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Sökning: onr:"swepub:oai:lup.lub.lu.se:500b45b2-547d-4ecf-9be6-f85e12eec7de" > Tumor attenuation b...

Tumor attenuation by combined heparan sulfate and polyamine depletion.

Belting, Mattias, (författare)
Forskargrupper vid Lunds universitet, Lund University Research Groups, Lunds universitet, Lund University, Medicinska fakulteten, Faculty of Medicine, Institutionen för kliniska vetenskaper, Lund, Department of Clinical Sciences, Lund, Tumörmikromiljö, Tumor microenvironment, Tumörmikromiljön, Tumor microenvironment, Sektion I, Section I
Borsig, Lubor (författare)
Fuster, Mark M (författare)
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Brown, Jillian R (författare)
Persson, Lo, (författare)
Lunds universitet, Lund University, Medicinska fakulteten, Faculty of Medicine, Institutionen för experimentell medicinsk vetenskap, Department of Experimental Medical Science
Fransson, Lars-Åke, (författare)
Lunds universitet, Lund University, Medicinska fakulteten, Faculty of Medicine, Institutionen för experimentell medicinsk vetenskap, Department of Experimental Medical Science
Esko, Jeffrey D (författare)
visa färre...
2002
Engelska.
Ingår i: Proceedings of the National Academy of Sciences. - National Acad Sciences. - 1091-6490. ; 99:1, s. 371-376
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Abstract Ämnesord
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  • Cells depend on polyamines for growth and their depletion represents a strategy for the treatment of cancer. Polyamines assemble de novo through a pathway sensitive to the inhibitor, alpha-difluoromethylornithine (DFMO). However, the presence of cell-surface heparan sulfate proteoglycans may provide a salvage pathway for uptake of circulating polyamines, thereby sparing cells from the cytostatic effect of DFMO. Here we show that genetic or pharmacologic manipulation of proteoglycan synthesis in the presence of DFMO inhibits cell proliferation in vitro and in vivo. In cell culture, mutant cells lacking heparan sulfate were more sensitive to the growth inhibitory effects of DFMO than wild-type cells or mutant cells transfected with the cDNA for the missing biosynthetic enzyme. Moreover, extracellular polyamines did not restore growth of mutant cells, but completely reversed the inhibitory effect of DFMO in wild-type cells. In a mouse model of experimental metastasis, DFMO provided in the water supply also dramatically diminished seeding and growth of tumor foci in the lungs by heparan sulfate-deficient mutant cells compared with the controls. Wild-type cells also formed tumors less efficiently in mice fed both DFMO and a xylose-based inhibitor of heparan sulfate proteoglycan assembly. The effect seemed to be specific for heparan sulfate, because a different xyloside known to affect only chondroitin sulfate did not inhibit tumor growth. Hence, combined inhibition of heparan sulfate assembly and polyamine synthesis may represent an additional strategy for cancer therapy.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)

Nyckelord

Neoplasm Metastasis
Models Genetic
Models Biological
Mice SCID
Mice
Heparitin Sulfate : pharmacology
Hamsters
Glucuronosyltransferase : biosynthesis
Female
Enzyme Inhibitors : pharmacology
Eflornithine : pharmacology
Dose-Response Relationship Drug
DNA Complementary : metabolism
CHO Cells
Animal
Antineoplastic Agents : pharmacology
Neoplasm Transplantation
Polyamines : metabolism
Proteoglycans : metabolism
Spermine : pharmacology
Support Non-U.S. Gov't
Support U.S. Gov't P.H.S.
Time Factors

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