ZD1839 (Iressa): an orally active inhibitor of epidermal growth factor signaling with potential for cancer therapy.
The epidermal growth factor receptor (EGFR) is a promising target for anticancer therapy because of its role in tumor growth, metastasis and angiogenesis, and tumor resistance to chemotherapy and radiotherapy. We have developed a low-molecular-weight EGFR tyrosine kinase inhibitor (EGFR-TKI), ZD1839 (Iressa(2) ). ZD1839, a substituted anilinoquinazoline, is a potent EGFR-TKI (IC(50) = 0.033 micro M) that selectively inhibits EGF-stimulated tumor cell growth (IC(50) = 0.054 micro M) and that blocks EGF-stimulated EGFR autophosphorylation in tumor cells. In studies with mice bearing a range of human tumor-derived xenografts, ZD1839 given p.o. once a day inhibited tumor growth in a dose-dependent manner. The level of expression of EGFR did not determine xenograft tumor sensitivity to ZD1839. Long-term ZD1839 (>3 months) treatment of mice bearing A431 xenografts was well tolerated, and ZD1839 completely inhibited tumor growth and induced regression of established tumors. No drug-resistant tumors appeared during ZD1839 treatment, but some tumors regrew after drug withdrawal. These studies indicate the potential utility of ZD1839 in the treatment of many human tumors and indicate that continuous once-a-day p.o. dosing might be a suitable therapeutic regimen.
Wakeling
Alan E
AE
Department of Cancer and Infection Research, AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
Guy
Simon P
SP
Woodburn
Jim R
JR
Ashton
Susan E
SE
Curry
Brenda J
BJ
Barker
Andrew J
AJ
Gibson
Keith H
KH
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D005260:Female; D000077156:Gefitinib; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation / Q000187:drug effects; D011799:Quinazolines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D006131:Growth Inhibitors; D011799:Quinazolines; D066246:ErbB Receptors; D000077156:Gefitinib