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Interleukin-4 receptor cytotoxin as therapy for human malignant pleural mesothelioma xenografts.
- Source :
-
The Annals of thoracic surgery [Ann Thorac Surg] 2004 Aug; Vol. 78 (2), pp. 436-43; discussion 436-43. - Publication Year :
- 2004
-
Abstract
- Background: Malignant pleural mesothelioma (MPM) is an uncommon but highly fatal neoplasm for which only limited treatment is available.<br />Methods: Immunohistochemical analysis was used to determine the expression of interleukin-4 receptors (IL-4R) on mesothelioma cell lines and resected mesothelioma tumors. Radioreceptor binding assays were used to show that these IL-4R were high-affinity receptors. Previously, we had shown that a chimeric protein composed of a circularly permuted IL-4 molecule fused to a truncated form of Pseudomonas exotoxin A, IL-4(38-37)-PE38KDEL, could be used to kill IL-4R-bearing tumor cells in vitro. The toxicity of this molecule to mesothelioma cell lines was tested using a protein synthesis inhibition assay. A human mesothelioma xenograft model was then developed to assess the efficacy of this molecule in vivo.<br />Results: All MPM cell lines tested were found to express high-affinity cell-surface IL-4R. Immunohistochemical analysis of resected mesothelioma tumor specimens from 13 patients revealed that all tumors expressed moderate-to-high levels of IL-4R. Coculture of malignant mesothelioma cell lines with IL-4(38-37)-PE38KDEL resulted in a dose-dependent inhibition of tumor cell protein synthesis through an interaction with cell-surface IL-4R. In a nude mouse xenograft model of human MPM, intratumoral administration of IL-4(38-37)-PE38KDEL mediated a dose-dependent decrease in tumor volume and a dose-dependent increase in survival.<br />Conclusions: The chimeric protein, IL-4(38-37)-PE38KDEL, has potent antitumor effects against MPM both in vitro and in vivo.
- Subjects :
- ADP Ribose Transferases administration & dosage
ADP Ribose Transferases chemistry
Aged
Animals
Bacterial Toxins administration & dosage
Bacterial Toxins chemistry
Cell Line, Tumor drug effects
Exotoxins administration & dosage
Exotoxins chemistry
Female
Humans
Interleukin-4 administration & dosage
Interleukin-4 chemistry
Male
Mesothelioma chemistry
Mice
Mice, Nude
Middle Aged
Neoplasm Proteins analysis
Pleural Neoplasms chemistry
Receptors, Interleukin-4 analysis
Specific Pathogen-Free Organisms
Virulence Factors administration & dosage
Virulence Factors chemistry
Xenograft Model Antitumor Assays
Pseudomonas aeruginosa Exotoxin A
ADP Ribose Transferases therapeutic use
Bacterial Toxins therapeutic use
Exotoxins therapeutic use
Immunotoxins therapeutic use
Mesothelioma drug therapy
Neoplasm Proteins drug effects
Pleural Neoplasms drug therapy
Receptors, Interleukin-4 drug effects
Virulence Factors therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1552-6259
- Volume :
- 78
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- The Annals of thoracic surgery
- Publication Type :
- Academic Journal
- Accession number :
- 15276492
- Full Text :
- https://doi.org/10.1016/j.athoracsur.2004.03.010