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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
Author(s) -
Naruse Ichiro,
Ohmori Tohru,
Ao Yoko,
Fukumoto Hisao,
Kuroki Toshio,
Mori Masatomo,
Saijo Nagahiro,
Nishio Kazuto
Publication year - 2001
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.10173
Subject(s) - k562 cells , biology , tyrosine kinase , cell culture , tyrosine kinase inhibitor , cell growth , cancer research , epidermal growth factor , pharmacology , microbiology and biotechnology , signal transduction , cancer , biochemistry , genetics
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.