A NOVEL HUMAN TUMOR-NECROSIS-FACTOR-ALPHA MUTEIN, F4614, INHIBITS IN-VITRO AND IN-VIVO GROWTH OF MURINE AND HUMAN HEPATOMA - IMPLICATION FOR IMMUNOTHERAPY OF HUMAN HEPATOCELLULAR-CARCINOMA
Y. Atarashi et al., A NOVEL HUMAN TUMOR-NECROSIS-FACTOR-ALPHA MUTEIN, F4614, INHIBITS IN-VITRO AND IN-VIVO GROWTH OF MURINE AND HUMAN HEPATOMA - IMPLICATION FOR IMMUNOTHERAPY OF HUMAN HEPATOCELLULAR-CARCINOMA, Hepatology, 28(1), 1998, pp. 57-67
Although treatment for hepatocellular carcinoma (HCC) has recently imp
roved, most patients still relapse and die from this disease. The deve
lopment of new therapeutic and preventive strategies for HCC is, there
fore, required. 12 novel mutant protein (mutein) of human tumor necros
is factor alfa (TNF-alpha mutein F4614, (1)SSSRGDSD... V-29 ... L-155)
was developed to decrease several adverse effects of TNF-alpha. F4614
is known to lack hypotensive effects of human TNF-alpha without losin
g its anti-tumor effect in mice transplanted with Meth-A sarcoma. Our
study investigated the anti-tumor effects of F4614 against hepatoma ce
lls in vitro and in vivo. F4614 significantly inhibited growth of all
four tumor cells in vitro. A murine hepatoma cell line, MH134, when in
cubated in the presence of F4614, exhibited upregulation of surface ma
jor histocompatibility complex (MHC) class-I, intercellular adhesion m
olecule-1 (ICAM-1) and B7-1 molecules, and a decreased proportion of c
ells in the G(2)/M phase of the cell cycle. In addition, F4614 induced
apoptosis in a significant number of MH134 cells. TNF-alpha and F4614
(5 mu g/mouse daily for 5 days) showed similar anti-tumor activities
in syngeneic MH134-bearing mice and heterogeneic PLC/PRF/5-bearing ath
ymic 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 elicite
d host immunoreactions. Thus, F4614 may be a new strategy for immunoth
erapy of HCC.