title: Interleukin 4 receptor on human lung cancer: a molecular target for cytotoxin therapy.
abstract: Previous studies have demonstrated that human lung tumor cell lines express interleukin 4 (IL-4) receptors, and IL-4 can mediate modest to moderate antiproliferative activity in vitro and in vivo in animal models of human lung tumors. On the basis of these studies, IL-4 was tested in clinical trials; however, it showed little antitumor activity in lung cancer patients. In the present study, we examined the expression of IL-4 receptors (IL-4Rs) in lung tumor samples and normal lung tissues and tested whether an IL-4R targeted agent will have better antitumor activity in vitro and in vivo compared with IL-4. IL-4R expression was tested by immunohistochemistry in 54 lung tumor samples and normal lung tissues in a tissue array, by reverse-transcription PCR and Northern blot analyses in lung tumor cell lines. Cytotoxic activity of IL-4 cytotoxin [IL-4(38-37)-PE38KDEL], composed of a circular permuted IL-4 and a mutated form of Pseudomonas exotoxin (PE38KDEL) was tested by protein synthesis inhibition and clonogenic assays in seven lung tumor cell lines. Antitumor activity of IL-4 cytotoxin was tested in vitro and in immunodeficient animal models of human lung tumors. We observed that IL-4Rs are expressed at higher levels in situ in lung tumor samples compared with normal lung tissues and IL-4 cytotoxin is highly and specifically cytotoxic to lung tumor cell lines in vitro. Intratumoral and i.p. administration of IL-4 cytotoxin to immunodeficient mice with s.c. established human lung H358 non-small cell lung cancer tumors mediated considerable antitumor activity in a dose-dependent manner with the higher dose producing durable complete responses. On the other hand, H460 non-small cell lung cancer tumors expressing low levels of IL-4R did not respond to IL-4 cytotoxin therapy. Because IL-4 cytotoxin mediates its antitumor activity through IL-4R, and a variety of lung tumors expressed high levels of IL-4R, we propose testing the safety of this agent in patients with lung cancer.
authors.affiliation: Laboratory of Molecular Tumor Biology, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892, USA.
authors.forename: Mariko
authors.initials: M
authors.lastname: Kawakami
authors.forename: Koji
authors.initials: K
authors.lastname: Kawakami
authors.forename: Vitaly A
authors.initials: VA
authors.lastname: Stepensky
authors.forename: Richard A
authors.initials: RA
authors.lastname: Maki
authors.forename: Howard
authors.initials: H
authors.lastname: Robin
authors.forename: Wayne
authors.initials: W
authors.lastname: Muller
authors.forename: Syed R
authors.initials: SR
authors.lastname: Husain
authors.forename: Raj K
authors.initials: RK
authors.lastname: Puri
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D001835:Body Weight; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology; D003603:Cytotoxins / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005098:Exotoxins / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D015847:Interleukin-4 / Q000378:metabolism; D007700:Kinetics; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009368:Neoplasm Transplantation; D016133:Polymerase Chain Reaction; D011485:Protein Binding; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011549:Pseudomonas / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011869:Radioligand Assay; D019948:Receptors, Interleukin-4 / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014407:Tumor Cells, Cultured
chemical_list: D003603:Cytotoxins; D005098:Exotoxins; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D019948:Receptors, Interleukin-4; D011994:Recombinant Proteins; D015847:Interleukin-4