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.
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).
Naruse
Ichiro
I
Pharmacology Division, National Cancer Center Research Institute, Tokyo, Japan.
Ohmori
Tohru
T
Ao
Yoko
Y
Fukumoto
Hisao
H
Kuroki
Toshio
T
Mori
Masatomo
M
Saijo
Nagahiro
N
Nishio
Kazuto
K
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002455:Cell Division / Q000187:drug effects; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005260:Female; D000077156:Gefitinib; D006801:Humans; D020014:K562 Cells; D007700:Kinetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use*; D012334:RNA, Neoplasm / Q000096:biosynthesis; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011799:Quinazolines; D012334:RNA, Neoplasm; D066246:ErbB Receptors; D013755:Tetradecanoylphorbol Acetate; D000077156:Gefitinib