IL-4 Receptors on Human Medulloblastoma Tumours Serve as a Sensitive Target for a Circular Permuted IL-4-Pseudomonas Exotoxin Fusion Protein

Br J Cancer. 2002 Jan 21;86(2):285-91. doi: 10.1038/sj.bjc.6600034.

Abstract

Cytotoxins directed to interleukin-4 receptors have shown to mediate relatively selective cytotoxicity against a variety of human cancer cells in vitro and in vivo. In an ongoing Phase I clinical trial, a recombinant protein comprised of circularly permuted IL-4 fused to a mutated form of Pseudomonas exotoxin (the fusion protein termed IL-4(38-37)-PE38KDEL or cpIL4-PE) has shown antitumour activity against malignant glioma. Human medulloblastomas are neuroectodermal tumours that occur in children and have a poor prognosis. The goal of this study was to determine whether human medulloblastoma derived cell lines express interleukin-4 receptor and whether interleukin-4 receptor expression is accompanied by sensitivity to cpIL4-PE. Medulloblastoma cell lines express interleukin-4 receptor at the protein and mRNA levels as determined by binding, indirect immunofluorescence and RT--PCR studies. These cells expressed IL-4Ralpha (also known as IL-4Rbeta) and IL-13Ralpha1 (also known as IL-13Ralpha') chains, however common gamma(c), a component of the interleukin-4 receptor system in immune cells was not detected. Consistent with the expression of IL-4R, cpIL4-PE was found to be highly and specifically cytotoxic to four of five medulloblastoma cell lines. Susceptibility of medulloblastoma cell lines to cpIL4-PE seemed to correlate closely to the functional IL-4 binding sites in general as demonstrated by 125I-IL-4 binding, but did not seem to correlate with mRNA or cell surface immunoreactive receptor protein expression. The sensitivity of medulloblastoma cells to cpIL4-PE could be eliminated by concurrent incubation with IL-4 or IL-13, but not with IL-2. None of these cell lines showed any change in proliferation upon treatment with exogenous IL-4. These studies establish the interleukin-4 receptor as a medulloblastoma-associated target for possible tumour-directed cancer therapy. Further studies are warranted to investigate interleukin-4 receptor expression in primary medulloblastoma tumours and sensitivity to cpIL-4PE in vitro and in vivo.

Publication types

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

MeSH terms

  • ADP Ribose Transferases*
  • Bacterial Toxins*
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / physiopathology
  • Exotoxins / pharmacokinetics*
  • Exotoxins / therapeutic use*
  • Fluorescent Antibody Technique
  • Humans
  • Immunoconjugates / pharmacokinetics
  • Immunoconjugates / therapeutic use
  • Medulloblastoma / drug therapy*
  • Medulloblastoma / physiopathology
  • RNA, Messenger / analysis
  • Receptors, Interleukin-4 / biosynthesis
  • Receptors, Interleukin-4 / drug effects*
  • Receptors, Interleukin-4 / physiology
  • Recombinant Fusion Proteins
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Cells, Cultured
  • Virulence Factors*

Substances

  • Bacterial Toxins
  • Exotoxins
  • Immunoconjugates
  • RNA, Messenger
  • Receptors, Interleukin-4
  • Recombinant Fusion Proteins
  • Virulence Factors
  • ADP Ribose Transferases
  • toxA protein, Pseudomonas aeruginosa