Additive antitumor effects of gefitinib and imatinib on anaplastic thyroid cancer cells.
OBJECTIVE
Anaplastic thyroid cancer (ATC) is one of the most aggressive malignancies. Although multidisciplinary treatments have been introduced, patients with this disease rarely survive longer than 1 year. These findings prompted us to investigate the antitumor activity of molecular targeting agents in thyroid cancer cells.


METHODS
Two tyrosine kinase inhibitors, gefitinib and imatinib, were tested in a poorly differentiated thyroid cancer cell line, KTC-1, and two ATC cell lines, KTC-2 and KTC-3.


RESULTS
All cell lines expressed not only a target molecule of gefitinib, HER1, but also a cognate receptor, HER2. They also expressed target molecules of imatinib, c-ABL and platelet-derived growth factor receptors at various levels. Both agents had modest antitumor activity in these cell lines. Combined treatment with gefitinib and imatinib led to an additional antitumor effect. Each agent induced apoptosis and their combined treatment enhanced apoptosis associated with the down-regulation of antiapoptotic proteins, Bcl-2 and Bcl-xL. Moreover, their combined treatment additionally inhibited the growth of KTC-3 xenografts in nude mice.


CONCLUSIONS
These are the first findings to suggest that both gefitinib and imatinib have antitumor activity against ATC cells and that their combined use has greater activity than either drug alone.
Kurebayashi
Junichi
J
Department of Breast and Thyroid Surgery, Kawasaki Medical School, Kurashiki, 701-0192, Okayama, Japan. kure@med.kawasaki-m.ac.jp
Okubo
Sumiko
S
Yamamoto
Yutaka
Y
Ikeda
Masahiko
M
Tanaka
Katsuhiro
K
Otsuki
Takemi
T
Sonoo
Hiroshi
H
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D045744:Cell Line, Tumor; D017931:DNA Primers / Q000235:genetics; D004357:Drug Synergism; D005260:Female; D000077156:Gefitinib; D006801:Humans; D000068877:Imatinib Mesylate; D051379:Mice; D010879:Piperazines / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology* / Q000627:therapeutic use; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013964:Thyroid Neoplasms / Q000188:drug therapy
D000970:Antineoplastic Agents; D001549:Benzamides; D017931:DNA Primers; D010879:Piperazines; D011743:Pyrimidines; D011799:Quinazolines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D000077156:Gefitinib