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

AbstractBACKGROUND:
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.
AuthorsBryce 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
JournalThe Annals of thoracic surgery (Ann Thorac Surg) Vol. 78 Issue 2 Pg. 436-43; discussion 436-43 (Aug 2004) ISSN: 1552-6259 [Electronic] Netherlands
PMID15276492 (Publication Type: Journal Article)
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
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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