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

✍ Scribed by Ichiro Naruse; Tohru Ohmori; Yoko Ao; Hisao Fukumoto; Toshio Kuroki; Masatomo Mori; Nagahiro Saijo; Kazuto Nishio

• Publisher: John Wiley and Sons
• Year: 2001
• Tongue: French
• Weight: 216 KB
• Volume: 98
• Category: Article
• ISSN: 0020-7136
• DOI: 10.1002/ijc.10173

✦ Synopsis

Abstract

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 μM; K562/TPA = 0.025 ± 0.002 μM) 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). © 2001 Wiley‐Liss, Inc.