PubMed Health⌕ Search

Biomedical subjects

W Zumkeller

Publications and source records attributed to W Zumkeller.

32 records · Page 2Linked to original sources
PubMed1995

IGF-II dependent autocrine growth in cell lines derived from renal tumours of childhood.

Aims-To determine the role of insulin-like growth factors (IGF) in the proliferation of tumour cells, by studying the mitogenic response to IGFs of three cell lines of differing phenotype established from both malignant rhabdoid and Wilms tumour, representing a range of cell types (GOS 4, G401, and T3/73).Methods-Production of IGF-II and IGF-I was measured by radioimmunoassay, and the presence of IGF binding protein complexes was observed by gel exclusion chromatography. Following growth analyses in serum-free media to ascertain the dependence of the cell lines on exogenous IGFs, the generation of autocrine growth was measured by a density dependence assay of proliferation in culture. Receptors were measured by radioligand cross linking and autocrine growth through these receptors assayed by the use of blocking antibodies.Results-While GOS 4 and G401 were able to proliferate in serum-free medium over a period of 5 d, T3/73 showed an absolute dependence on IGFs added daily at 1-10 ng/ml. Plating at clonal density showed that cell growth was directly density dependent in serum-free medium. The serum independent proliferation of G401 and GOS 4 was blocked by the addition of an antibody to the type 1 IGF receptor (alpha-IR3) suggesting that the effects of autocrine factors are mediated through type 1 IGF receptors. S1 nuclease protection analysis indicated that all three cell lines produced significant amounts of mRNA derived mainly from the P3 IGF-II promoter, but transcripts for IGF-I were undetectable. Radioimmunoassay of IGFs from conditioned media showed that all the lines made assayable IGF-II (8.6, 8.4, and 6.1 ng/ml/24 h/10(6) cells for GOS 4, G401, and T3/73 respectively). The presence of species consistent with both type 1 and type II IGF receptors was demonstrated using radioligand binding to cell membranes followed by cross linking.Conclusions-Autocrine IGF-II may contribute to the serum independence of GOS 4 and G401 cells, whereas T3/73 may depend on exogenous IGF-II for proliferation.

Journal Article↗
PubMed1993

Insulin-like growth factor (IGF)-I, -II and IGF-binding proteins in the cyst fluid of a patient with astrocytoma.

Insulin-like growth factor (IGF)-I, -II and IGF-binding proteins (IGFBPs) were demonstrated in the cyst fluid of a patient with a hypothalamic astrocytoma. The astrocytoma cyst fluid was subjected to gel chromatography at low pH and the IGF-I and IGF-II levels were measured by specific radioimmunoassays. Immunoreactive IGF-I and IGF-II levels were 19 ng/ml and 78 ng/ml respectively. Several-fold higher IGF-II values were obtained when cyst fluid was not extracted or was extracted with acid ethanol before radioimmunoassay analysis. The immunoreactive IGFBP-1 concentration was 26 ng/ml. Sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) and subsequent Western ligand blotting with [125I]IGF-II revealed bands at approximately 200, 34.5, 29.5, 24 and 21 kD as visualized by autoradiography. Binding studies demonstrated that these binding proteins bind specifically [125I]IGF-I and [125I]IGF-II. These observations suggest that IGFs as well as IGF-binding proteins are produced by astrocytoma cells and may act in a paracrine or autocrine fashion capable of modulating the growth of astrocytoma tumours.

Blotting, Western↗
PubMed1993

Insulin-like growth factor (IGF)-I, -II and IGF binding protein-2 (IGFBP-2) in the plasma of children with Wilms' tumour.

Insulin-like growth factors (IGF)-I, -II and IGF binding protein-2 (IGFBP-2) have been measured in plasma of children with Wilms' tumour. The mean levels for total serum IGF-I and -II were not significantly altered in Wilms' tumour as compared with normal control plasma. However, the chromatographic profiles for IGF-I and -II in these groups were different with regard to the presence of IGF binding proteins and high molecular weight forms of IGFs; the high molecular weight form (9-15 kD) of IGF-II was significantly reduced in Wilms' tumour. Levels of IGFBP-2 were substantially elevated in serum from Wilms' tumour patients (1025 +/- 112 ng/ml compared with 416 +/- 44 ng/ml in controls), and inversely correlated with the levels of high molecular weight forms of IGF-II. We suggest that IGFBP-2 measurements might be of value as a marker for monitoring this type of tumour, either as an adjunct to diagnosis or surveillance of tumour growth during therapy.

Biomarkers, Tumor↗
PubMed1992

The role of insulin-like growth factors and IGF-binding proteins in the physiological and pathological processes of the kidney.

Insulin-like growth factors (IGFs) and their binding proteins are implicated in the growth regulation of the kidney during embryogenesis and differentiation. Recent evidence also suggests that IGFs play a role in kidney physiology (glomerular filtration rate, renal plasma flow) and pathology (diabetic renal hypertrophy, nephritis, glomerulosclerosis, kidney tumours, chronic renal failure). This review focuses on the biology of IGFs at the molecular, protein and receptor levels and considers their importance in renal physiology and pathology. The current data demonstrate a central role for the IGFs in the mediation of a wide variety of effects on renal growth, function and malignancy.

Amino Acid Sequence↗
PubMed1992

Testosterone increases serum 1,25-dihydroxyvitamin D and insulin-like growth factor-I in hypogonadal men.

The short-term metabolic effects of testosterone treatment on circulating levels of 1,25-dihydroxyvitamin D and insulin-like growth factor-I (IGF-I) were studied in 13 hypogonadal men. The study group included 11 men with Klinefelter's syndrome, with varying degree of androgen deficiency, and two men with secondary hypogonadism. Pretreatment levels of 1,25-dihydroxyvitamin D, vitamin D-binding protein and IGF-binding protein-I were all within the normal range. The levels of IGF-I were lower than normal in 5/11 of the Klinefelter patients and in one patient with GH-deficiency. Testosterone treatment increased circulating total 1,25-dihydroxyvitamin D significantly from 75 +/- 4 pmol l-1 (mean +/- SEM) to 86 +/- 4 (P less than 0.01) and the free 1,25-dihydroxyvitamin D-index from 1.95 +/- 0.11 to 2.39 +/- 0.12 (P less than 0.01). Serum levels of IGF-I increased from 117 +/- 22 micrograms/l to 143 +/- 23 (P less than 0.01) during androgen treatment. No significant effects on levels of IGF-binding protein-I were seen. It is concluded that androgen therapy increases the availability of 1,25-dihydroxyvitamin D and the level of IGF-I, which may be important links in the action of testosterone.

Adolescent↗
PubMed1991

Demonstration of insulin-like growth factors I, II and heterogeneous insulin-like growth factor binding proteins in the cyst fluid of patients with craniopharyngioma.

Insulin-like growth factor (IGF)-II and its binding proteins were demonstrated to be present in human craniopharyngioma cyst fluid using gel filtration and ligand blot analyses. Immunoreactive IGF-II in 3 patients was found to be 274, 232 and 310 ng/ml after gel chromatography whereas IGF-I concentrations were 13, 8 and 15 ng/ml. The IGF-II levels were severalfold higher in cyst fluid than in spinal fluid while the IGF-I levels in both fluids did not differ significantly. The binding proteins showed high affinities for [125I]IGF-II which could be displaced by unlabelled IGF-II. With the ligand blot analysis, [125I]IGF-II shows bands at 300, 175 and 46/43 kilodaltons probably representing IGF-II receptor and IGFBP-3. IGFBP-1 levels 17, 22 and 45 ng/ml, respectively, were undetectable by ligand blot.

Adult↗
PubMed1990

Immunoreactive insulin-like growth factor II in urine.

Insulin-like growth factor II and insulin-like growth factor binding protein-1 were identified and quantified in the urine of 23 healthy subjects between 17 and 76 years of age. IGF-II was measured after separation by gel chromatography at low pH and compared with IGF-I levels in the same samples, whereas IGF binding protein-1 was measured in dialysed urine. Urinary IGF-II was found at much higher concentrations than IGF-I (mean +/- SEM: 717 +/- 69 vs 110 +/- 5 ng/mmol creatinine). The chromatographic profile indicates that pro-IGF-II may also be present. The concentrations of IGF-II appear to be less variable than the other reported parameters. The mean IGF binding protein-1 concentrations in these urine samples was 414 +/- 83 ng/mmol creatinine. IGFs in the urine are in part bound to binding proteins.

Adolescent↗
PubMedDate not supplied

The role of the GH/IGF system in pituitary tumorigenesis.

Pituitary adenomas are mostly benign tumours that originate from differentiated anterior pituitary cells. Altered expression of growth factors or their receptors could enhance clonal expansion of pituitary adenoma cells. GHRH overstimulation or an activating point mutation in the Gs a-subunit leads to increased GH secretion and tumour formation. In contrast, IGF-I suppresses basal and GHRH-stimulated GH secretion in pituitary adenoma cells, whereas prolactin secretion is unaffected. Somatostatin analogues and pegvisomant, a novel growth hormone-receptor antagonist, results in a reduction of serum IGF-I levels and clinical improvement in patients suffering from pituitary adenoma. Thus, this review focuses on the role of the growth hormone/insulin-like growth factor system in pituitary tumorigenesis with particular focus on the genetic alterations described in pituitary adenomas up to now.

Adenoma↗
PubMedDate not supplied

Insulin-like growth factor system in neuroblastoma tumorigenesis and apoptosis: potential diagnostic and therapeutic perspectives.

Apoptosis is a cell death program which is modulated by a variety of factors including growth factors, signal transduction molecules and inducers of gene expression or DNA replication. Of particular interest is Type I insulin-like growth factor receptor which contains a tyrosine kinase domain linked to the ras-raf-MAPK cascade. This receptor has antiapoptotic effects in a number of in vivo and in vitro models, thus making IGF-I-R a potential target for gene therapy. Particularly the growth of neuroblastoma depends on IGFs which exert their effect through the Type I IGF receptor. This review highlights the role of the IGF-system in neuroblastoma and points at possible modulators with the aim of inducing differentiation or apoptosis of tumor cells.

Apoptosis↗
PubMedDate not supplied

Growth factors, cytokines and soluble forms of receptor molecules in cancer patients.

A wide range of growth factors has been identified in recent years, some of which have been found to play a crucial role in neoplastic processes. Some tumours produce considerable amounts of these peptides and their requirement for growth factors is often much reduced leading to a degree of autonomy which may itself contribute to tumourigenicity. In addition, growth factors such as TGF-alpha, PDGF, FGF and IGFs have been found to be overexpressed in tumours. The growth factor effector pathway is thus open to intervention, e.g. by blocking the receptor using specific antibodies or interfering with posttranscriptional activation. This is even more evident as oncogenes such as erbB and v-sis encode for growth factor receptors. Soluble receptors, due to high affinity binding, might also be used to sequester growth factors from its specific membrane-bound receptors. Tyrosine-specific protein kinase activity may be inhibited by tyrosine analogues such as erbstatin or by more specific tyrosine-kinase inhibitors. Some therapeutical concepts have already been developed in clinical trials. Tumour necrosis factor (TNF) has successfully been used in extremity melanoma and sarcoma and monoclonal antibodies directed against the EGF receptor has also been applied in patients with advanced squamous lung cancer. Synthetic growth factor analogues which bind to the receptor without eliciting a signal may soon become a supplementary part in cancer treatment. Growth factor action is also blocked by suramin and its analogues and clinical phase I and II trials are underway. These novel therapeutical aspects will profoundly change the nature of cancer treatment.

Antineoplastic Agents↗