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Biomedical subjects

K Grankvist

Publications and source records attributed to K Grankvist.

At least 91 records · Page 5Linked to original sources
PubMed1988

Protective effect of iron chelators on epirubicin-induced fibroblast toxicity.

Free oxygen radicals generated by anthracycline/iron complexes have been implicated in anthracycline cytotoxicity. We therefore tested whether enzymatic scavengers of free radicals or metal chelators were able to inhibit anthracycline toxicity. The survival of Chinese hamster fibroblasts was reduced when the cells were exposed to 0.1-1.0 mg/l 4'-epidoxorubicin (epirubicin). Superoxide dismutase (SOD) (250 mg/l), or catalase (250 mg/l) did not affect the clonogenic survival of the fibroblasts. The metal-chelators, diethylenetriamine-pentaacetic acid (DTPA) (100 mumol/l), EDTA (100 mumol/l), and desferrioxamine (100 mumol/l) all protected against epirubicin-induced clonogenic survival. The protection of chelators against epirubicin toxicity implies that chelators might also be able to modulate anthracycline toxicity in vivo.

Animals↗
PubMed1988

Glycoprotein tumour markers in head and neck neoplasms--a consecutive study on CA-50, CA 19-9, and CEA.

Serum levels of three glycoprotein tumour antigens (carcino-embryonic antigen, CEA; cancer-associated antigen 50, CA-50; gastrointestinal cancer-associated antigen, CA 19-9) were determined on 125 consecutive patients with tumours of the head and neck region. Elevated CEA values (greater than 5 units/ml) were found in 13/70 squamous cell carcinomas, 3/21 benign and 4/18 malignant salivary gland neoplasms. Elevated CA-50 values (greater than 17 units/ml) were found in 19/70 squamous cell carcinomas, 6/18 malignant and 1/21 benign salivary neoplasms. CA 19-9 displayed higher values (greater than 37 units/ml) in 9/68 squamous cell carcinomas, 4/18 malignant and none of 21 benign salivary gland tumours. Combination of CEA and CA-50 analyses increased the proportion of elevated values to 30/70 in squamous cell carcinomas and 10/18 in salivary gland malignancies. In squamous cell carcinomas no correlation between staging or grading and serum levels was detected for any of the markers. Among malignant salivary gland tumours, CA-50 displayed enhanced serum values in 4/6 mucoepidermoid carcinomas. The mean values for CA-50 and CA 19-9 serum levels were significantly higher for malignant salivary gland neoplasms compared to benign tumours. There was a close correlation between CA-50 and CA 19-9 serum levels. Although, the results suggest that at present none of the tumour markers tested have a place alone in the routine examination of patients with tumours affecting the head and neck region, further studies on salivary gland neoplasms and combinations of the tumour markers are justified.

Antigens, Neoplasm↗
PubMed1988

Estramustine binding protein and anti-proliferative effect of estramustine in human glioma cell lines.

Four human cell lines derived from malignant gliomas were immunohistochemically examined for their content of estramustine-binding protein (EMBP). EMBP was detected in a large amount in all glioma cells during the entire cell cycle. EMBP has previously been demonstrated to be the major receptor protein in prostatic cancers for the cytostatic drug estramustine-phosphate (EMP). EMP caused a dose-dependent inhibition of exponentially growing cells by increasing the number of cells in G2/M stage of the cell cycle as monitored by flow cytofluorometry. The effect may be coupled to arrest of the glioma cells at metaphase. The presence of EMBP may suggest a selective binding and effect of EMP in glioma cells.

Carrier Proteins↗
PubMed1988

No effect of superoxide dismutase on spontaneous development of diabetes in db/db mice.

B-cells have previously been shown to be very susceptible to damage induced by superoxide radicals, and protection against such damage has been achieved both in vitro and in vivo with superoxide dismutase. During maturation, db/db mice develop diabetes and accumulation of potentially superoxide radical-producing leucocytes can be demonstrated in the islets during the process. To test for the possibility that superoxide radical-induced damage contributes to the development of diabetes, db/db mice were given daily ip injections of 200 mg/kg polyethylene glycol-substituted CuZn superoxide dismutase. No effect of the treatment could be demonstrated.

Animals↗
PubMed1987

Doxorubicin and epirubicin iron-induced generation of free radicals in vitro. A comparative study.

To ascertain any differences in myocardial injury exerted by the anthracyclines doxorubicin and epirubicin, their ability to generate oxygen free radicals when mixed with Fe(II) was examined in vitro using an oxygen electrode. 5-250 micrograms/ml doxorubicin or epirubicin consumed oxygen when mixed with 50 or 100 mumol/l Fe(II). Addition of 75 mumol/l cytochrome C showed that of the consumed oxygen, approximately 80% entered the monovalent pathway of oxygen reduction. The strong inhibitory effect of 250 mg/l catalase indicates that most of the superoxide radicals generated are further reduced to hydrogen peroxide by both anthracyclines. Addition of metal chelators DTPA (100 mumol/l), or DDTC (50 mumol/l) did not affect oxygen consumption, whereas EDTA (100 mumol/l) or desferrioxamine (100 mumol/l) with anthracyclines and Fe(II) rather stimulated oxygen consumption. It is concluded that there are no significant differences in the amount or proportion of generated oxygen free radicals between doxorubicin and epirubicin when mixed with Fe(II) in a cell-free system in vitro. Thus, the ability of the anthracyclines, in conjunction with iron alone, to generate radicals does not explain the differences of the drugs in causing myocardial injury.

Doxorubicin↗
PubMed1987

Misleading T3-test values in psychiatric patients treated with orphenadrine.

Thyroid laboratory tests were assessed in 74 psychiatric patients without clinical evidence of overt thyroid disorder. In a first screening of 42 patients, 13 were found to have elevated levels of triiodothyronine uptake test (T3-test) by a Sephadex method. Ten of these patients also had an elevated free thyroxine index (fT4-index). Of the 13 patients with increased T3-test values, 10 were on orphenadrine (Disipal) treatment or had recently stopped taking the drug. In a second study, thyroid function tests were compared in 15 pairs of matched psychiatric patients treated with orphenadrine or other anticholinergic drugs. Values of T3-test and free thyroxine index were significantly higher among patients treated with orphenadrine. Finally, orphenadrine was instituted in four patients and withdrawn in six patients. T3-test values and free thyroxine indices increased gradually after orphenadrine treatment had been initiated and decreased gradually when it was withdrawn.

Adult↗
PubMed1986

Effect of extracellularly generated free radicals on the plasma membrane permeability of isolated pancreatic B-cells.

Previous experiments on alloxan diabetogenicity suggest that alloxan increases the permeability of B-cell plasma membranes by generation of noxious free radicals. Whether the radicals are generated intra- or extracellularly has however been disputed. To test if extracellularly generated free radicals could decrease trypan blue exclusion of dispersed islet cells, a radical-generating solution of xanthine oxidase/hypoxanthine was employed. The solution increased dye uptake by cells in the cell suspension. Superoxide dismutase and catalase but not scavengers of hydroxyl radicals protected against the increase in dye uptake. Both L- and D-glucose protected the cells from injury. It is concluded that extracellularly generated free radicals induce damage to the plasma membrane of islet cells. The result strengthens the hypothesis of plasma membrane damage by extracellularly generated free radicals as the primary event in alloxan diabetogenicity and may provide a link for explanation of damage caused by islet inflammation in juvenile diabetes.

Animals↗
PubMed1986

Rubidium uptake by mouse pancreatic islets exposed to 6-hydroxydopamine, ninhydrin, or other generators of hydroxyl radicals.

The purpose was to study the toxicity of drugs known to generate free radicals on isolated pancreatic islets. The accumulation of 86Rb+ by mouse pancreatic islets was measured in vitro. Exposing the islets to 6-hydroxydopamine, ninhydrin, or phenazine methosulphate+NADH inhibited the Rb+ uptake, whereas paraquat or acetylphenylhydrazine had no effect. This effect of 6-hydroxydopamine was prevented by either of the hydroxyl radical scavengers, sodium benzoate and mannitol, but not by the non-scavenger, urea; ninhydrin was partially protected against by mannitol but not by benzoate. Protection against 6-hydroxydopamine was also afforded by D-glucose but not by L-glucose or 3-O-methyl-D-glucose; none of the sugars protected against ninhydrin. In damaging islet beta-cells and in being protected against by D-glucose, 6-hydroxydopamine closely resembles the diabetogenic drug, alloxan. It is suggested that protection against alloxan may involve both glucose metabolism and the interaction of glucose with its membrane-located carrier, while protection against 6-hydroxydopamine appears to be unrelated to the hexose carrier mechanism.

Animals↗
PubMed1986

Testosterone, SHBG and albumin in patients with ovarian carcinoma.

Plasma testosterone, unbound testosterone, Sex Hormone Binding Globulin (SHBG) and albumin were studied in women with 'non-endocrine' ovarian carcinoma prior to and during chemotherapy. Fifty-one postmenopausal or oophorectomized women with cancer of the ovary were studied. The histologic types were IC, IIC, IIIC, V and FIGO stages I-IV. Tumor volumes were evaluated once a month using bimanual recto-vaginal palpation under anesthesia. Blood samples were drawn for testosterone radio-immunoassay, SHBG and albumin analysis on four occasions at monthly intervals. Plasma levels were compared with a control group of postmenopausal women, a control group of fertile women in the follicular phase of the menstrual cycle, and finally a control group of postmenopausal women with non-gynecologic disseminated malignant disease. Testosterone concentrations were found to be higher in women with carcinoma of the ovary than in postmenopausal controls and showed a relationship to tumor volume. Histologic type and FIGO stage were found to be less closely related to plasma testosterone concentration. No significant change was found in the unbound testosterone fraction. SHBG concentrations were elevated in the Large-tumor group. Albumin concentrations were decreased in the Large-tumor group, advanced tumor stage group and in the control group with non-gynecologic disseminated malignant disease.

Adult↗
PubMed1986

Diethyldithiocarbamate, but not disulfiram, inhibits alloxan-induced dye accumulation of isolated mouse islet beta-cells.

The diabetogenic action of alloxan on pancreatic beta-cells is thought to be mediated by hydroxyl radicals. The initial attack of the radicals is probably at the plasma membrane level. Diethyldithiocarbamate (DDTC) and its dimer disulfiram (Antabuse) have recently been shown to protect against damage by free radical generating agents. The ability of DDTC and disulfiram to inhibit alloxan-induced dye accumulation of isolated ob/ob mice islet beta-cells was therefore studied. Evans blue was used as an indicator of plasma membrane permeability. DDTC (100 microM 1 mM) but not disulfiram (100 microM 1 mM) inhibited alloxan-induced dye uptake of beta-cells. The effect of DDTC on oxygen consumption in a mixture of reduced glutathione (GSH), alloxan and FeSO4 was studied with a Clark-type oxygen electrode. DDTC (20, 100 microM) had no effect on the oxygen consumption of this mixture. It is suggested that the DDTC inhibition of alloxan-induced dye uptake of isolated beta-cells takes place at a step beyond the generation of free radicals.

Alloxan↗
PubMed1985

In vivo fluorescence microscopy of blood flow in mouse pancreatic islets: adrenergic effects in lean and obese-hyperglycemic mice.

The microcirculation in the islets of Langerhans was examined by fluorescence microscopy in living mice injected with fluorescent dextran. The islet capillary network was denser and more tortuously arranged in obese-hyperglycemic (ob/ob) mice than in lean controls. Injection of norepinephrine (0.5-4.0 micrograms/kg body wt) immediately led to a pronounced inhibition of islet blood flow in ob/ob mice. In experiments with lean mice less striking effects were seen. With as high a dose as 20 micrograms norepinephrine/kg body wt only a slight retardation and very brief stop of the flow occurred. The inhibition in ob/ob mice was blocked by phentolamine, indicating that the norepinephrine-induced inhibition was mediated by alpha-adrenoceptors. The alpha-2-adrenoceptor agonist, clonidine, had no effect on islet blood flow, suggesting that the effect of norepinephrine was due to alpha-1-adrenoceptor stimulation. It is concluded that in the living animal norepinephrine inhibits insulin secretion from the pancreas by a twofold mechanism involving inhibition of exocytosis (alpha-2-receptors on the beta-cells) as well as retardation of blood flow (alpha-1-receptors on blood vessels).

Animals↗
PubMed1984

Ultrastructure and membrane permeability of cultured pancreatic beta-cells exposed to alloxan or 6-hydroxydopamine.

Stereological techniques on electron microscopy micrographs were used to evaluate the morphological changes of cultured islet beta cells that had been exposed to alloxan or 6-hydroxydopamine. Trypan Blue exclusion by cells cultured for 3 days indicated that the cells were 100% viable. Electron microscopy revealed that nearly all of the surviving cultured cells were beta cells. Exposure to 5 mmol/l alloxan or 1-5 mmol/l 6-hydroxydopamine for 10 or 30 min caused a general swelling of the cultured cells with a concomitant swelling of mitochondria and nuclei. The size of the secretory granules was not affected by the drugs. Only 3-10% of the cells excluded Trypan Blue after exposure to 5 mmol/l alloxan or 6-hydroxydopamine. The data conform with the hypothesis that a primary action of alloxan and 6-hydroxydopamine is at the plasma membrane level of beta cells.

Alloxan↗
PubMed1984

Partial protection against streptozotocin-induced hyperglycaemia by superoxide dismutase linked to polyethylene glycol.

To test the possible role of superoxide radicals in the diabetogenic action of streptozotocin, blood glucose levels were measured in mice after a single high-dose (150 mg/kg body weight) or multiple low-dose (40 mg/kg for 5 days) injections of streptozotocin. Pretreatment 6 h before streptozotocin with 250-300 mg/kg superoxide dismutase coupled to polyethylene glycol reduced the hyperglycaemic response in mice injected with a single dose of streptozotocin. The blood glucose levels after multiple low doses of streptozotocin were not affected by superoxide dismutase-polyethylene glycol. Enzymatically inactive superoxide dismutase did not affect the development of hyperglycaemia. The results suggest that superoxide radicals may play a role in the diabetogenic action of streptozotocin injected as a high-dose single bolus.

Animals↗
PubMed1983

Opposite effects of two metal-chelators on alloxan-induced diabetes in mice.

Alloxan diabetes may be mediated by an iron-catalyzed formation of hydroxyl radicals. The iron chelators desferrioxamine and diethylenetriaminepentacetic acid (DETAPAC) which inhibit hydroxyl radical formation in vitro were tested against alloxan diabetes in mice. DETAPAC inhibited while desferrioxamine stimulated the hyperglycemic response to alloxan. The diverging treatment results are discussed.

Alloxan↗
PubMed1981

Alloxan-induced luminol luminescence as a tool for investigating mechanisms of radical-mediated diabetogenicity.

Chemiluminescence of luminol in a cell-free system was used to investigate the mechanism of alloxan-dependent free-radical generation. In the presence of alloxan and reduced glutathione (GSH), luminescence was greatly stimulated by FeSO4. Replacing GSH by oxidized glutathione or NAD(P)(H), or replacing FeSO4 by CuSO4, ZNSO4 or FeCl3, did not yield chemiluminescence. The chemiluminescence of a mixture of alloxan. GSH, FeSO4 and luminol was inhibited by catalase, superoxide dismutase, scavengers of hydroxyl radicals (sodium benzoate, n-butanol, D-mannitol, dimethyl sulphoxide) or metal-ion chelators (EDTA, diethylenetriaminepenta-acetic acid, diethyldithiocarbamate. desferroxamine), D-glucose, L-glucose, D-mannose, D-fructose, 3-O-methyl-D-glucose, NAD+, NADH, NADP+ or NADPH, but not by urea or enzymically inactive superoxide dismutase. The results support the hypothesis that the diabetogenic action of alloxan is mediated by hydroxyl radicals generated in an iron-catalysed reaction. Protection against alloxan in vivo depends both on the chemical reactivity of protector with radicals or radical-generating systems and on the stereospecific requirement of some strategic site in the B-cell.

Alloxan↗
PubMed1981

CuZn-superoxide dismutase, Mn-superoxide dismutase, catalase and glutathione peroxidase in pancreatic islets and other tissues in the mouse.

Exogenous superoxide dismutase, catalase and scavengers of the hydroxyl radical protect pancreatic-islet cells against the toxic actions of alloxan in vitro [Grankvist et al. (1979) Biochem. J. 182, 17--25]. To test whether the extraordinary sensitivity of islet cells to alloxan is due to a deficiency of endogenous enzymes protecting against oxygen-reduction products, we assayed CuZn-superoxide dismutase, Mn-superoxide dismutase, catalase and glutathione peroxidase in mouse islets and other tissues. To correct for any blood contamination, haemoglobin was also measured in the tissue samples. Pancreatic islets were found to belong to tissues with relatively little activity of the protective enzymes. However, the deviation from other tissues in this respect is probably not large enough to explain the especially great susceptibility of islet cells to alloxan.

Alloxan↗