Combination therapy of apoptosis induction and molecular targeting for hepatocellular carcinoma. -Transgenic mice study-

肝细胞癌是世界上最难治的癌症之一。近年来，分子靶向技术的进展使得受体激动剂或拮抗剂能够特异性地抑制癌细胞的生长。肝癌细胞中含有丰富的EGF受体，但EGF受体拮抗剂对肝癌的治疗作用尚未被证实。另一方面，我们阐明了PPAR Ganma激动剂、罗格列酮和吡格列酮对PLC/PRF/5、HuH7和HepG2三种肝癌细胞株的诱导凋亡作用。此外，抗癌药物表柔比星比5FU和CDDP更能促进细胞的凋亡。检测EGF受体拮抗剂对PPAR激动剂的协同作用。因此，吡格列酮增强了ZD1839的作用。实时荧光定量聚合酶链式反应检测到肝癌细胞株HepG2中EGF-R的表达较其他两株系有所降低，但与ZD1839的作用无关。进一步的裸鼠实验和TGFα转基因肝癌小鼠实验正在进行中。

Hepatocellular carcinoma is one of the most intractable cancers in the world. Recent progress of molecular targeting enables the specific growth inhibition of cancer cells by the receptor agonist or antagonist. EGF-receptor is abundant in liver cancer cell but the effect of EGF receptor antagonist on hepatoma has not been proved to be effective. On the other hand, we have clarified the three-hepatocellular carcinoma cell lines including PLC/PRF/5, Huh7 and HepG2 were induced apoptosis by PPAR ganma agonist, rosiglitazone and pioglitazone. Furthermore anticancer drugs epirubicine more enhanced the apoptosis than 5FU and CDDP. Then we tested the collaborative effect of EGF-receptor antagonist on the PPAR agonist. As a result, pioglitazone enhanced the effect of ZD1839. The expression of EGF-R assayed by real time PCR was decreased in HepG2 compared with the other two lines but it was not correlated the effect of ZD1839.Further study using nude mice and TGFalpha transgenic mice bearing liver cancer are on schedule.