Kurebayashi Junichi, Okubo Sumiko, Yamamoto Yutaka, Ikeda Masahiko, Tanaka Katsuhiro, Otsuki Takemi, Sonoo Hiroshi
Department of Breast and Thyroid Surgery, Kawasaki Medical School, Kurashiki, 701-0192, Okayama, Japan.
Cancer Chemother Pharmacol. 2006 Oct;58(4):460-70. doi: 10.1007/s00280-006-0185-x. Epub 2006 Jan 25.
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.
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.
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.
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.
间变性甲状腺癌（ATC）是最具侵袭性的恶性肿瘤之一。尽管已经采用了多学科治疗方法，但患有这种疾病的患者很少能存活超过1年。这些发现促使我们研究分子靶向药物在甲状腺癌细胞中的抗肿瘤活性。
在低分化甲状腺癌细胞系KTC-1以及两个ATC细胞系KTC-2和KTC-3中测试了两种酪氨酸激酶抑制剂吉非替尼和伊马替尼。
所有细胞系不仅表达吉非替尼的靶分子HER1，还表达同源受体HER2。它们还不同程度地表达伊马替尼的靶分子c-ABL和血小板衍生生长因子受体。这两种药物在这些细胞系中均具有适度的抗肿瘤活性。吉非替尼和伊马替尼联合治疗产生了额外的抗肿瘤作用。每种药物均诱导细胞凋亡，联合治疗增强了与抗凋亡蛋白Bcl-2和Bcl-xL下调相关的细胞凋亡。此外，联合治疗还额外抑制了KTC-3异种移植瘤在裸鼠中的生长。
这些是首次表明吉非替尼和伊马替尼均对ATC细胞具有抗肿瘤活性且联合使用比单独使用任何一种药物具有更强活性的发现。
