Abstract | BACKGROUND: 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. 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. CONCLUSIONS: The chimeric protein, IL-4(38-37)-PE38KDEL, has potent antitumor effects against MPM both in vitro and in vivo.
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Authors | Bryce D Beseth, Robert B Cameron, Pamela Leland, Liang You, Frederick Varricchio, Robert J Kreitman, Richard A Maki, David M Jablons, Syed R Husain, Raj K Puri |
Journal | The Annals of thoracic surgery
(Ann Thorac Surg)
Vol. 78
Issue 2
Pg. 436-43; discussion 436-43
(Aug 2004)
ISSN: 1552-6259 [Electronic] Netherlands |
PMID | 15276492
(Publication Type: Journal Article)
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Chemical References |
- Bacterial Toxins
- Exotoxins
- Immunotoxins
- Neoplasm Proteins
- Receptors, Interleukin-4
- Virulence Factors
- interleukin 4 (38-37)-PE38KDEL
- Interleukin-4
- ADP Ribose Transferases
- Pseudomonas aeruginosa exotoxin A
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Topics |
- ADP Ribose Transferases
(administration & dosage, chemistry, therapeutic use)
- Aged
- Animals
- Bacterial Toxins
(administration & dosage, chemistry, therapeutic use)
- Cell Line, Tumor
(drug effects)
- Exotoxins
(administration & dosage, chemistry, therapeutic use)
- Female
- Humans
- Immunotoxins
(therapeutic use)
- Interleukin-4
(administration & dosage, chemistry)
- Male
- Mesothelioma
(chemistry, drug therapy)
- Mice
- Mice, Nude
- Middle Aged
- Neoplasm Proteins
(analysis, drug effects)
- Pleural Neoplasms
(chemistry, drug therapy)
- Receptors, Interleukin-4
(analysis, drug effects)
- Specific Pathogen-Free Organisms
- Virulence Factors
(administration & dosage, chemistry, therapeutic use)
- Xenograft Model Antitumor Assays
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