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Interleukin-4 receptor cytotoxin as therapy for human malignant pleural mesothelioma xenografts |
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| Authors: | Beseth Bryce D Cameron Robert B Leland Pamela You Liang Varricchio Frederick Kreitman Robert J Maki Richard A Jablons David M Husain Syed R Puri Raj K |
| Affiliation: | a Section of General Thoracic Surgery, University of California, Los Angeles, California, USA b Laboratory of Molecular Tumor Biology, Division of Cellular and Gene Therapy, Center for Biologics Evaluation and Research (CBER), Food and Drug Administration (FDA), Bethesda, Maryland, USA c Division of Biostatistics, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland, USA d Laboratory of Molecular Biology, National Cancer Institutes, National Institutes of Health, Bethesda, Maryland, USA e Neurocrine Biosciences, San Diego, California, USA |
| Abstract: | BackgroundMalignant pleural mesothelioma (MPM) is an uncommon but highly fatal neoplasm for which only limited treatment is available.MethodsImmunohistochemical 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.ResultsAll 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.ConclusionsThe chimeric protein, IL-4(38-37)-PE38KDEL, has potent antitumor effects against MPM both in vitro and in vivo. |
| Keywords: | 14 |
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