Uridylate-trapping sugar analogs in combination with inhibitors of uridylate synthesis de novo and 5-fluorouridine

Keppler, Dietrich; Fauler, Joachim; Gasser, Thomas; Holstege, Axel; Leube, Karen; Schulz-Holstege, Christa; Weckbecker, Gisbert

doi:10.1016/0065-2571(85)90040-8

Cited by 13 publications

(3 citation statements)

References 21 publications

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“…The metabolic effects of D-galactose analogues have been found to be most pronounced in hepatocytes and hepatoma cells, since the enzymes of the D-galactose pathway exhibit high activities in these cells (Cuatrecasas & Segal, 1965;Bauer et al, 1980). Major metabolic effects include an accumulation of UDP-hexose analogues (De Robichon Szulmajster, 1961;Maley et al, 1968;Keppler et al, 1970Keppler et al, , 1974Keppler et al, , 1982Smith & Keppler, 1977;Starling & Keppler, 1977;Ishiwata et al, 1988;Kanazawa et al, 1988;Grun et al, 1990) and consequently a depletion of the hepatic UTP pool (Keppler et al, 1974(Keppler et al, , 1985Grun et al, 1990). In addition to these effects, inhibition of protein N-glycosylation has been found in the presence of the D-galactose analogue Dgalactosamine (Gross et al, 1990a).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of protein N-glycosylation by 2-deoxy-2-fluoro-d-galactose

Groß

Hull

Berger

et al. 1992

Biochemical Journal

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The effects of 2-deoxy-2-fluoro-D-galactose (dGalF) on N- and O-glycosylation of proteins was studied in rat hepatocyte primary cultures and in human monocytes. In hepatocytes, dGalF at concentrations of 1 mM or higher completely inhibited N-glycosylation of alpha 1-antitrypsin and alpha 1-acid glycoprotein, whereas 4 mM-2-deoxy-D-galactose (dGal) only slightly impaired N-glycosylation. In monocytes, 1 mM- or 4 mM-dGalF blocked N-glycosylation of alpha 1-antitrypsin and of interleukin-6, while O-glycosylation of interleukin-6 remained unaffected. In monocytes, dGal had no effect on protein N-glycosylation. Addition of uridine effectively prevented the UTP deficiency induced by dGalF, but had no effect on the inhibition of protein N-glycosylation by dGalF. Using 19F-n.m.r. spectroscopy, 2-deoxy-2-fluoro-D-galactose 1-phosphate (dGalF-1-P), UDP-dGalF and UDP-dGlcF could be identified as the major metabolites of dGalF in hepatocytes as well as in monocytes. In conclusion, compared with dGal, dGalF is a more efficient inhibitor of protein N-glycosylation. The effect is not caused by the depletion of UTP induced by dGalF, but rather by metabolites of dGalF. dGalF is metabolized not only in hepatocytes but also in peripheral blood monocytes, which can be used for ex vivo studies of disturbances in D-galactose metabolism.

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Section: Discussionmentioning

confidence: 99%

Inhibition of protein N-glycosylation by 2-deoxy-2-fluoro-d-galactose

Groß

Hull

Berger

et al. 1992

Biochemical Journal

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“…It has been reported that D-glucosone is metabolized to UDP-glucosone in cultures of TA3 mammary tumor cells [4]. More definitive experiments about the metabolic pathway of D-glucosone will be needed to clarify the mechanism of the biological action of D-glucosone as an analogue of D-glucose.…”

Section: Discussionmentioning

confidence: 99%

Biochemical Response to D-Glucosone in Terms of Motility of the Stomach, Insulin Secretion, and Sweetness

Taguchi

Miwa

Okuda

1988

J. Clin. Biochem. Nutr.

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D-Glucosone (D-arabino-hexos-2-ulose) was prepared by use of an immobilized glucose 2-oxidase-catalase gel, and the biochemical response to D-glucosone by three kinds of glucose-recognizing systems in higher animals was studied. The enhanced motility of rat stomach caused by glucopenia was reduced by carotid arterial injection of D-glucosone like in the case of D-glucose. D-Glucosone (16.7 mM) showed no effect on the secretion of insulin from the pancreatic islets of the rat, and the secretion of insulin caused by D-glucose (16.7 mM) was markedly depressed by the addition of D-glucosone (16.7 mM). The relative sweetness of D-glucosone, compared with that of 5 % sucrose as 1.0, was estimated to be 0.4-0.6, which is similar to that of D-glucose. These results suggest that D-glucosone is a useful model compound for D-glucose to investigate the biochemical mechanism of glucose-recognizing systems.

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“…Thus, while 2-DGal will inhibit glycolysis in tumors it will also have the added function of inhibiting protein glycosylation. And, phosphorylation of 2-DGal will deprive the tumor cell of part of its phosphate pool as well [25, 26]. …”

Section: Tumor Glycolysis As a Therapeutic Strategymentioning

confidence: 99%

Metabolic Targeting of Malignant Tumors: Small-Molecule Inhibitors of Bioenergetic Flux

Mathupala¹

2011

PRA

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Metabolism in tumors deviates significantly from that of normal tissues. Increasingly, the underlying aberrant metabolic pathways are being considered as novel targets for cancer therapy. Denoted “metabolic targeting”, small molecule drugs are under investigation for focused inhibition of key metabolic steps that are utilized by tumors, since such inhibitors should harbor minimal toxicity towards surrounding normal tissues.This review will examine the primary biochemical pathways that tumors harness to enhance their bioenergetic capacity, which in turn, help their rapid proliferation and metastasis within the host. It is hoped that “metabolite-mimetic” drugs can be utilized to interfere with metabolic flux pathways active within the tumor, and across tumor-microenvironment boundary. In fact, the major pathways of mammalian metabolism, i.e., the carbohydrate, amino-acid, and fatty-acid metabolic pathways have been examined as putative targets for drug development, with some drug candidates advancing to phase II/III stages. In this regard, glucose metabolism, i.e., the glycolytic pathway - that predominates the bio-energetic flux in tumors, and the associated mitochondrial metabolism have received the most attention as suitable “druggable” targets, focused either at the pathway enzymes or at the plasma-membrane-bound metabolite transporters. Outlined in this review are pre-clinical studies that have led to the discovery of promising drug candidates to target tumor-metabolic flux, and ensuing patents, with descriptions of the biochemical rationale for the combinatorial strategy of a particular metabolic pathway-drug candidate pair.

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Uridylate-trapping sugar analogs in combination with inhibitors of uridylate synthesis de novo and 5-fluorouridine

Cited by 13 publications

References 21 publications

Inhibition of protein N-glycosylation by 2-deoxy-2-fluoro-d-galactose

Inhibition of protein N-glycosylation by 2-deoxy-2-fluoro-d-galactose

Biochemical Response to D-Glucosone in Terms of Motility of the Stomach, Insulin Secretion, and Sweetness

Metabolic Targeting of Malignant Tumors: Small-Molecule Inhibitors of Bioenergetic Flux

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