Interleukin-4 receptor cytotoxin as therapy for human malignant pleural mesothelioma xenografts.
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.
Section of General Thoracic Surgery, University of California, Los Angeles, California 90095-1741, USA.
Bryce D
BD
Beseth
Robert B
RB
Cameron
Pamela
P
Leland
Liang
L
You
Frederick
F
Varricchio
Robert J
RJ
Kreitman
Richard A
RA
Maki
David M
DM
Jablons
Syed R
SR
Husain
Raj K
RK
Puri
D036002:ADP Ribose Transferases / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D000368:Aged; D000818:Animals; D001427:Bacterial Toxins / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D045744:Cell Line, Tumor / Q000187:drug effects; D005098:Exotoxins / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D000922:Immunotoxins / Q000627:therapeutic use*; D015847:Interleukin-4 / Q000008:administration & dosage / Q000737:chemistry; D008297:Male; D008654:Mesothelioma / Q000737:chemistry / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000032:analysis / Q000187:drug effects*; D010997:Pleural Neoplasms / Q000737:chemistry / Q000188:drug therapy*; D019948:Receptors, Interleukin-4 / Q000032:analysis / Q000187:drug effects*; D013047:Specific Pathogen-Free Organisms; D037521:Virulence Factors / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D001427:Bacterial Toxins; D005098:Exotoxins; D000922:Immunotoxins; D015847:Interleukin-4; D009363:Neoplasm Proteins; D019948:Receptors, Interleukin-4; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A; C120228:interleukin 4 (38-37)-PE38KDEL