Immunotoxin therapy for primary malignant brain tumors

Ki Uk Kim, Daniel A Vallera, Hsiao Tzu Ni, Kwan H. Cho, Stephen R. Spellman, Walter C Low, Walter A. Hall

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

The prognosis of malignant brain tumors is poor in spite of aggressive treatment. Immunotoxin therapy is a novel approach for the treatment of tumors. Targeted fusion toxins, chimeric protein consisting of the cytotoxic domain of the natural toxin and carrier ligands such as a growth factor or an antibody, have been introduced in the treatment of malignant central nervous system (CNS) tumors, with promising results. The toxin is internalized into the cytosol of the target cell via cell-surface receptors and it is essential for these receptors on the tumor cell to be highly expressed in order for the immunotoxin to have specific anti-tumor activity. Studies on expression of cell-surface receptor for immunotoxin targeting was performed on transferring (TR), insulin-like growth factor-1 (IGF-1R), and interleukin-4 (IL-4R) receptors of human glioblastoma (U373-MG and T98-G) and medulloblastoma (Daoy) cell lines, and the effect of irradiation on expressibility of these receptors was studied. Recombinant diphtheria toxin–murine interleukin-4 conjugate (DT390–mIL4) was developed and its cytotoxic efficacy against murine glioblastoma (SMA-560) and neuroblastoma (Neuro-2a and NB41-A3) cell lines was examined, and the combined effect with irradiation was tested. Receptors were expressed in all cases except IGF-1R on T98-G. After irradiation, TR expression was increased for Daoy, IGF-1R expression was increased on Daoy and U373-MG, and IL-4R expression was decreased on Daoy and U373-MG. DT390–mIL4 exhibited dose-dependent, specific cytotoxic effects on all cell lines tested with IC50 (concentration of DT390–mIL4 that inhibit 50% of protein synthesis) value of 0.56×10−9 M in SMA-560, 1.28×10−9 M in Neuro-2a and 0.95×10−10 M in NB41-A3. Cytotoxicity was additive when DT390–mIL4 at 10−9 M was administered with irradiation. Targeted fusion toxins are characterized by great potency and high specificity with minimal damage to normal neuronal tissue, and interleukin-4 receptor is one of the proper targets for fusion toxin. The cytotoxicity of the immunotoxin is additive when it is administrated with irradiation. Targeted toxin therapy is a promising adjuvant treatment modality for the malignant brain tumors.

Original languageEnglish (US)
Pages (from-to)185-197
Number of pages13
JournalInternational Congress Series
Volume1247
Issue numberC
DOIs
StatePublished - Dec 1 2002

Keywords

  • Absolute expression index
  • Glioblastoma
  • Immunotoxin
  • Insulin-like growth factor receptor
  • Interleukin-4 receptor
  • Transferrin receptor

Fingerprint Dive into the research topics of 'Immunotoxin therapy for primary malignant brain tumors'. Together they form a unique fingerprint.

Cite this