Anti-Mesothelin Recombinant Immunotoxin Therapy for Colorectal Cancer.
ADP Ribose Transferases
/ administration & dosage
Animals
Antigens, Neoplasm
/ immunology
Antineoplastic Agents, Immunological
/ administration & dosage
Bacterial Toxins
/ administration & dosage
Cell Line, Tumor
Colorectal Neoplasms
/ drug therapy
Exotoxins
/ administration & dosage
Female
GPI-Linked Proteins
/ antagonists & inhibitors
Humans
Immunotoxins
/ administration & dosage
Mesothelin
Mice
Recombinant Proteins
/ administration & dosage
Virulence Factors
/ administration & dosage
Xenograft Model Antitumor Assays
Pseudomonas aeruginosa Exotoxin A
Actinomycin D
HTB39
LMB100
LMB164
SW48
Journal
Clinical colorectal cancer
ISSN: 1938-0674
Titre abrégé: Clin Colorectal Cancer
Pays: United States
ID NLM: 101120693
Informations de publication
Date de publication:
09 2019
09 2019
Historique:
received:
04
04
2019
revised:
20
06
2019
accepted:
25
06
2019
pubmed:
28
7
2019
medline:
7
7
2020
entrez:
27
7
2019
Statut:
ppublish
Résumé
Mesothelin (MSLN) is a cell surface glycoprotein expressed at a high level on many malignancies, including pancreatic adenocarcinoma, serous ovarian cancer, and epithelioid mesothelioma. MSLN-targeted recombinant immunotoxins (RITs) consist of an anti-MSLN Fv fused to the catalytic domain of Pseudomonas exotoxin A. Recent data has also shown that MSLN is expressed at clinically relevant levels on the surface of colorectal cancer (CRC). In this study, CRC cell lines were tested for MSLN expression and susceptibility to MSLN-targeted RITs. CRC cell lines were tested for membranous MSLN expression via flow cytometry. Cell lines expressing MSLN were tested by WST-8 cell viability assay for sensitivity to various RITs and chemotherapeutic agents. CRC cell line SW-48 was tested in a mouse model for response to RIT as a single agent or in combination with actinomycin D and oxaliplatin. CRC cell lines were susceptible to anti-MSLN RITs at half maximal inhibitory concentration levels comparable with those previously described in pancreatic cancer cell lines. In a nude mouse model, MSLN-targeted RIT treatment of SW48 CRC tumors resulted in a significant decrease in tumor volume. Although combination therapy with standard of care chemotherapeutic oxaliplatin did not improve tumor regressions, combination therapy with actinomycin D resulted in > 90% tumor volume reduction with 50% complete regressions. These data support the development of anti-MSLN RITs as well as other MSLN-targeted therapies for CRC.
Sections du résumé
BACKGROUND
Mesothelin (MSLN) is a cell surface glycoprotein expressed at a high level on many malignancies, including pancreatic adenocarcinoma, serous ovarian cancer, and epithelioid mesothelioma. MSLN-targeted recombinant immunotoxins (RITs) consist of an anti-MSLN Fv fused to the catalytic domain of Pseudomonas exotoxin A. Recent data has also shown that MSLN is expressed at clinically relevant levels on the surface of colorectal cancer (CRC). In this study, CRC cell lines were tested for MSLN expression and susceptibility to MSLN-targeted RITs.
MATERIALS AND METHODS
CRC cell lines were tested for membranous MSLN expression via flow cytometry. Cell lines expressing MSLN were tested by WST-8 cell viability assay for sensitivity to various RITs and chemotherapeutic agents. CRC cell line SW-48 was tested in a mouse model for response to RIT as a single agent or in combination with actinomycin D and oxaliplatin.
RESULTS
CRC cell lines were susceptible to anti-MSLN RITs at half maximal inhibitory concentration levels comparable with those previously described in pancreatic cancer cell lines. In a nude mouse model, MSLN-targeted RIT treatment of SW48 CRC tumors resulted in a significant decrease in tumor volume. Although combination therapy with standard of care chemotherapeutic oxaliplatin did not improve tumor regressions, combination therapy with actinomycin D resulted in > 90% tumor volume reduction with 50% complete regressions.
CONCLUSIONS
These data support the development of anti-MSLN RITs as well as other MSLN-targeted therapies for CRC.
Identifiants
pubmed: 31345777
pii: S1533-0028(19)30176-8
doi: 10.1016/j.clcc.2019.06.006
pmc: PMC8317202
mid: NIHMS1533408
pii:
doi:
Substances chimiques
Antigens, Neoplasm
0
Antineoplastic Agents, Immunological
0
Bacterial Toxins
0
Exotoxins
0
GPI-Linked Proteins
0
Immunotoxins
0
MSLN protein, human
0
Msln protein, mouse
0
Recombinant Proteins
0
Virulence Factors
0
ADP Ribose Transferases
EC 2.4.2.-
Mesothelin
J27WDC343N
Types de publication
Journal Article
Research Support, N.I.H., Intramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
192-199.e1Subventions
Organisme : Intramural NIH HHS
ID : ZIA BC008753
Pays : United States
Informations de copyright
Published by Elsevier Inc.
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