RRC ID 18907
Author Zhang DX, Zhao PT, Xia L, Liu LL, Liang J, Zhai HH, Zhang HB, Guo XG, Wu KC, Xu YM, Jia LT, Yang AG, Chen SY, Fan DM.
Title Potent inhibition of human gastric cancer by HER2-directed induction of apoptosis with anti-HER2 antibody and caspase-3 fusion protein.
Journal Gut
Abstract BACKGROUND AND AIMS:HER2, an oncogene, has been found to be over-expressed in 10-40% of human gastric carcinomas. The aims of this study were to investigate if a fusion protein consisting of anti-HER2 sFv and constitutively active caspase-3 was capable of inducing apoptosis in HER2-expressing human gastric cancer cells and blocking the growth of human gastric cancer xenografts in nude mice.
METHODS:NIH3T3 cells stably transduced with the pcDNA3.1-HER-PE-CP3 recombinant plasmid containing a secretion signal, a single-chain anti-HER2 monoclonal antibody fragment, a Pseudomonas exotoxin A translocation domain and a constitutively active caspase-3 molecule were used to induce apoptosis in human gastric cancer cells both in vitro and in vivo. Immunofluorescence staining and western blotting were used to examine the expression of the recombinant protein HER-PE-CP3. Apoptosis was determined by flow cytometry and TUNEL assay.
RESULTS:Co-cultivation of HER-PE-CP3/ NIH3T3 with human gastric cancer cells led to internalisation of HER-PE-CP3 and apoptosis in HER2-expressing human gastric cancer cells but not in HER2-negative cancer cells. Inoculation of HER-PE-CP3/NIH3T3 in nude mice resulted in potent inhibition of human gastric cancer xenografts and much prolonged survival time of the tumour-bearing mice compared with the control. Significantly more apoptotic cells were detected in xenografts in mice receiving HER-PE-CP3/NIH3T3 than in control mice.
CONCLUSIONS:The HER-PE-CP3 chimeric molecule could induce selective apoptosis and potent growth inhibition of HER2-positive human gastric cancer cells and might represent a novel HER2-directed treatment option for human gastric cancer.
Volume 59(3)
Pages 292-9
Published 2010-3
DOI 10.1136/gut.2008.155226
PII gut.2008.155226
PMID 19951902
MeSH Animals Antibodies, Monoclonal / therapeutic use Antineoplastic Agents / pharmacology Antineoplastic Agents / therapeutic use* Apoptosis / drug effects* Caspase 3 / therapeutic use Drug Evaluation, Preclinical / methods Humans Mice Mice, Inbred BALB C Mice, Nude Neoplasm Proteins / metabolism Receptor, ErbB-2 / immunology* Receptor, ErbB-2 / metabolism Recombinant Fusion Proteins / pharmacology Recombinant Fusion Proteins / therapeutic use* Stomach Neoplasms / drug therapy* Stomach Neoplasms / metabolism Stomach Neoplasms / pathology Tumor Cells, Cultured Xenograft Model Antitumor Assays
IF 17.016
Times Cited 7
Human and Animal Cells MKN45 (RCB1001) MKN28 (RCB1000)