Targeted therapy of hepatocellular carcinoma by histone deacetylase inhibitor and preliminary study on the targeted imaging probe [18F]FAHA.

• Main Authors: Yi-Shiuan Chen, 陳懿璿
• Other Authors: Ran-Chou Chen
• Format: Others
• Language: zh-TW
• Published: 2013
• Online Access: http://ndltd.ncl.edu.tw/handle/60667104232816495752

碩士 === 國立陽明大學 === 生物醫學影像暨放射科學系 === 101 === Histone deacetylase (HDAC) inhibitors are emerging as a new class of anticancer agents. Recent studies have shown HDACIs have notable effects on cell proliferation, apoptosis, differentiation and angiogenesis in vitro and in vivo. Currently, there are phase I and II clinical trials involving using the HDAC inhibitors in patients with hematological and solid malignancies, and the result demonstrated that treatment with HDAC inhibitors leads to tumor regression. Hepatocellular carcinoma (HCC) has been considered as a candidate for HDAC inhibitors treatment and will be the targeted cancer in this thesis. The objectives of this thesis are to compare the treatment effect of HDAC inhibitors SAHA (vorinostat), VPA (valproic acid), and TSA (trichostatin A) for HCC targeted therapy, and to examine the uptake of [18F]FAHA, a potential PET imaging agent and substrate for HDAC activity, on HCC cell lines. In this thesis, we studied the grade of differentiation and the HDACs mRNA expression in human HCC cell lines including HepG2, Hep3B, Huh7, PLC/PRF/5, and SK-Hep1. We observed that well differentiated HCC cell lines were sensitive to SAHA treatment, while poorly differentiated HCC cell lines were sensitive to VPA treatment. In animal tumor model, VPA caused growth inhibition in SK-Hep1 tumor (poorly differentiated HCC). The western blotting showed SAHA caused continuous H3 reacetylation in HepG2, Huh7, and SK-Hep1 cells, while VPA upregulated the acetyl H3 expression of HCC cells within 24 hours at 5mM, but the level of acetyl H3 expression decreased rapidly with time. The cellular uptake suggested that the class I HDACs expression affected the [18F]FAHA uptake in HCC cell lines. [18F]FAHA uptake was also observed in SK-Hep1 tumor –bearing animal in in vivo PET imaging. In conclusion, the three HDAC inhibitors show potent anti-tumor effect in human HCC cell lines. The optimal therapeutic algorithsm should consider the differentiation grade of the tumor cell and the drug effective time to achieve the best treatment effect.