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A Novel Therapeutic Strategy for Pancreatic Cancer: Targeting Cell Surface Glycan Using rBC2LC-N Lectin-Drug Conjugate (LDC)

Molecular cancer therapeutics, 2018-01, Vol.17 (1), p.183-195 [Peer Reviewed Journal]

2017 American Association for Cancer Research. ;Copyright American Association for Cancer Research Inc Jan 2018 ;ISSN: 1535-7163 ;EISSN: 1538-8514 ;DOI: 10.1158/1535-7163.mct-17-0232 ;PMID: 28939555

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Title:
A Novel Therapeutic Strategy for Pancreatic Cancer: Targeting Cell Surface Glycan Using rBC2LC-N Lectin-Drug Conjugate (LDC)
Author: Shimomura, Osamu ; Oda, Tatsuya ; Tateno, Hiroaki ; Ozawa, Yusuke ; Kimura, Sota ; Sakashita, Shingo ; Noguchi, Masayuki ; Hirabayashi, Jun ; Asashima, Makoto ; Ohkohchi, Nobuhiro
Subjects: Adenocarcinoma ; Animals ; Anticancer properties ; Antitumor activity ; Cancer ; Cell Line, Tumor ; Cell surface ; Disease Models, Animal ; Drug carriers ; Drug delivery ; Drugs ; Erythrocytes ; Exotoxins ; Female ; Glycan ; Hemagglutination ; Humans ; Immunotoxins ; Intravenous administration ; Lectins ; Lectins - pharmacology ; Lectins - therapeutic use ; Mice ; Mice, Nude ; Nodules ; Pancreatic cancer ; Pancreatic Neoplasms ; Pancreatic Neoplasms - drug therapy ; Pancreatic Neoplasms - genetics ; Pancreatic Neoplasms - pathology ; Peritoneum ; Polysaccharides ; Polysaccharides - pharmacology ; Polysaccharides - therapeutic use ; Proteins ; Signal Transduction ; Weight reduction ; Xenografts ; Xenotransplantation
Is Part Of: Molecular cancer therapeutics, 2018-01, Vol.17 (1), p.183-195
Description: Various cancers, including pancreatic ductal adenocarcinoma (PDAC), remain intractable even with costly tumor-targeting antibody drugs. Because the outermost coatings of cancer cells are composed of cell-specific glycan layers (glycocalyx), lectins, proteins with glycan-binding potential, were evaluated for possible use as drug carriers in PDAC treatment. A human PDAC cell line with well-to-moderately differentiated properties (Capan-1) was subjected to lectin microarray analysis to identify specific lectin-glycan pairs. The selected lectin was fused with a bacterial exotoxin for the construction of a lectin-drug conjugate (LDC), and its safety and antitumor effects were evaluated. A specific affinity between a recombinant bacterial C-type lectin (rBC2LC-N) and Capan-1 was identified, and its positivity was confirmed in 69 human samples. In contrast to the belief that all lectins mediate harmful hemagglutination, rBC2LC-N did not cause hemagglutination with human erythrocytes and was safely administered to mice. The 50% inhibitory concentration of LDC to Capan-1 (1.04 pg/mL = 0.0195 pmol/L) was 1/1,000 lower than that reported for conventional immunotoxins. The intraperitoneal administration of LDC reduced the tumor weight from 390 to 130.8 mg ( < 0.01) in an orthotopic model and reduced the number of nodules from 48 to 3 ( < 0.001) and improved survival from 62 to 105 days in a peritoneal dissemination model ( < 0.0001). In addition, the effect of LDC was reproduced in nodules from patient-derived PDAC xenografts through intravenous injection. Herein, we show the concept of utilizing lectins as drug carriers to target glycans on the cancer cell surface, highlighting new insights into cancer treatments. .
Publisher: United States: American Association for Cancer Research Inc
Language: English
Identifier: ISSN: 1535-7163
EISSN: 1538-8514
DOI: 10.1158/1535-7163.mct-17-0232
PMID: 28939555
Source: GFMER Free Medical Journals
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A Novel Therapeutic Strategy for Pancreatic Cancer: Targeting Cell Surface Glycan Using rBC2LC-N Lectin-Drug Conjugate (LDC)

2017 American Association for Cancer Research. ;Copyright American Association for Cancer Research Inc Jan 2018 ;ISSN: 1535-7163 ;EISSN: 1538-8514 ;DOI: 10.1158/1535-7163.mct-17-0232 ;PMID: 28939555

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