Treatment of hepatocellular carcinoma by AdAFPep/Rep, AdAFPep/p53, and 5-fluorouracil in mice
Treatment of hepatocellular carcinoma by AdAFPep/Rep, AdAFPep/p53, and 5-fluorouracil in mice
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DOI：
10.1002/hep.22420
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发表时间：
2008-09-01
期刊：
影响因子：
13.5
通讯作者：
Niitsu, Yoshiro
中科院分区：
文献类型：
--
作者：
Sagawa, Tamotsu;Yamada, Yasuyuki;Niitsu, Yoshiro
尽管条件复制型腺病毒（CRAd）已被用于肝细胞癌（HCC）的临床治疗，但其具有抗肿瘤活性相对较低的固有缺点。在此，我们力求克服这一缺点。首先，我们将由甲胎蛋白增强子/启动子（ATPep）驱动的CRAd（AdAFPep/Rep）与携带也由AFPep驱动的p53转基因的无复制能力的腺病毒组合。这种组合的协同作用通过由AdAFPep/Rep转录的早期区域1A反式激活p53，对人HCC细胞系Hep 3B产生显著改善的杀肿瘤作用，与其他人HCC细胞系相比，Hep 3B具有相对短的倍增时间。这种协同相互作用通过加入亚肿瘤杀伤剂量而增强（0.5 μ g/mL）的5-氟尿嘧啶（5-FU），其增强p53表达并促进病毒体从肿瘤细胞中释放。当在裸鼠中生长的相对较大（直径10 mm）的Hep 3B肿瘤被注射两种病毒组合时，与分别用每种病毒治疗的肿瘤相比，它们显示出显著受损的生长。低剂量（600 μ g）的5-FU增强了病毒组合的生长抑制作用。用这三种药物治疗的荷瘤小鼠的生存期明显长于对照小鼠。此外，随着这些药剂的重复注射，肿瘤完全消失。结论：这种联合策略有望治疗临床上可能遇到的相对较大且生长迅速的HCC。
Although conditionally replicable adenovirus (CRAd) has been used in the clinical treatment of hepatocellular carcinoma (HCC), it suffers from the inherent drawback of having relatively low antitumor activity. Here, we have sought to overcome this drawback. First, we combined CRAd (AdAFPep/Rep) driven by a-fetoprotein enhancer/promoter (ATPep) with a replication-incompetent adenovirus carrying a p53 transgene that is also driven by AFPep. The synergism of this combination produced a significantly improved tumoricidal effect on the human HCC cell line Hep3B, which has a relatively short doubling time in comparison with other human HCC cell lines, through the transactivation of p53 by early region 1A transcribed by AdAFPep/Rep. This synergistic interaction was augmented by the addition of a subtumoricidal dose (0.5 mu g/mL) of 5-fluorouracil (5-FU), which enhanced p53 expression and facilitated the release of virions from tumor cells. When relatively large (10-mm-diameter) Hep3B tumors grown in nude mice were injected with the two viruses in combination, they showed significantly impaired growth in comparison with those treated with each virus separately. The growth suppression effect of the virus combination was enhanced by a low dose (600 mu g) of 5-FU. Survival of the tumor-bearing mice treated with these three agents was significantly longer than that of control mice. Moreover, the tumor completely disappeared with the repeated injection of these agents. Conclusion: This combination strategy holds promise for the treatment of relatively large and rapidly growing HCCs that may be encountered clinically.