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Immunotoxin targeting glypican-3 regresses liver cancer via dual inhibition of
Wnt signalling and protein synthesis
#MMPMID25758784
Gao W
; Tang Z
; Zhang YF
; Feng M
; Qian M
; Dimitrov DS
; Ho M
Nat Commun
2015[Mar]; 6
(?): 6536
PMID25758784
show ga
Glypican-3 is a cell surface glycoprotein that associates with Wnt in liver
cancer. We develop two antibodies targeting glypican-3, HN3 and YP7. The first
antibody recognizes a functional epitope and inhibits Wnt signalling, whereas the
second antibody recognizes a C-terminal epitope but does not inhibit Wnt
signalling. Both are fused to a fragment of Pseudomonas exotoxin A (PE38) to
create immunotoxins. Interestingly, the immunotoxin based on HN3 (HN3-PE38) has
superior antitumor activity as compared with YP7 (YP7-PE38) both in vitro and in
vivo. Intravenous administration of HN3-PE38 alone, or in combination with
chemotherapy, induces regression of Hep3B and HepG2 liver tumour xenografts in
mice. This study establishes glypican-3 as a promising candidate for
immunotoxin-based liver cancer therapy. Our results demonstrate
immunotoxin-induced tumour regression via dual mechanisms: inactivation of cancer
signalling via the antibody and inhibition of protein synthesis via the toxin.
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