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Ann Thorac Surg 2004 Aug;78(2):436-43

Interleukin-4 receptor cytotoxin as therapy for human malignant pleural mesothelioma xenografts.

Beseth BD, Cameron RB, Leland P, You L, Varricchio F, Kreitman RJ, Maki RA, Jablons DM, Husain SR, Puri RK

Cameron RB, Univ Calif Los Angeles, Sch Med, Dept Surg, Sect Gen Thorac Surg, 10833 Le Conte Ave,Room 62-215 CHS,POB 951741, Los Angeles, CA 90095 USA Univ Calif Los Angeles, Sch Med, Dept Surg, Sect Gen Thorac Surg, Los Angeles, CA 90095 USA US FDA, Ctr Biol Evaluat & Res, Lab Mol Tumor Biol, Div Cellular & Gene Therapy, Bethesda, MD 20014 USA US FDA, Ctr Biol Evaluat & Res, Div Biostat, Bethesda, MD 20014 USA NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA Neurocrine Biosci, San Diego, CA USA

Abstract

BACKGROUND: Malignant pleural mesothelioma (MPM) is an uncommon but highly fatal neoplasm for which only limited treatment is available. 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.


Category: Journal Article, Peer
PubMed ID: #15276492
Includes FDA Authors from Scientific Area(s): Biologics
Entry Created: 2011-10-04 Entry Last Modified: 2012-08-29
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