Interleukin 4 receptor on human lung cancer: a molecular target for cytotoxin therapy

Clin Cancer Res. 2002 Nov;8(11):3503-11.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Blotting, Northern
  • Body Weight
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cytotoxins / pharmacology
  • Dose-Response Relationship, Drug
  • Exotoxins / pharmacology
  • Humans
  • Immunohistochemistry
  • Interleukin-4 / metabolism
  • Kinetics
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / pathology
  • Male
  • Mice
  • Mice, Nude
  • Mutation
  • Neoplasm Transplantation
  • Polymerase Chain Reaction
  • Protein Binding
  • Protein Synthesis Inhibitors / pharmacology
  • Pseudomonas / metabolism
  • RNA, Messenger / metabolism
  • Radioligand Assay
  • Receptors, Interleukin-4 / metabolism*
  • Recombinant Proteins / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Time Factors
  • Tumor Cells, Cultured


  • Cytotoxins
  • Exotoxins
  • Protein Synthesis Inhibitors
  • RNA, Messenger
  • Receptors, Interleukin-4
  • Recombinant Proteins
  • Interleukin-4