Antitumor activity of the selective epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) Iressa (ZD1839) in an EGFR-expressing multidrug-resistant cell line in vitro and in vivo

Int J Cancer. 2002 Mar 10;98(2):310-5. doi: 10.1002/ijc.10173.


Selective tyrosine kinase inhibitors are regarded as promising antitumor agents for cancer treatment. Iressa (ZD1839) is an orally active, selective EGFR-TKI (epidermal growth factor receptor-tyrosine kinase inhibitor) that blocks signal transduction pathways implicated in cancer cell proliferation, survival and other host-dependent processes promoting cancer growth. The cellular mechanisms of ZD1839 action against human malignant cells and drug-resistant cells were evaluated in vitro. Among the cell lines tested, ZD1839 showed a strong growth-inhibitory effect in vitro on human leukemic cells resistant to phorbol ester. This cell line, K562/TPA, shows a non-P-glycoprotein-mediated multidrug-resistant phenotype. The IC50 value of ZD1839 on K562/TPA was approximately 400-fold lower than that on the parental K562 cell (K562 = 12 +/- 2 microM; K562/TPA = 0.025 +/- 0.002 microM) in vitro as determined by a dye formation assay. The expression of EGFR and EGFR mRNA was clearly present in K562/TPA but not in parental K562 cells as determined by Western blotting and RT-PCR. EGFR was autophosphorylated in K562/TPA detected by the antiphosphotyrosine antibody. The in vivo antitumor effects of ZD1839 on K562 and K562/TPA cells were also investigated in BALB/c nude mice. K562/TPA cells transplanted subcutaneously into mice disappeared completely with ZD1839 treatment (20 mg/kg/day, days 3-9). This was not the case in K562 cells. These results suggest that ZD1839 is highly active against tumor cells with non-P-glycoprotein-mediated multidrug resistance that express EGFR. Iressa is a trademark of AstraZeneca (Cheshire, UK).

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Cell Division / drug effects
  • Drug Resistance, Multiple
  • Drug Resistance, Neoplasm*
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use*
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • Female
  • Gefitinib
  • Humans
  • K562 Cells
  • Kinetics
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasm Transplantation
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Phosphorylation / drug effects
  • Quinazolines / pharmacology
  • Quinazolines / therapeutic use*
  • RNA, Neoplasm / biosynthesis
  • Tetradecanoylphorbol Acetate / pharmacology
  • Tumor Cells, Cultured


  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Quinazolines
  • RNA, Neoplasm
  • ErbB Receptors
  • Tetradecanoylphorbol Acetate
  • Gefitinib