Changes of cytokines in patients with liver cirrhosis and advanced hepatocellular carcinoma treated by sorafenib.
OBJECTIVE
Recently, the oral multikinase inhibitor sorafenib has been used to treat advanced hepatocellular carcinoma (aHCC). Tumor necrosis factor (TNF) induces apoptosis of tumor cells by binding to TNF-related apoptosis-inducing ligand, while binding of the Fas ligand on cytotoxic T lymphocytes to the Fas receptor on hepatocytes also causes apoptosis. The aim of this study was to retrospectively evaluate changes of cytokines in patients with liver cirrhosis (LC) and aHCC receiving sorafenib therapy.


METHODS
Fifty-seven adult Japanese LC patients received sorafenib for aHCC (200-800 mg/day for 4 weeks) between 2009 and 2012 at our hospital. Blood samples were collected in the early morning before and after treatment, and the serum levels of soluble TNF-alpha (sTNF-alpha), soluble TNF receptor (sTNF-R), soluble Fas ligand (sFas L), and soluble Fas (sFas) were evaluated.


RESULTS
Ten patients were treated with sorafenib at 200 mg/day (200 mg group), 37 patients were given 400 mg/day (400 mg group), and 10 patients received 800 mg/day (800 mg group). The serum level of sTNF-alpha was significantly increased after treatment compared with before treatment in the 400 and 800 mg groups. The serum level of sTNF-R also showed a significant increase after treatment in the 400 mg group, although there was no significant difference of sTNF-R between before and after treatment in the 200 and 800 mg groups. sFas showed a significant decrease after treatment compared with before treatment in the 400 and 800 mg groups, although the serum level of sFas L never exceeded 0.15 ng/ml.


CONCLUSIONS
These findings suggest that treatment with sorafenib at doses ≥400 mg/day might promote TNF-related or Fas-related apoptosis by increasing the circulating level of TNF-alpha or decreasing that of sFas.
Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), Faculty of Medicine, School of Medicine, Toho University, 6-11-1, Omorinishi, Ota-ku, Tokyo, 143-8541, Japan, hidenari@aol.com.
Hidenari
H
Nagai
Takenori
T
Kanekawa
Kojiro
K
Kobayashi
Takanori
T
Mukozu
Daigo
D
Matsui
Teppei
T
Matsui
Masahiro
M
Kanayama
Noritaka
N
Wakui
Kouichi
K
Momiyama
Mie
M
Shinohara
Koji
K
Ishii
Yoshinori
Y
Igarashi
Yasukiyo
Y
Sumino
D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D016207:Cytokines / Q000097:blood*; D005260:Female; D006801:Humans; D008103:Liver Cirrhosis / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D008113:Liver Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D012189:Retrospective Studies; D000077157:Sorafenib
D000970:Antineoplastic Agents; D016207:Cytokines; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib