Angelucci Adriano, Gravina Giovanni Luca, Rucci Nadia, Millimaggi Danilo, Festuccia Claudio, Muzi Paola, Teti Anna, Vicentini Carlo, Bologna Mauro
Department of Surgery, University of L'Aquila via Vetoio, Coppito 2, 67100 L'Aquila, Italy.
Endocr Relat Cancer. 2006 Mar;13(1):197-210. doi: 10.1677/erc.1.01100.
The activation of epidermal growth factor receptor (EGF-R) plays a key role in the promotion of proliferation and invasion in prostatic carcinoma (PCa). Gefitinib (Iressa; ZD1839), an orally active EGF-R tyrosine kinase inhibitor, has shown an important anti-proliferative activity in tumors expressing EGF-R both in vitro and in vivo. Our aim was to elucidate the role of gefitinib in the modulation of the metastatic spread of PCa cells. The therapeutic role of gefitinib was investigated by evaluating the proliferative and invasive ability of the PCa cell line PC3 and of its high metastatic sub-line, PCb2, by in vitro assays and intracardiac injection in nude mice. The inhibitory effect of gefitinib was tested in vivo by injecting PCa cells subcutaneously or in the left ventricle of nude mice and by administering daily 150 mg/kg of gefitinib. While xenograft growth was equally reduced in all PCa lines (about 50%), the bone metastasis formation was inhibited especially for the high metastatic PCb2 sub-line (81%) in comparison to PC3 cells (47%). The comparative in vitro analysis among PCa cell lines showed that PCb2 cells were more sensitive to the inhibitory effect of gefitinib in their invasive ability compared to parental PC3 cells but not in their proliferation rate. Moreover, PCb2 cells demonstrated an increased invasive ability in vitro in response to bone stromal cell conditioned medium (BCM). The simultaneous presence of 0.1 ng/ml gefitinib was sufficient to reduce the number of invaded cells in the presence of both EGF and BCM. The molecular characterization of the highly aggressive PCa sub-lines demonstrated that this phenomenon was associated with an increment in uPA/uPAR axis but not in EGF-R expression. In conclusion, our data suggest that the use of gefitinib as a therapeutic agent may be indicated in the control of PCa spreading to bone.
表皮生长因子受体（EGF-R）的激活在前列腺癌（PCa）的增殖和侵袭促进过程中起关键作用。吉非替尼（易瑞沙；ZD1839）是一种口服活性EGF-R酪氨酸激酶抑制剂，已在体外和体内对表达EGF-R的肿瘤显示出重要的抗增殖活性。我们的目的是阐明吉非替尼在调节PCa细胞转移扩散中的作用。通过体外试验和对裸鼠进行心内注射，评估PCa细胞系PC3及其高转移亚系PCb2的增殖和侵袭能力，研究吉非替尼的治疗作用。通过将PCa细胞皮下注射或注射到裸鼠左心室，并每日给予150 mg/kg吉非替尼，在体内测试吉非替尼的抑制作用。虽然所有PCa细胞系中的异种移植瘤生长均同等程度降低（约50%），但与PC3细胞（47%）相比，骨转移形成尤其受到抑制，特别是高转移的PCb2亚系（81%）。PCa细胞系之间的体外比较分析表明，与亲代PC3细胞相比，PCb2细胞在侵袭能力方面对吉非替尼的抑制作用更敏感，但在增殖率方面并非如此。此外，PCb2细胞在体外对骨基质细胞条件培养基（BCM）有更高的侵袭能力。同时存在0.1 ng/ml吉非替尼足以在有EGF和BCM存在的情况下减少侵袭细胞的数量。对高侵袭性PCa亚系的分子特征分析表明，这种现象与uPA/uPAR轴的增加有关，而与EGF-R表达无关。总之，我们的数据表明，使用吉非替尼作为治疗药物可能有助于控制PCa向骨转移。
