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Single chain fragment anti-heparan sulfate antibody targets the polyamine transport system and attenuates polyamine-dependent cell proliferation.

Welch, Johanna E; Bengtson, Per LU ; Svensson, Katrin LU ; Wittrup, Anders LU ; Jenniskens, Guido J; Ten Dam, Gerdy B; Van Kuppevelt, Toin H and Belting, Mattias LU (2008) In International Journal of Oncology 32(4). p.749-756
Abstract
The growth-promoting polyamines are polybasic compounds that efficiently enter cancer cells by as yet incompletely defined mechanisms. Strategies to inhibit their internalization may have important implications in the management of tumor disease. Here, we show that cellular binding and uptake of polyamines are inhibited by a single chain variable fragment anti-heparan sulfate (HS) antibody. Polyamine uptake was inhibited in a dose-dependent manner, and was associated with compensatory up-regulation of ornithine decarboxylase (ODC), i.e. the key enzyme of the polyamine biosynthesis pathway. Conversely, depletion of intracellular polyamines by the specific ODC-inhibitor alpha-difluoromethylornithine (DFMO) resulted in increased cellular... (More)
The growth-promoting polyamines are polybasic compounds that efficiently enter cancer cells by as yet incompletely defined mechanisms. Strategies to inhibit their internalization may have important implications in the management of tumor disease. Here, we show that cellular binding and uptake of polyamines are inhibited by a single chain variable fragment anti-heparan sulfate (HS) antibody. Polyamine uptake was inhibited in a dose-dependent manner, and was associated with compensatory up-regulation of ornithine decarboxylase (ODC), i.e. the key enzyme of the polyamine biosynthesis pathway. Conversely, depletion of intracellular polyamines by the specific ODC-inhibitor alpha-difluoromethylornithine (DFMO) resulted in increased cellular binding of polyamine and anti-HS antibody. Importantly, anti-HS antibody also efficiently targeted DFMO-induced polyamine uptake, and combined polyamine biosynthesis inhibition by DFMO, and uptake inhibition by anti-HS antibody attenuated tumor cell proliferation in vitro. In conclusion, cell-surface HS proteoglycan is a relevant target for antibody-mediated inhibition of the uptake of polyamines, and polyamine-dependent cell proliferation. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
International Journal of Oncology
volume
32
issue
4
pages
749 - 756
publisher
D.A. Spandidos
external identifiers
  • PMID:18360702
  • WOS:000254357600003
  • Scopus:44449117559
ISSN
1019-6439
language
English
LU publication?
yes
id
69d1dd42-625a-45d5-8ca0-67e3405bd901 (old id 1052224)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/18360702?dopt=Abstract
date added to LUP
2008-04-03 08:16:10
date last changed
2017-01-01 07:45:32
@article{69d1dd42-625a-45d5-8ca0-67e3405bd901,
  abstract     = {The growth-promoting polyamines are polybasic compounds that efficiently enter cancer cells by as yet incompletely defined mechanisms. Strategies to inhibit their internalization may have important implications in the management of tumor disease. Here, we show that cellular binding and uptake of polyamines are inhibited by a single chain variable fragment anti-heparan sulfate (HS) antibody. Polyamine uptake was inhibited in a dose-dependent manner, and was associated with compensatory up-regulation of ornithine decarboxylase (ODC), i.e. the key enzyme of the polyamine biosynthesis pathway. Conversely, depletion of intracellular polyamines by the specific ODC-inhibitor alpha-difluoromethylornithine (DFMO) resulted in increased cellular binding of polyamine and anti-HS antibody. Importantly, anti-HS antibody also efficiently targeted DFMO-induced polyamine uptake, and combined polyamine biosynthesis inhibition by DFMO, and uptake inhibition by anti-HS antibody attenuated tumor cell proliferation in vitro. In conclusion, cell-surface HS proteoglycan is a relevant target for antibody-mediated inhibition of the uptake of polyamines, and polyamine-dependent cell proliferation.},
  author       = {Welch, Johanna E and Bengtson, Per and Svensson, Katrin and Wittrup, Anders and Jenniskens, Guido J and Ten Dam, Gerdy B and Van Kuppevelt, Toin H and Belting, Mattias},
  issn         = {1019-6439},
  language     = {eng},
  number       = {4},
  pages        = {749--756},
  publisher    = {D.A. Spandidos},
  series       = {International Journal of Oncology},
  title        = {Single chain fragment anti-heparan sulfate antibody targets the polyamine transport system and attenuates polyamine-dependent cell proliferation.},
  volume       = {32},
  year         = {2008},
}