymphocyte Cells stably retained the label and were fully viable for at least 3 days Labeled lymphocytes showed adhesion to human endothelial cells similar to unlabeled cells, indicating no effect of labeling on cell surface expression of adhesion proteins No particle-mediated cytotoxicity could be observed The detection threshold of MRI for detecting labeled lymphocytes in the current study was 25 × 106 cells/30 μL sampling volume Following intravenous injection of labeled lymphocytes into rats, cells accumulated in spleen, lymph nodes and liver with a similar bio-

Increased rates of CD4+ and CD8+ T lymphocyte turnover in simian immunodeficiency virus-infected macaques

Abstract: Defining the rate at which T cells turn over has important implications for our understanding of T lymphocyte homeostasis and AIDS pathogenesis, yet little information on T cell turnover is available. We used the nucleoside analogue bromodeoxyuridine (BrdUrd) in combination with five-color flow cytometric analysis to evaluate T lymphocyte turnover rates in normal and simian immunodeficiency virus (SIV)-infected rhesus macaques. T cells in normal animals turned over at relatively rapid rates, with memory cells turning over more quickly than naive cells. In SIV-infected animals, the labeling and elimination rates of both CD4+ and CD8+ BrdUrd-labeled cells were increased by 2- to 3-fold as compared with normal controls. In normal and SIV-infected animals, the rates of CD4+ T cell BrdUrd-labeling and decay were closely correlated with those of CD8+ T cells. The elimination rate of BrdUrd-labeled cells was accelerated in both naive and memory T lymphocytes in SIV-infected animals. Our results provide direct evidence for increased rates of both CD4+ and CD8+ T cell turnover in AIDS virus infection and have important implications for our understanding of T cell homeostasis and the mechanisms responsible for CD4+ T cell depletion in AIDS.

Erratum: Role of HIF-1α in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis: correction

Abstract: This corrects the article DOI: 10.1038/28867

Intratumoral infusion of fluid: estimation of hydraulic conductivity and implications for the delivery of therapeutic agents.

Abstract: We have developed a new technique to measure in vivo tumour tissue fluid transport parameters (hydraulic conductivity and compliance) that influence the systemic and intratumoral delivery of therapeutic agents. An infusion needle approximating a point source was constructed to produce a radially symmetrical fluid source in the centre of human tumours in immunodeficient mice. At constant flow, the pressure gradient generated in the tumour by the infusion of fluid (Evans blue-albumin in saline) was measured as a function of the radial position with micropipettes connected to a servo-null system. To evaluate whether the fluid infused was reabsorbed by blood vessels, infusions were also performed after circulatory arrest. In the colon adenocarcinoma LS174T with a spherically symmetrical distribution of Evans blue-albumin, the median hydraulic conductivity in vivo and after circulatory arrest at a flow rate of 0.1 microl min(-1) was, respectively, 1.7x10(-7) and 2.3x10(-7) cm2 mmHg(-1) s. Compliance estimates were 35 microl mmHg(-1) in vivo, and 100 microl mmHg(-1) after circulatory arrest. In the sarcoma HSTS 26T, hydraulic conductivity and compliance were not calculated because of the asymmetric distribution of the fluid infused. The technique will be helpful in identifying strategies to improve the intratumoral and systemic delivery of gene targeting vectors and other therapeutic agents.

Mice Lacking E-Selection Show Normal Numbers of Rolling Leukocytes but Reduced Leukocyte Stable Arrest on Cytokine-Activated Microvascular Endothelium

Abstract: Objective:Previous work indicated that E-selectin mediates transient interactions between leukocytes and cytokine-activated endothelium in vitro. Here we examine the role of E-selectin in blood leukocyte interactions with microvascular endothelium in vivo. Methods:E-selectin-deficient (E−/−mice were produced by gene targeting. The effect of this null mutation on leukocyte-endothelial interactions was determined by intravital microscopy before and 4 to 5 hours after local administration of the proinflammatory cytokine tumor necrosis factor α (TNFα) in dermal microvessels with low blood flow (dorsal skin-fold chambers, intact ear skin), and after endotoxin activation in exteriorized mesenteric microvessels with higher blood flow. Results:E−/−mice were viable, fertile with normal circulating leukocyte and platelet profiles. Approximately 60% of circulating leukocytes rolled in dermal microvessels of both normal (E+/+) and E−/−mice without inflammatory stimulation. After local administration of TNFα, rolling ...

Cancer, angiogenesis and fractals.

Abstract: To the editor—The recent commentary by Coffey emphasizes the value of nonlinear dynamics and fractals as tools for studying aspects of biological pattern formation that are not readily accessible to strictly molecular methods. Our studies of the vascular architecture in tumors support Coffey’s points about the delicate interplay among gradients in diffusible cytokines, heterogeneity of cell pheno-

Primary Tumor Size-dependent Inhibition of Angiogenesis at a Secondary Site: An Intravital Microscopic Study in Mice

Abstract: Some primary tumors are capable of suppressing the growth of their metastases by presumably generating antiangiogenic factors such as angiostatin. We hypothesized that the amount of inhibitor(s) released by a tumor increases with tumor growth. We tested this hypothesis by evaluating the relationship between the size of a primary tumor and its ability to inhibit angiogenesis at a secondary site. Furthermore, we characterized the effects of the primary tumor on physiological properties of newly formed vessels at the secondary site. Angiogenesis and physiological properties were measured using intravital microscopy of angiogenic vessels in the gels containing basic fibroblast growth factor placed into cranial windows of immunodeficient mice bearing human prostatic carcinoma (PC-3) in their flank. The PC-3 tumor inhibited angiogenesis in the gels, and surgical resection of tumor reversed this inhibition. The inhibition of angiogenesis 20 days after gel implantation (range, 0-83%) correlated positively (r = 0.625; P < 0.008) with the tumor size on the day of gel implantation (range, 19-980 mm3). The primary tumor also suppressed leukocyte-adhesion in angiogenic vessels, thus helping them evade the immune recognition. These results provide an additional rationale for combining antiangiogenic treatment with local therapies.

Dynamic T1-weighted magnetic resonance imaging and positron emission tomography in patients with lung cancer: correlating vascular physiology with glucose metabolism.

Abstract: The management of primary lung cancer relies on sophisticated imaging methods to assist in the diagnosis, staging, and evaluation of tumor regression during treatment. The information provided is generally anatomical in nature, except for that provided by positron emission tomography with [18F]fluorodeoxyglucose, a modality that yields physiological data that have been shown to be useful in identifying neoplasia, based on an elevated glucose metabolic rate. Because the metabolism of malignant tissue depends intimately on neovascularization to provide oxygen and glucose in sufficient quantities to allow tumor growth, the characterization of tumor vascular physiology could be an important tool for assessing and predicting the likely effectiveness of treatment. Our goal was to show the feasibility and practical value of parameters of tumor vascular physiology obtained using dynamic T1-weighted magnetic resonance imaging (MRI), to correlate them with glucose metabolism and to demonstrate changes in these parameters during and after treatment in patients with lung cancer. Parameters of vascular physiology [permeability-surface area (PS) product and extracellular contrast agent distribution volume] and glucose metabolism were assessed in 14 patients with lung cancer. Glucose metabolism was measured by using [18F]fluorodeoxyglucose-positron emission tomography. Vascular physiology was assessed by dynamic T1-weighted, contrast-enhanced MRI. The mean PS product in tumor was 0.0015 +/- 0.0002 s(-1) (n = 13) before, 0.0023 +/- 0.0003 s(-1) (n = 3, P = 0.053) midway through, and 0.00075 +/- 0.0002 s(-1) (n = 5, P < 0.03) 2 weeks after treatment. Values for the extracellular contrast distribution space were 0.321 +/- 0.03 before, 0.289 +/- 0.02 midway through, and 0.195 +/- 0.02 (P < 0.01) 2 weeks after therapy. The glucose metabolic rate was significantly correlated with the PS product (P < 0.01) but not with the extracellular contrast distribution space. Our results demonstrate that tumor PS product correlates with glucose metabolism, that chemo- and radiotherapy induce observable and quantifiable changes in these parameters, and that such changes can be measured by in vivo dynamic MRI. Quantitative dynamic T1-weighted MRI of tumor vascular physiology may have a useful role in the clinical management of lung cancer.

Tumor pretargeting for radioimmunodetection and radioimmunotherapy

Abstract: UNLABELLED The limited success of the sole use of monoclonal antibodies for cancer detection and treatment has led to the development of multistep methods using antibodies in conjunction with low molecular weight agents. For tumor pretargeting, it is important to optimize dose and schedule of relevant agents and to understand barriers to targeted delivery. Here, we address these issues for the anti-carcinoembryonic antigen bifunctional antibody-hapten and the streptavidinylated antibody-biotin systems using a recently developed physiologically based pharmacokinetic model. METHODS For baseline conditions of a standard 70-kg man with a 20-g tumor embedded in the liver, the model was used in conjunction with the Medical Internal Radiation Dosimetry schema to: estimate absorbed doses in tumor and normal tissues; determine the dose dependence of effector agent accumulation in tumor; simulate tumor-to-background effector agent uptake ratio; and calculate the therapeutic ratio for different antibody forms and radionuclides. Alternative drug administration schemes and variable tumor physiological conditions were considered. RESULTS Model simulations showed that 131I-labeled biotin with the streptavidinylated F(ab')2 provided the highest therapeutic ratio under the optimized conditions. The simulations also showed that biotin with the bifunctional streptavidinylated immunoglobulin G provided the highest tumor-to-liver uptake ratio during the early period. Sensitivity analysis showed that antibody extravasation was the major factor limiting the accretion of the effector agent in tumor, whereas antigen expression in normal tissues and tumor antigen shedding had little effect on the absorbed doses. CONCLUSION Tumor pretargeting should provide a definite advantage over direct antibody targeting with up to a 200% increase in tumor-to-background ratio in radioimmunodetection and up to a 76% increase in tumor-to-bone marrow therapeutic ratio in radioimmunotherapy. Rapid antibody clearance from the bloodstream before effector agent injection is expected to improve the therapeutic ratio marginally (3%-10%). However, continuous plasmapheresis dramatically increased the tumor-to-background ratio by a factor of 10 in RAID and the tumor-to-bone marrow therapeutic ratio by more than 110% for short-lived radionuclides in RAIT. Apart from drastic measures such as extended plasmapheresis, pretargeting selectivity was neither sensitive enough for radioimmunodetection nor effective enough for radioimmunotherapy in patients with typical solid tumors even using the optimized protocols.

Inhibition of L- and P-selectin by a rationally synthesized novel core 2-like branched structure containing GalNAc-Lewisx and Neu5Acα2–3Galβ1–3GalNAc sequences

Abstract: The selectins interact in important normal and pathological situations with certain sialylated, fucosylated glycoconjugate ligands containing sialyl Lewisx(Neu5Acalpha2-3Galbeta1-4(Fucalpha1-3)GlcN Ac). Much effort has gone into the synthesis of sialylated and sulfated Lewisxanalogs as competitive ligands for the selectins. Since the natural selectin ligands GlyCAM-1 and PSGL-1 carry sialyl Lewisxas part of a branched Core 2 O-linked structure, we recently synthesized Galbeta1-4(Fucalpha1-3)GlcNAcbeta1-6(SE-3Galbeta1++ +-3)GalNAc1alphaOMe and found it to be a moderately superior ligand for L and P-selectin (Koenig et al. , Glycobiology 7, 79-93, 1997). Other studies have shown that sulfate esters can replace sialic acid in some selectin ligands (Yeun et al. , Biochemistry, 31, 9126-9131, 1992; Imai et al. , Nature, 361, 555, 1993). Based upon these observations, we hypothesized that Neu5Acalpha2-3Galbeta1-3GalNAc might have the capability of interacting with L- and P-selectin. To examine this hypothesis, we synthesized Galbeta1-4(Fucalpha1-3)GlcNAcbeta1-6(Neu5Acalpha2++ +-3Galbeta1-3)-GalNAc alpha1-OB, which was found to be 2- to 3-fold better than sialyl Lexfor P and L selectin, respectively. We also report the synthesis of an unusual structure GalNAcbeta1-4(Fucalpha1- 3)GlcNAcbeta1-OMe (GalNAc-Lewisx-O-methyl glycoside), which also proved to be a better inhibitor of L- and P-selectin than sialyl Lewisx-OMe. Combining this with our knowledge of Core 2 branched structures, we have synthesized a molecule that is 5- to 6-fold better at inhibiting L- and P-selectin than sialyl Lewisx-OMe, By contrast to unbranched structures, substitution of a sulfate ester group for a sialic acid residue in such a molecule resulted in a considerable loss of inhibition ability. Thus, the combination of a sialic acid residue on the primary (beta1-3) arm, and a modified Lexunit on the branched (beta1-6) arm on an O-linked Core 2 structure generated a monovalent synthetic oliogosaccharide inhibitor superior to SLexfor both L- and P-selectin.

Antimicrobial screening of Cassia occidentalis L. in vivo and in vitro

Abstract: Ethanol extracts of different parts and the calli of Cassia occidentalis, and sequential extracts (petroleum ether, benzene, chloroform, ethanol and water) of whole plant and metabolite-rich fractions (anthraquinones, sennosides and flavonoids) of leaves, pods, flowers and callus have been tested against indicator human pathogenic bacteria and fungi. Likewise, an ethanol extract (whole plant) was tested against selected viruses and for antitumour and cytotoxicity following established protocols. The anthraquinones were found to be more active against E. coli and S. aureus (IZ 22 mm) while sennosides were more active against A. flavus (IZ 28 mm). However, no antiviral, antitumour or cytotoxicity effect was exhibited against the test systems. © 1998 John Wiley & Sons, Ltd.

Combinatorial library of moenomycin analogs and methods of producing same

Abstract: A combinatorial chemical library of compounds structurally related to the moenomycin class of antibiotics has formula (I) wherein D is a donor mono- or disaccharide, A is an acceptor monosaccharide, and P-R is a lipophosphoglycerate mimetic group. Members of the library have a glycosidic linkage between the anomeric carbon of D and the C2 carbon of A, and the D-A moiety is in turn covalently linked through the anomeric carbon of A to the P-R group. Members of the library exhibit their greatest structural diversity in terms of substitutions occurring at the C3 position of the A residue, substitutions at the C2 position of the D residue, and different P-R groups used in assembling the compounds. Members of the library are preferably synthesized by solid phase techniques involving stepwise coupling of the respective units to a support, functionalizing the A and/or D saccharides either before or after immobilizing them on the support, and cleaving the assembled compounds from the support. Preferred functionalities attached to the sugar residues are amides, carbamates, ureas, sulfonamides, substituted amines, esters, carbonates, and sulfates. Exemplary P-R groups are derivatives of homoserine, glyceric acid, salicylates and mandelic acid. Members of the library can be screened for anti-microbial activity by contacting them with a culture of microbes and monitoring the growth rate of the microbes.

Synthesis of Gal-beta-(1-->4)-GlcNac-beta-(1-->6)-[Gal-beta-(1-->3]-GalNAc-alpha- OBn oligosaccharides bearing O-methyl or O-sulfo groups at C-3 of the Gal residue: specific acceptors for Gal: 3-O-sulfotransferases.

Abstract: Our recent studies have revealed the existence of two distinct Gal: 3-O-sulfotransferases capable of acting on the C-3 position of galactose in a Core 2 branched structure, e.g., Galβ1→4GlcNAcβ1→6(Galβ1→3)GalNacα1→OBenzyl as acceptor to give 3-O-sulfoGalβ1→4GlcNAcβ1→3(Galβ1→3)GalNAcα1→OB 20 and Galβ1→4GlcNAcβ1→6(3-O-sulfoGalβ1→3)GalNAcα1→OB 23. We herein report the synthesis of these two compounds and also that of other modified analogs that are highly specific acceptors for the two sulfotransferases. Appropriately protected 1-thio-glycosides 7, 8, and 10 were employed as glycosyl donors for the synthesis of our target compounds.

Modulation of multicellular aggregates by pressure from growth in a matrix

Abstract: Cells in a matrix or in the matrix in a vessel are grown to form a multicellular aggregate. Pressure is exerted on the growing cells by the matrix or the matrix together with the vessel due to growing cellular mass displacing the matrix. A value representing pressure exerted on the cells is calculated and the pressure is modulated to control growth of the multicellular aggregate, or to produce a multicellular aggregate of a pre-selected size or a pre-selected size and shape. Matrices include agarose, alginate and collagen gels, and the pressure exerted on the cells can be non-isotropic. The cells may be tumor cells, or liver, pancreatic, brain, skin, bone or muscle cells, and cell growth can be in vitro or in vivo. When collagen forms the matrix, the matrix may contain glycosaminoglycan.

Synthetic Core 2-Like Branched Structures as Ligands for Selectins

Abstract: Compounds which bind to selectin receptors and thus may modulate the course of inflammation, cancer and related processes by intervening with cell-cell adhesion events. Further, such compounds can be used for identification and analysis of such receptors. In this regard the invention is directed to compounds of formula ( I ). wherein R 1 is independently H alkyl, aryl, an aryl alkyl, alkenyl or one or more additional saccharide residues; R 2 = H or OH provided that when R 2 is H, R 3 is OH; R 3 = H or OH provided that when R 3 is H, R 2 is OH; X = H, SO 3 - or PO 4 - ; Y is independently H, OH, OR 4 or NHCOR 4 , wherein R 4 is alkyl, and Z is an organic acid residue. α-L-Fucose residue (a) can be modified or replaced with suitable bioisosters or a different saccharide residue such as D-mannose. Modification of L-fucose may include replacement of each or all of the hydroxyl groups with H or OR' wherein R