Search PubMed⌕ Search

Biomedical subjects

J Zapf

Publications and source records attributed to J Zapf.

At least 145 records · Page 8Linked to original sources
PubMed1987

Therapy of malignant brain tumors: comparison of the in vitro activities of vidarabin-monophosphate, BCNU and 5-fluorouracil.

BCNU (carmustine), 5-Fluorouracil (5-FU) and Vidarabin-monophosphate (ARA-A5'P) were compared in their activities against 30 cell lines of primary (n = 21) and metastatic (n = 9) brain tumors, which were characterized in tissue culture by cytochemical, immunological and cytogenetic criteria. In vivo achievable concentration-time products were correlated with in vitro pharmacokinetic data. A micro assay was employed to screen for drug toxicity in individual tumor cell lines; cells were exposed to the drugs at exposure doses relevant to in vivo pharmacokinetics. After 5-8 population doubling times of untreated controls, RNA-synthesis, as a parameter of cell metabolism and proliferation, was determined by incorporation of (5, 6-3H)-uridine into cellular RNA (liquid scintillation counting protocol). A tumor stem cell assay was performed under similar conditions. The cytotoxic effect of each drug on individual cell lines was expressed in terms of a sensitivity index SI (SI = 1 indicating complete resistance) to compare effects of different drugs on the individual tumor cell lines. Mean sensitivity indices for ARA-A5'P, BCNU and 5-FU in brain tumor cell lines (in brackets: primary CNS-tumors) were 0.64 (0.59), 0.89 (0.82) and 0.35 (0.33) respectively. 5-FU was significantly more active than BCNU and ARA-A5'P (P less than 0.001), whereas BCNU was significantly less active than ARA-A5'P (P less than 0.001). ARA-A5'P had a suppressive effect on formation of brain tumor stem cell colonies. There was no cross-resistance of ARA-A5'P to either BCNU or 5-FU. We conclude that ARA-A5'P and 5-FU are potent agents in experimental therapy of human brain tumors, compared with BCNU.

Brain Neoplasms↗
PubMed1987

Insulin-like growth factor I and II in 14 animal species and man as determined by three radioligand assays and two bioassays.

Insulin-like growth factor I and II (IGF I and II) were determined by five different assays in human serum, in the sera of ten mammalian species and in chicken, turtle, and frog serum. Sera of all tested mammals contain two different IGFs corresponding to human immunoreactive IGF I and receptor reactive IGF II. Receptor reactive IGF II of most animal species does not show significant cross-reactivity in the RIA for human IGF II. IGF activity was also detected in sera of non-mammals, such as chicken and turtles, but not in frog serum. The IGF values obtained with the different assay system corresponded rather well: there is a good correlation between the values obtained in the protein binding and the fat cell assay, and between the results of the latter assays and the sum of immunoreactive IGF I and receptor reactive IGF II. The results suggest that those regions in the IGF I and II molecules which are responsible for reactivity with the type I IGF and the insulin receptor have not essentially changed during evolution. Similarly, the C-region, which mainly determines the immunological properties of IGFs, appears to have remained relatively constant in the IGF I, but not in the IGF II molecule.

Animals↗
PubMed1987

Pre-operative treatment of 5 acromegalics with a somatostatin analogue: endocrine and clinical observations.

Five acromegalic patients were treated preoperatively over a period of 1-4 weeks with the somatostatin analogue SMS 201-995. The patients received daily 3 X 100 micrograms of SMS 201-995 subcutaneously. This schedule resulted in a rapid improvement of the clinical symptoms in 4 out of 5 patients. In these same patients plasma growth hormone concentrations decreased markedly. However, only in one patient were growth hormone concentrations normalized. Plasma IGF I, which was elevated in all patients, was normalized only in this same patient. Tumour volume as determined by thin section CT-scans decreased only in one case by 17%. All tumours appeared extraordinarily soft upon operation. Conventional light microscopy showed no difference between tumours of SMS-pre-treated and untreated patients. Ultrastructural investigation showed the usual heterogeneity.

Acromegaly↗
PubMed1986

[Acromegaly and insulin-like growth factors].

The insulin-like growth factors (IGF) I and II are structural homologues of insulin with a molecular weight of 7500. In contrast to insulin, their insulin-like effects are not suppressible by insulin antibodies. They are mainly produced by the liver under the influence of growth hormone and are bound to specific carrier proteins in the circulation. According to the somatomedin concept, they mediate the effects of growth hormone on growth. IGF I is identical to somatomedin A and somatomedin C. In acromegalic patients oversecretion of growth hormone is accompanied by a significant increase in the serum IGF I level, whereas IGF II levels are normal. IGF I can, therefore, serve as a useful additional laboratory index in the diagnosis of acromegaly and in evaluating successful surgery and/or radiotherapy of this disease. Bromocriptine therapy often improves the clinical symptoms of acromegaly and lowers growth hormone levels without normalizing IGF I. In most of these patients, however, suppression of growth hormone under oral glucose load is not normal. In our opinion the determination of IGF I should not replace growth hormone determinations during an oral glucose tolerance test; rather, it should be performed to complement this test, above all when its results cannot be unambiguously interpreted.

Acromegaly↗
PubMed1986

Human leukemic cells: receptor binding and biological effects of insulin and insulin-like growth factors.

Receptor binding and biological effects of insulin and insulin-like growth factors I and II (IGF I/II) were assessed in three human malignant cell lines: a Burkitt-type ALL-cell line, a ANLL-cell line and a Hodgkin's disease-cell line. Insulin receptor binding could be demonstrated in Burkitt-type ALL cells and ANLL cells, whereas no insulin receptor binding was detectable in Hodgkin cells. IGF I and IGF II binding could be demonstrated in all leukemic cells. Insulin stimulated glycogen synthesis in the insulin receptor bearing cell lines. DNA synthesis was stimulated by insulin, IGF I and II. IGF I was more active in stimulating DNA synthesis than IGF II.

Cell Line↗
PubMed1986

Insulin-like growth factors/somatomedins: structure, secretion, biological actions and physiological role.

Insulin-like growth factors (IGFs, somatomedins) are structural homologues of insulin with insulin-like biological activity. They are mainly synthesized and secreted by the liver, but may also be produced by extrahepatic tissues. In their native from in blood they are bound to specific carrier protein(s). This determines essentially their biological actions. The complexed factors stimulate growth indices in vitro and in vivo, but, in contrast to the free factors, do not exert acute effects on insulin target tissues.

Animals↗
PubMed1986

Pathophysiological and clinical aspects of the insulin-like growth factors.

Except in acromegaly, where insulin-like growth factor I (IGF I) levels are elevated, only decreased IGF levels have been observed under pathophysiological conditions. These are hypopituitarism, Laron dwarfism, leprechaunism, liver disease, primary hypothyroidism, extrapancreatic tumor hypoglycemia and severe insulin deficiency in experimental animals. For most of these diseases the diagnostic value of IGF determinations is limited. IGF I determinations may serve as a useful additional diagnostic index in acromegaly and in the evaluation of successful operative and/or radiotherapy of this disease.

Acromegaly↗
PubMed1986

Acute metabolic effects and half-lives of intravenously administered insulinlike growth factors I and II in normal and hypophysectomized rats.

Insulinlike growth factors (IGF) act qualitatively like insulin on insulin target tissues in vitro. In the circulation in vivo they are bound to specific carrier proteins. In this form or when continuously infused into hypophysectomized (hypox) rats they do not exert acute insulinlike effects on glucose homeostasis. This study definitively shows that intravenous bolus injections of pure IGF I or II act acutely on glucose homeostasis: they lower the blood sugar, enhance the disappearance of U-[14C]glucose from serum and increase its incorporation into diaphragm glycogen in normal and hypox rats in the presence of antiinsulin serum. The same effects were obtained with recombinant human IGF I injected intravenously either with or without antiinsulin serum into normal rats. Free fatty acid levels decreased transiently only in normal animals. Lipid synthesis from glucose in adipose tissue was not stimulated in hypox and barely stimulated in normal rats. The half-life of injected IGF I or II in normal rats (approximately 4 h) is strikingly different from that in hypophysectomized rats (20-30 min) and appears to depend on the growth hormone-induced 150,000-200,000-mol wt IGF carrier protein that is lacking in hypophysectomized rats. 15 min after the bolus serum IGF I and II concentrations were similar to steady state levels during long-term infusion in hypox rats. Free IGF was barely detectable, however, in the infused animals, whereas 40-100% was found free 15 min after the bolus. These observations for the first time confirm the hypothesis that only free IGF, but not the IGF carrier protein complex, is bioavailable to insulin target tissues.

Animals↗
PubMed1986

Human fetal and adult chondrocytes. Effect of insulinlike growth factors I and II, insulin, and growth hormone on clonal growth.

Clonal proliferation of freshly isolated human fetal chondrocytes and adult chondrocytes in response to human insulinlike growth factors I and II (IGF I, IGF II), human biosynthetic insulin, and human growth hormone (GH) was assessed. IGF I (25 ng/ml) stimulated clonal growth of fetal chondrocytes (54 +/- 12 colonies/1,000 inserted cells, mean +/- 1 SD), but IGF II (25 ng/ml) was significantly more effective (106 +/- 12 colonies/1,000 inserted cells, P less than 0.05, unstimulated control: 14 +/- 4 colonies/1,000 inserted cells). In contrast, IGF I (25 ng/ml) was more effective in adult chondrocytes (42 +/- 6 colonies/1,000 inserted cells) than IGF II (25 ng/ml) (21 +/- 6 colonies/1,000 inserted cells; P less than 0.05, unstimulated control: 6 +/- 3 colonies/1,000 inserted cells). GH and human biosynthetic insulin did not affect clonal growth of fetal or adult chondrocytes. The clonal growth pattern of IGF-stimulated fetal and adult chondrocytes was not significantly changed when chondrocytes were first grown in monolayer culture, harvested, and then inserted in the clonal culture system. However, the adult chondrocytes showed a time-dependent decrease of stimulation of clonal growth by IGF I and II. This was not true for fetal chondrocytes. The results are compatible with the concept that IGF II is a more potent stimulant of clonal growth of chondrocytes during fetal life, whereas IGF I is more effective in stimulating clonal growth of chondrocytes during postnatal life.

Adult↗
PubMed1985

In vivo effects of the insulin-like growth factors (IGFs) in the hypophysectomized rat: comparison with human growth hormone and the possible role of the specific IGF carrier proteins.

Insulin-like growth factors (IGF) I and II produce acute insulin-like effects or promote growth indices in hypophysectomized rats, depending on their mode of administration. Intravenous bolus injections of IGF I and II, like insulin, lower the blood sugar level and lead to a pronounced stimulation of glycogen synthesis in skeletal muscle. The two factors are equipotent in this respect. Continuous subcutaneous infusions of IGF I or II over six days have no hypoglycaemic effect. They mimic the effects of growth hormone, increasing the width of the tibial epiphysis and stimulating the thymidine-incorporating activity of costal cartilage in the absence of growth hormone. IGF I (identical to somatomedin C) is more potent than IGF II and causes a dose-dependent increase in body weight at concentrations where IGF II is still ineffective. The absence of acute insulin-like effects in long-term experiments is explained by the presence in serum of highly specific carrier proteins that interfere with the insulin-like properties of IGF I and II and restrict their capillary permeability. Growth hormone induces the formation of both IGF and the major IGF carrier protein in the liver. Thus, while IGFs mediate the actions of growth hormone on growth, growth hormone appears to modulate these actions via IGF carrier proteins.

Animals↗
PubMed1985

Insulin-like growth factors and insulin: comparative aspects.

IGF I and IGF II are two insulin-like growth factors resembling insulin in many respects. They stem from a common precursor, act through receptors similar to the insulin receptor with which they cross-react. When administered in large amounts they produce hypoglycemia. Their major effects, however, are on replication and differentiation of cells of mesodermal origin. IGF I is the major growth promoting factor in vivo. The synthesis and secretion of IGF I by the liver depend on the growth hormone status, insulin and nutrition. In contrast to insulin, the IGFs circulate in blood bound to the carrier proteins. Their half-life in man is in the order of 16 h. IGF I deficiency results in dwarfism (pygmy, Laron dwarf, toy poodle) despite normal or elevated growth hormone secretion. The anabolic actions of insulin and of the IGFs appear to complement each other as shown in Figure 7.

Animals↗
PubMed1985

Activity in fetal bovine serum that stimulates erythroid colony formation in fetal mouse livers is insulinlike growth factor I.

In the present study, the erythropoietic activity of fetal serum was characterized. Using fetal bovine serum (FBS) as a source of the erythropoietic activity and serum-free cultures of fetal mouse livers (FMLC assay) as a detection system, we found that FBS stimulated colony formation from late erythroid progenitor cells (CFU-E) in a dose-dependent fashion. The slope of the dose-response curve, however, was significantly different from that for erythropoietin (Ep), the best-characterized erythropoietic activity so far. The erythropoietic activity of FBS was found in the 120-160- and 40-70-kD range at neutral pH. In the presence of 1 M acetic acid, however, the erythropoietic activity had an apparent molecular mass between 3 and 13 kD. From ion exchange experiments with DEAE-cellulose, the isoionic point of the activity was estimated to about pH 5. Furthermore, the erythropoietic activity of FBS was found to be co-eluted on Sephadex G-150 with the binding proteins of insulinlike growth factors (IGF). The IGF I concentration determined by radioimmunoassay was 70 ng IGF I/ml. The Ep activity of FBS was less than 5 mU/ml when determined with the posthypoxic polycythemic mouse assay for Ep. These results suggest that the erythropoietic activity of FBS is related to IGF and not to Ep. The erythropoietic activity of FBS was abolished by an antiserum against IGF I. Furthermore, IGF I was a factor of approximately 40 more potent than IGF II in stimulating erythroid colony formation. All of these findings suggest that the erythropoietic activity of FBS is IGF I.

Animals↗
PubMed1985

Comparison of in vivo effects of insulin-like growth factors I and II and of growth hormone in hypophysectomized rats.

Pure human IGF I (43 and 103 micrograms/day) and IGF II (131 micrograms/day) were infused into hypophysectomized rats during 6 days by means of sc implanted minipumps. Their effects on several growth indices were compared with those of various doses of sc infused human growth hormone. Growth hormone infusion produced a dose-dependent rise of endogenous rat IGF from 39 (without growth hormone) to 86 microU equivalents/ml (with 400 mU hGH/day) as determined by a competitive protein binding assay with a human IGF standard. In rats receiving the two doses of IGF I, total serum IGF levels rose to 83 and 99 microU equivalents/ml, respectively, in those receiving the IGF II dose the total serum IGF level rose to 146 microU equivalents/ml. These increases corresponded to steady state levels of 168 and 286 ng/ml of immunoreactive insulin-like growth factor (IR-IGF) I and 320 ng/ml of IR-IGF II. IGF I, but not IGF II led to an increase in body weight similar to that induced by the low doses of hGH (12.5 and 25 mU, respectively). The rise of endogenous rat IGF as well as the infused human IGF I and II caused a widening of the tibial epiphysis and an increase of the [3H]thymidine incorporation into costal cartilage. With respect to these two indices IGF II was clearly less potent that IGF I. When expressed in microU equivalents of the protein binding assay, endogenous rat IGF induced by hGH appeared to be relatively more effective than infused human IGF I or II.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Effects of insulin-like growth factors on chick embryo hepatocytes.

Biological effects of insulin-like growth factors (IGF) I and II on primary cultures of chick embryo liver cells have been investigated and compared 1) with the biological effect of insulin and 2) with competitive binding of the three hormones to their respective binding sites. IGF I and II stimulate the incorporation of D[U-14C]-glucose into liver cell glycogen in a time- and dose-dependent manner, but with a 5-10-fold lower potency than insulin. Both IGFs also lead to enhanced incorporation of 5-[3H]uridine and L[U-14C]valine into trichloroacetic acid (TCA) insoluble material and to activation of ornithine decarboxylase activity. Their potency in stimulating RNA synthesis and ornithine decarboxylase activity is comparable to that of insulin. Protein synthesis is maximally stimulated at 3 nM by all three hormones. In the competitive binding studies, IGF I and II are 10-fold less potent than insulin in competing for [125I]insulin binding, but 100-fold more potent than insulin in competing for [125I]IGF I or II binding. These studies show that IGF I and II stimulate the same metabolic indices as insulin in the chick embryo liver. By comparing these biological effects with competitive binding data it appears that IGFs act on glucose metabolism in the chick embryo liver via the insulin receptor, whereas stimulation of growth indices by IGFs and insulin appears to be mediated by their own specific receptors.

Animals↗
PubMed1985

Serum thymidine activity and insulin-like growth factors in the neonatal period.

Growth-promoting activity measured as [3H] thymidine incorporation into lectin-activated lymphocytes was determined simultaneously with radioimmunoassayable IGF I and IGF II in cord and capillary blood collected from human neonates 30 min and 24 h after birth. All the parameters studied in cord blood were lower than in normal adults. During the early postnatal period, IGF I decreased and IGF II remained unchanged, but thymidine activity increased above the normal adult level. The differences between the values found in cord blood and in capillary blood collected within the first 1/2 h after birth agree with a production of growth factors by the infant. All these growth factors may play a role in foetal growth, as suggested by their correlation with birth weight. Finally, factors other than IGFs contributing to thymidine activity may play a role in neonatal growth since they are higher in newborns than in adults.

Age Factors↗
PubMed1985

Insulin-like growth factors (IGF) 1 and 2 in human foetal plasma and relationship to gestational age and foetal size during midpregnancy.

IGF-1 and IGF-2 were measured by specific radioimmunoassay after acid-ethanol extraction of plasma obtained by foetoscopy from 20 normal foetuses aged 15-23 weeks. IGF-1 and IGF-2 levels were 36 +/- 11 and 162 +/- 55 ng/ml, respectively. In comparison, levels in cord blood were 84 +/- 58 and 264 +/- 176 ng/ml, respectively, and in adult plasma were 410 +/- 106 and 818 +/- 272 ng/ml. Both IGF-1 and IGF-2 were in the normal foetal range in a further three foetuses with anencephaly and two foetuses with spina bifida. No sex difference was observed. IGF-1 was positively correlated with foetal body weight (P less than 0.001), placenta weight (P less than 0.02) and with body length measured crown-rump (P less than 0.01) or crown-heel (P less than 0.02). No correlation between IGF-2 and body weight, length, placenta weight or gestational age was found. Both IGF-1 and IGF-2 are present in the human foetal circulation earlier in gestation than has previously been demonstrated, the levels being low throughout this period of gestation in comparison with adult plasma.

Abortion, Induced↗