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Biomedical subjects

R Christofferson

Publications and source records attributed to R Christofferson.

At least 19 recordsLinked to original sources
PubMed2004

Synovial concentrations of the angiogenic peptides bFGF and VEGF do not discriminate rheumatoid arthritis from other forms of inflammatory arthritis.

OBJECTIVES: To investigate whether concentrations of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) in aspirated synovial fluid can be used to distinguish rheumatoid arthritis from other forms of inflammatory arthritis. METHODS: bFGF and VEGF concentrations were measured in aspirated synovial fluid and serum samples from 66 patients with active arthritis (clinical diagnoses: rheumatoid arthritis (35 patients), psoriatic arthritis (9), reactive arthritis (11) and arthritis UNS (11)) utilizing commercial ELISA kits. RESULTS: In comparison with controls, elevated concentrations of VEGF were found in synovial fluid compared with in serum in all forms of arthritis. There were no significant differences in synovial fluid bFGF or VEGF concentrations between rheumatoid arthritis and the other forms of inflammatory arthritis. CONCLUSION: Both serum bFGF and VEGF concentrations were increased in patients with rheumatoid arthritis. Patients treated with steroids had lower synovial fluid bFGF concentrations. Synovial fluid levels of bFGF and VEGF were elevated but could not be used to distinguish rheumatoid arthritis from other forms of inflammatory arthritis.

Adult↗
PubMed2001

Comparative evaluation of the antitumor activity of antiangiogenic proteins delivered by gene transfer.

Although the systemic administration of a number of different gene products has been shown to result in the inhibition of angiogenesis and tumor growth in different animal tumor models, the relative potency of those gene products has not been studied rigorously. To address this issue, recombinant adenoviruses encoding angiostatin, endostatin, and the ligand-binding ectodomains of the vascular endothelial growth factor receptors Flk1, Flt1, and neuropilin were generated and used to systemically deliver the different gene products in several different preexisting murine tumor models. Single i.v. injections of viruses encoding soluble forms of Flk1 or Flt1 resulted in approximately 80% inhibition of preexisting tumor growth in murine models involving both murine (Lewis lung carcinoma, T241 fibrosarcoma) and human (BxPC3 pancreatic carcinoma) tumors. In contrast, adenoviruses encoding angiostatin, endostatin, or neuropilin were significantly less effective. A strong correlation was observed between the effects of the different viruses on tumor growth and the activity of the viruses in the inhibition of corneal micropocket angiogenesis. These data underscore the need for comparative analyses of different therapeutic approaches that target tumor angiogenesis and provide a rationale for the selection of specific antiangiogenic gene products as lead candidates for use in gene therapy approaches aimed at the treatment of malignant and ocular disorders.

Adenoviridae↗
PubMed2001

Oligomerization-dependent regulation of motility and morphogenesis by the collagen XVIII NC1/endostatin domain.

Collagen XVIII (c18) is a triple helical endothelial/epithelial basement membrane protein whose noncollagenous (NC)1 region trimerizes a COOH-terminal endostatin (ES) domain conserved in vertebrates, Caenorhabditis elegans and Drosophila. Here, the c18 NC1 domain functioned as a motility-inducing factor regulating the extracellular matrix (ECM)-dependent morphogenesis of endothelial and other cell types. This motogenic activity required ES domain oligomerization, was dependent on rac, cdc42, and mitogen-activated protein kinase, and exhibited functional distinction from the archetypal motogenic scatter factors hepatocyte growth factor and macrophage stimulatory protein. The motility-inducing and mitogen-activated protein kinase-stimulating activities of c18 NC1 were blocked by its physiologic cleavage product ES monomer, consistent with a proteolysis-dependent negative feedback mechanism. These data indicate that the collagen XVIII NC1 region encodes a motogen strictly requiring ES domain oligomerization and suggest a previously unsuspected mechanism for ECM regulation of motility and morphogenesis.

Angiogenesis Inhibitors↗
PubMed2001

Angiogenesis and angiogenic growth factors in Wilms tumor.

PURPOSE: Angiogenesis, that is new blood vessel formation, is a prerequisite for growth and metastasis of solid tumors. This study was undertaken to quantify tumor capillaries, investigate immunohistochemical expression and measure serum concentrations of angiogenic growth factors in patients with Wilms tumor. MATERIALS AND METHODS: The hospital records of 33 patients were reviewed and new slides were stained for the endothelial cell marker CD31. Capillaries were quantified in the most vascularized part of the tumor (hot spot) and in the whole slide. New slides were stained immunohistochemically for the angiogenic growth factors angiogenin, basic fibroblast growth factor (bFGF), transforming growth factor alpha, transforming growth factor beta1-3, tumor necrosis factor alpha and vascular endothelial growth factor (VEGF), and their immunoreactivity was quantified. Pretreatment serum samples from 14 patients and 56 healthy control children were analyzed using enzyme-linked immunosorbent assay kits for angiogenin, basic fibroblast growth factor, epidermal growth factor, hepatocyte growth factor, tumor necrosis factor alpha and VEGF. RESULTS: Logistic regression analysis and Kaplan-Meier estimates showed that quantifications based on the tumor hot spot had a significant impact on survival probability (p <0.05). The tumor hot spot counts were highest in the blastemal compartment. Levels of hepatocyte growth factor and VEGF in serum were 3 times higher than those in controls (p <0.01). CONCLUSIONS: Although the sample size is small in this study, the results imply that angiogenesis in Wilms tumor is driven by angiogenic growth factors, and that intratumoral capillary quantification and determinations of serum levels of angiogenic growth factors may be of clinical value.

Child↗
PubMed1999

Angiogenesis and angioarchitecture of transplanted fetal porcine islet-like cell clusters.

Normoglycemic, athymic nude mice were implanted with 3 microl (approximately 250) fetal, porcine islet-like cell clusters under the renal capsule. The angioarchitecture of the transplanted islets was studied by microvascular corrosion casts 3 or 52 weeks after implantation. Arterioles were few, and observed mainly in the older age group. This is likely to be due to the fact that the arterioles were derived from intrarenal blood vessels, i.e., they were not visible on the graft surface. Within the grafts nests of capillaries, probably supplying a single islet-like cell clusters, could be seen in both groups. Numerous capillary sprouts were seen within the graft after 3 weeks, and to a slighter extent also after 1 year. Moreover, especially in grafts examined 3 weeks, but also 52 weeks, after transplantation, holes were observed in dilated capillary segments, suggesting that intussusceptive microvascular growth occurred in parallel with angiogenesis. A well-developed microvasculature could be observed 52 weeks after transplantation, whereas the number of capillaries in the implant was less pronounced 3 weeks postimplantation. The efferent venules were located peripherally in the islets and drained immediately into larger veins, derived from capsular veins clearly seen on the surface of the graft. It is concluded that xenotransplanted islet-like cell clusters develop an autonomous microcirculation by stimulating angiogenesis from surrounding blood vessels. Our findings suggest that single islet-like cell clusters remain morphologically intact after transplantation, and probably function as single endocrine units rather than forming a single homogenous endocrine tissue. Furthermore, it seems as if a continuous reorganization of the vasculature, with an associated angiogenesis, occurs throughout the observation period.

Animals↗
PubMed1999

Inhibition of angiogenesis induces chromaffin differentiation and apoptosis in neuroblastoma.

Inhibition of angiogenesis has been shown to reduce tumor growth, metastasis, and tumor microvascular density in experimental models. To these effects we would now like to add induction of differentiation, based on biological analysis of xenografted human neuroblastoma (SH-SY5Y, WAG rnu/rnu) treated with the angiogenesis inhibitor TNP-470. Treatment with TNP-470 (10 mg/kg s.c., n = 15) reduced the tumor growth by 66% and stereological vascular parameters (Lv, Vv, Sv) by 36-45%. The tumor cell apoptotic fraction increased more than threefold, resulting in a decrease in viable tumor cells by 33%. In contrast, the mean vascular diameter (29 microm) and the mean tumor cell proliferative index (49%) were unaffected. TNP-470-treated tumors exhibited striking chromaffin differentiation of neuroblastoma cells, observed as increased expression of insulin-like growth factor II gene (+88%), tyrosine hydroxylase (+96%), chromogranin A, and cellular processes. Statistical analysis revealed an inverse correlation between differentiation and angiogenesis. It is suggested that by inhibiting angiogenesis, TNP-470 induces metabolic stress, resulting in chromaffin differentiation and apoptosis in neuroblastoma. Such agonal differentiation may be the link between angiostatic therapy and tumor cell apoptosis.

Animals↗
PubMed1999

Phosphoinositide 3 kinase is critical for survival, mitogenesis and migration but not for differentiation of endothelial cells.

Angiogenesis involves endothelial cell invasion and migration into the surrounding tissue where cells differentiate, to form new lumen-containing vessels. We have investigated the role of phosphoinositide 3-kinase (PI3-kinase) in vascular endothelial growth factor (VEGF)- and fibroblast growth factor (FGF)-induced angiogenesis. Angiogenesis in vivo in chick embryos was inhibited by treatment with the PI3-kinase inhibitors wortmannin and LY294002. Stimulation of primary bovine capillary endothelial (BCE) cells with FGF-2, VEGF-A(165), or a combination of the two induced PI3-kinase activity in vitro and subsequent activation of the serine/threonine kinase Akt. The combination of FGF-2 and VEGF-A(165) led to an additive response. Activation of PI3-kinase was strictly required for FGF-2- and VEGF-A(165)-induced migration and DNA synthesis of BCE cells. Tubular morphogenesis was unaffected by treatment with wortmannin or LY294002, but survival of the tubular structures was dependent on PI3-kinase activity. VEGF-A(165) and FGF-2 induced increased stability of the tubular structures in a synergistic manner. These data indicate that PI3-kinase activity is required for migration, mitogenicity and survival but not for differentiation of endothelial cells during angiogenesis.

Journal Article↗
PubMed1998

[Angiogenesis inhibitors in advanced cancer. Many current clinical trials show promising results].

Tumour growth and metastasis are dependent on angiogenesis, the formation of new blood vessels. In experimental models, tumour regression can be induced by the administration of specific angiostatic agents. The inhibition of angiogenesis represents a new approach in cancer therapy. Specific inhibition of angiogenesis is not characterised by the typical dose-limiting toxicity of chemotherapy. By targeting the untransformed and genetically stable vascular endothelium, drug delivery is no problem, and angiostatic therapy is not associated with the development of drug resistance. However, the treatment has to be continued for months or years, and some angiostatic agents are known to interfere with fertility. Approximately thirty angiostatic agents are undergoing clinical trials, and another fifty agents preclinical testing. Since the clinical trials are performed on patients with advanced tumours intractable to conventional therapy, and as the test drugs are first generation angiostatic agents, their effect is measured in terms of delay in tumour progression or reduction in values for surrogate endpoints such as tumour markers. In this article, based on reports presented at a recent international conference on angiogenesis antagonists, a few angiostatic agents are reviewed with brief comments on their performance in early clinical trials, and some new and promising angiostatic strategies are outlined.

Clinical Trials as Topic↗
PubMed1997

Hyaluronan oligosaccharides induce tube formation of a brain endothelial cell line in vitro.

In remodeling tissues the formation of new blood vessels is an essential process which is regulated by different factors. During such processes an increase in hyaluronan synthesis and turnover is often seen and recent observations have suggested that hyaluronan can both promote and inhibit neovascularization depending on its molecular mass. In this work we show that a brain capillary endothelial cell line forms tubes in a collagen gel after stimulation by hyaluronan oligosaccharides. Ultrastructural examination of the tubes by transmission electron microscopy revealed that the cord-like outgrowths consisted of 2-10 tightly packed cells containing a continuous lumen. The tube formation in response to hyaluronan oligosaccharide was not mediated by activation of receptors for fibroblast growth factor. The endothelial cell line, which does not synthesize hyaluronan, exhibited specific hyaluronan-binding sites, with about 3000 hyaluronan molecules (M(r) 3.85 x 10(6)) bound per cell at saturation and Kd was 0.05 x 10(-9) M. Furthermore, the cell line was stained with mAb IVd4 that recognizes a novel class of hyaluronan-binding proteins and mAb IM7 which recognizes CD44 molecules.

Animals↗
PubMed1997

Angiostatic treatment of neuroblastoma.

The growth of solid tumours has been shown to be dependent on new blood vessel formation, i.e. angiogenesis. Several steps in the metastatic process have also been found to be angiogenesis dependent. The mediators of tumour angiogenesis are now being elucidated, and angiostatic agents have been developed. Some of these agents are currently undergoing clinical trials. In addition to inhibition of angiogenesis, two other clinical applications of angiogenetic research in tumour diseases are monitoring of disease activity by analyses of circulating angiogenic peptides and prediction of a poor outcome by tumour microvascular counts. Neuroblastomas grow quickly, are highly vascularised and metastasise early and hence inhibition of angiogenesis--angiostatic therapy--may be indicated in this disease. The effects of treatment with the angiostatic agent TNP-470 in an experimental model results in a significant reduction of the tumour growth rate, reduced microvascular counts and a reduced fraction of viable tumour cells compared to controls. TNP-470 as single therapy has an objective tumoristatic effect in our neuroblastoma model. Angiostatic treatment of neuroblastoma is a new and theoretically promising treatment modality that merits clinical investigations. The feasibility of assessing disease activity by repeated determinations of the levels of circulating angiogenic peptides should also be determined, as well as the use of microvascular counts to predict a poor outcome.

Animals↗
PubMed1997

The angiogenesis inhibitor TNP-470 reduces the growth rate of human neuroblastoma in nude rats.

A new animal experimental model of human neuroblastoma is described. The model involves xenotransplantation of a poorly differentiated human neuroblastoma cell line (SH-SY5Y) to the subcutaneous tissue in the hind leg of nude rats (WAG mu/rnu). Injection of 20 million cells suspended in 0.2 mL of medium in each hind leg yielded an 89% tumor take (41/46) in 23 nude rats. Tumor take was evident after 2 wk. The tumors grew exponentially and reached a volume of 5.2 +/- 1.6 mL 4 wk after transplantation. The tumor cells retained their morphologic phenotype at the ultrastructural level after transplantation and were immunohistochemically positive for neuron-specific enolase and for chromogranins A and B. Subcutaneous injections of the angiogenesis inhibitor TNP-470 (10 mg/kg of body weight) every other day gave a treated/control quotient for mean tumor volume of 0.34 after 12 d of treatment. This implies that angiogenesis inhibition may be of value as a complement to chemotherapy in the treatment of human neuroblastoma. The presented animal experimental model is designed for investigations of the effects of chemotherapy, angiogenesis inhibitors, radiotherapy, and/or surgery on the growth rate of human neuroblastoma.

Animals↗
PubMed1996

Plasma levels of chromogranin A are directly proportional to tumour burden in neuroblastoma.

A novel animal experimental model involving the human, poorly differentiated, and adrenergic neuroblastoma cell line SH-SY5Y xenotransplanted to subcutaneous tissue of 13 nude rats (WAG rnu/rnu) was used to investigate the usefulness of six proposed neuroblastoma markers. It was shown that the plasma concentrations of human chromogranin A (CgA) as measured by RIA were directly proportional to tumour volume (r = 0.83, P < 0.001). To rule out possible liberation of CgA by tumour cell lysis, the CgA degradation product pancreastatin was also measured in plasma by a specific RIA, but was not detectable. Plasma neurone-specific enolase (NSE) was elevated in tumour-bearing animals (P < 0.01), but did not correlate with tumour volume (r = 0.49, P > 0.05). Urine homovanillic acid (HVA), detected by HPLC, was elevated in tumour-bearing animals (P < 0.01), but did not correlate with tumour volume (r = -0.32, P > 0.05). Urine vanillyl mandelic acid was not detectable. Urine dopamine was found in low concentrations that did not correlate with tumour volume. In summary, although plasma NSE and urinary HVA were elevated in tumour-bearing animals only plasma CgA correlated with tumour burden. This makes CgA a promising biochemical marker for neuroblastomas.

Adrenal Gland Neoplasms↗
PubMed1991

[Vascular architecture and neovascularization is surveyed with a new casting technique].

Tubular, alveolar and caval systems in the body can be replicated by injecting a solidifying mass, surrounding tissue then being removed and the corroded cast of the cavity analyzed. Long recognized, this approach has gained impetus with the advent of the scanning electron microscope and acrylic polymers. Microvascular corrosion casting combined with analysis in the scanning electron microscope is now a powerful tool for the investigation of e.g. vascular architecture and angiogenesis in different organs and species (including man) and under both physiological, experimental and pathological conditions. Different questions at issue and the morphology of the microcirculation are presented briefly with some key references.

Animals↗
PubMed1990

Mechanism of erythrocyte trapping in ischaemic acute renal failure.

Forty-five minutes of warm ischaemia and 20 min of recirculation in the rat kidney was found to result in (1) a massive transient extravasation of plasma upon recirculation and (2) an increase in plasma-lymph transport of proteins during the first hours after onset of circulation. This was accompanied by trapping of erythrocytes, as determined with 51Cr-labelled erythrocytes, in the capillaries, mainly in the inner stripe of the outer medulla. At scanning electron microscopy of vibratome sections, the trapping appeared as aggregates of polygonally shaped erythrocytes. It is concluded that 45 min of ischaemia and 20 min of recirculation results in an increase in the permeability of the renal capillaries. This increase leads to extravasation of capillary plasma with consequent local haemoconcentration, causing an increase in vascular resistance and in capillary hydrostatic pressure. This elevated pressure will, in turn, lead to perpetuating extravasation of plasma, further haemoconcentration and so on, eventually resulting in dense packing of polygonal erythrocytes, obstructing the blood flow. It is believed that oxygen-derived free radicals generated in the early recirculation phase contribute to the increase in macromolecular permeability, since the scavenger bovine superoxide dismutase and allopurinol, a xanthine oxidase inhibitor, were found to prevent this unfavourable chain of events.

Acute Kidney Injury↗