Selective toxicity of TGF-alpha-PE40 to EGFR-positive cell lines: selective protection of low EGFR-expressing cell lines by EGF

Br J Cancer. 1994 Jun;69(6):988-94. doi: 10.1038/bjc.1994.194.

Abstract

The sensitivity of human breast and lung cancer cell lines to TGF-alpha-PE40, a novel chimeric recombinant cytotoxin composed of two independent domains, (i) TGF-alpha and (ii) a 40 kDa segment of the Pseudomonas exotoxin protein, PE-40, was investigated. Toxicity varied widely, correlated with epidermal growth factor receptor (EGFR) levels (P = 0.01) and was greatly reduced by EGF, indicating that binding of TGF-alpha-PE40 to EGFR is important in mediating toxicity. Cell lines expressing low EGFR levels were most highly protected by EGF, indicating that normal (low EGFR-expressing) tissue may be selectively protected by EGF in vivo. P-glycoprotein did not confer resistance to TGF-alpha-PE40, and toxicity was unaffected by multidrug resistance-modulating agents (cyclosporin A, tamoxifen, verapamil), indicating a role for TGF-alpha-PE40 in the clinical management of drug-resistant tumours.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms
  • Carcinoma, Non-Small-Cell Lung
  • Carcinoma, Small Cell
  • Cell Division / drug effects
  • Cell Line
  • Cyclosporine / toxicity
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Epidermal Growth Factor / pharmacology*
  • ErbB Receptors / analysis
  • ErbB Receptors / drug effects
  • ErbB Receptors / metabolism*
  • Exotoxins / toxicity*
  • Female
  • Humans
  • Lung Neoplasms
  • Recombinant Fusion Proteins / toxicity
  • Recombinant Proteins / toxicity
  • Tamoxifen / toxicity
  • Transforming Growth Factor alpha / toxicity*
  • Tumor Cells, Cultured
  • Verapamil / pharmacology

Substances

  • Exotoxins
  • Recombinant Fusion Proteins
  • Recombinant Proteins
  • Transforming Growth Factor alpha
  • transforming growth factor type alpha-Pseudomonas exotoxin A
  • Tamoxifen
  • Epidermal Growth Factor
  • Cyclosporine
  • Verapamil
  • ErbB Receptors