Atarashi Y, Yasumura S, Nambu S, Yoshio Y, Murakami J, Takahara T, Higuchi K, Watanabe A, Miyata K, Kato M
Third Department of Internal Medicine, Toyama Medical and Pharmaceutical University, Sugitani, Japan.
Hepatology. 1998 Jul;28(1):57-67. doi: 10.1002/hep.510280110.
Although treatment for hepatocellular carcinoma (HCC) has recently improved, most patients still relapse and die from this disease. The development of new therapeutic and preventive strategies for HCC is, therefore, required. A novel mutant protein (mutein) of human tumor necrosis factor alfa (TNF-alpha mutein F4614, 1SSSRGDSD... 29V ... 155L) was developed to decrease several adverse effects of TNF-alpha. F4614 is known to lack hypotensive effects of human TNF-alpha without losing its anti-tumor effect in mice transplanted with Meth-A sarcoma. Our study investigated the anti-tumor effects of F4614 against hepatoma cells in vitro and in vivo. F4614 significantly inhibited growth of all four tumor cells in vitro. A murine hepatoma cell line, MH134, when incubated in the presence of F4614, exhibited upregulation of surface major histocompatibility complex (MHC) class-I, intercellular adhesion molecule-1 (ICAM-1) and B7-1 molecules, and a decreased proportion of cells in the G2/M phase of the cell cycle. In addition, F4614 induced apoptosis in a significant number of MH134 cells. TNF-alpha and F4614 (5 microg/mouse daily for 5 days) showed similar anti-tumor activities in syngeneic MH134-bearing mice and heterogeneic PLC/PRF/5-bearing athymic nude mice. Intratumoral injection of F4614 or TNF-alpha was more effective than intravenous injection. Immunohistochemical analysis of the tumors treated by F4614 revealed that tumors were surrounded with a large number of Mac-1+ cells and a small number of CD4+ and CD8+ T cells; that suggests that intratumoral injection of F4614 elicited host immunoreactions. Thus, F4614 may be a new strategy for immunotherapy of HCC.
尽管肝细胞癌（HCC）的治疗近来有所改善，但大多数患者仍会复发并死于该疾病。因此，需要开发针对HCC的新治疗和预防策略。为了减少肿瘤坏死因子α（TNF-α）的几种不良反应，人们开发了一种新型的人肿瘤坏死因子α突变蛋白（突变蛋白）（TNF-α突变蛋白F4614，1SSSRGDSD...29V...155L）。已知F4614在移植了Meth-A肉瘤的小鼠中没有人类TNF-α的降压作用，但仍保留其抗肿瘤作用。我们的研究调查了F4614在体外和体内对肝癌细胞的抗肿瘤作用。F4614在体外显著抑制了所有四种肿瘤细胞的生长。一种小鼠肝癌细胞系MH134，在F4614存在的情况下培养时，表面主要组织相容性复合体（MHC）I类、细胞间黏附分子-1（ICAM-1）和B7-1分子上调，并且细胞周期G2/M期的细胞比例降低。此外，F4614诱导大量MH134细胞凋亡。在同基因的荷MH134小鼠和异基因的荷PLC/PRF/5无胸腺裸小鼠中，TNF-α和F4614（每天5μg/小鼠，共5天）显示出相似的抗肿瘤活性。瘤内注射F4614或TNF-α比静脉注射更有效。对接受F4614治疗的肿瘤进行免疫组织化学分析显示，肿瘤被大量Mac-1+细胞和少量CD4+和CD8+T细胞包围；这表明瘤内注射F4614引发了宿主免疫反应。因此，F4614可能是HCC免疫治疗的一种新策略。
