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  • 1990-1994  (4)
  • 1960-1964
  • Dexniguldipine  (1)
  • Energy metabolism  (1)
  • N-acetyl-transferase  (1)
  • Pineal  (1)
Materialart
Erscheinungszeitraum
  • 1990-1994  (4)
  • 1960-1964
Jahr
Schlagwörter
  • 1
    ISSN: 1432-1335
    Schlagwort(e): Multidrug resistance ; Reversibility ; Cyclosporin A ; Verapamil ; Dexniguldipine
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Multidrug-resistant tumor cells can be resensitized by combined application of the selecting cytostatic drug and a chemosensitizer, such as cyclosporin A (CsA) or a calcium channel blocker. Since clinical trials on the circumvention of multidrug resistance (MDR) with chemosensitizers report disparate results, we investigated whether tumor cells of the MDR phenotype can develop additional resistance to the cytostatic chemosensitizer combination. Thus, the Adriamycin(ADR)-selected, P-glycoprotein-positive MDR Friend leukemia cell line F4-6RADR was exposed to stepwise increased concentrations of CsA at a constant level of 0.05 μg/ml ADR. The initial CsA concentration (plus 0.05 μg/ml ADR) to inhibit cell growth of F4-6RADR cells by 50% (IC50) was 0.04 μg/ml. By continuous incubation for more than 6 months, the IC50 for CsA (at constant ADR) was elevated to 3.6 μg/ml (90-fold), thus generating the variant F4-6RADR-CsA. The F4-6RADR-CsA cells were cross-resistant for cyclosporin H (CsH), a non-immunosuppressive derivative of CsA. As shown by immunocytochemistry as well as by the polymerase chain reaction and by Western blotting including densitometry, P-glycoprotein was preserved in the F4-6RADR-CsA variant and was expressed at a 4-fold higher level than in F4-6RADR cells. Sodium dodecyl sulfate/polyacrylamide gel electrophoresis analysis could detect no new proteins in F4-6RADR-CsA as compared to F4-6RADR. Interestingly, resistance of F4-6RADR-CsA cells remained reversible for the calcium antagonists verapamil and dihydropyridine B859-35 (dexniguldipine-HCl), indicating that CsA and these compounds interfere with the P glycoprotein function by different pharmacodynamic mechanisms. Transport studies with [14C]ADR, performed in the presence and absence of chemosensitizers, confirmed the good correlation of P-glycoprotein function with the pattern of resistance found in proliferation assays. Cellular accumulation of [3H]cyclosporin was reduced to 71% of that of the F4-6 controls in F4-6RADR-CsA cells, but remained at the level of controls in F4-6RADR cells. Results indicate that increased amounts of the P-glycoprotein — besides other, perhaps more important mechanisms that are as yet unknown — partially mediate CsA resistance in F4-6RADR-CsA cells. We have designated this new form of resistance “secondary combined resistance” (SCR). The results suggest that at least some clinical cases of insensitivity to chemosensitizers or of relapse after reversing therapy could be explained by SCR, and that resensitizing treatment of tumor patients should be based on the consideration of several chemosensitizers of different pharmacodynamics.
    Materialart: Digitale Medien
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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  • 2
    ISSN: 1432-0878
    Schlagwort(e): Pineal gland ; Synaptic ribbons ; N-acetyl-transferase ; Melatonin ; Serotonin ; Protein synthesis ; Rat (Sprague-Dawley)
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Biologie , Medizin
    Notizen: Summary To elucidate the role of protein synthesis in the nocturnal increase of synaptic ribbons in the rat pineal gland, actinomycin-D, which inhibits transcription, and cycloheximide, an inhibitor of translation, were used. To assure that the drugs were effective and to relate morphological changes to pineal biosynthetic phenomena, the activity of N-acetyltransferase and levels of pineal indoleamine were measured. Results of in-vivo, short-term and long-term treatment with either drug suggest that transcription of proteins related to synaptic ribbon formation occurs during the first half of the light phase, whereas translation takes place during the first few hours of the dark phase. In contrast, proteins involved in enhanced melatonin synthesis are transcribed and translated during the first few hours of the dark phase. In vitro, preincubation with inhibitors of protein synthesis abolished the increase in the numbers of synaptic ribbons after stimulation with dibutyryl-adenosinecyclic-monophosphate, indicating that the results of the in-vivo experiments are due to an interaction of the drugs with the pineal gland itself. The present study shows that, although in the rat pineal enhanced melatonin synthesis and increased numbers of synaptic ribbons occur at the same time, transcription of proteins involved in both rhythms is temporally separated.
    Materialart: Digitale Medien
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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  • 3
    ISSN: 1439-6327
    Schlagwort(e): Training ; Overtraining ; Catecholamines ; Lipids ; Energy metabolism
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary The influence of an increase in training volume (ITV; February 1989) vs intensity (ITI; February 1990) on performance, catecholamines, energy metabolism and serum lipids was examined in two studies on eight, and nine experienced middle- or long-distance runners; seven participated in both studies. During ITV, mean training volume was doubled from 85.9 km · week−1 (pretrial phase) to 174.6 km within 3 weeks. Some 96%–98% of the training was performed at 67 (SD 8)% of maximal performance. During ITI, speed-endurance, high-speed and interval runs increased within 3 weeks from 9 km · week−1 (pretrial phase) to 22.7 km · week−1 and the total training distance from 61.6 to 84.7 km · week−1. The ITV resulted in stagnation of running velocity at 4 mmol lactate concentration and a decrease in total running distance in the increment test. Heart rate, energy metabolic parameters, nocturnal urinary catecholamine excretion, low density, very low density lipoprotein-cholesterol and triglyceride concentrations decreased significantly; the exercise-related catecholamine plasma concentrations increased at an identical exercise intensity. The ITI produced an improvement in running velocity at 4 mmol lactate concentration and in total running distance in the increment test; heart rate, energy metabolic parameters, nocturnal catecholamine excretion, and serum lipids remained nearly constant, and the exercise-related plasma catecholamine concentrations decreased at an identical exercise intensity. The ITV-related changes in metabolism and catecholamines may have indicated an exhaustion syndrome in the majority of the athletes examined but this hypothesis has to be proven by future experimental studies.
    Materialart: Digitale Medien
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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  • 4
    ISSN: 1435-1463
    Schlagwort(e): Pineal ; synaptic ribbons ; serotonin N-acetyltransferase ; neurotransmitters
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary The pineal contains a large number of classical transmitters and neuropeptides. Some of these neurochemicals are involved in the regulation of serotonin N-acetyltransferase (NAT) activity and hence in melatonin synthesis. Synaptic ribbons present in the pineal gland also exhibit a numerical day/night rhythm parallel to that of NAT activity. There is scarcity of information regarding the regulation of synaptic ribbon (SR) numbers. In the present study, we have investigated in vitro effects of a number of classical neurotransmitters and neuropeptides. NAT activity was used to monitor melatonin synthesis under the experimental conditions used. Norepinephrine (NE), Delta sleep-inducing peptide (DSIP), vasoactive intestinal polypeptide (VIP), adenosine and N-acetylasp-glu (NAAG) significantly increased NAT activity in rat pineal. DSIP and VIP also increase the stimulatory effect of NE on NAT activity. These neurochemicals had no effect on SR numbers. Gamma aminobutyric acid (GABA), serotonin and taurine affected neither NAT activity nor SR. Somatostatin increased SR numbers significantly, without having any effect on NAT activity. The effect of somatostatin is regarded to be pharmacologic, since rather high dosages (10−4 M) were required to obtain a significant effect. Although somatostatin is present in the pineal and may change rhythmically, the inconsistency of the day/night rhythmicity and the lack of such a rhythm in female rats and male gerbils speaks against an important physiological role of somatostatin in regulating SR numbers.
    Materialart: Digitale Medien
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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