Systemic administration of liposome-encapsulated OK-432 prolongs the survival of rats with hepatocellular carcinoma through the induction of IFN-gamma-producing hepatic lymphocytes.
BACKGROUND
OK-432 is known to increase the host antitumor response. We previously reported that systemic administration of OK-432 (OK-Lipo) specifically induced hepatic lymphocytes in mice. Here we aimed to investigate the antitumor effect of OK-Lipo on hepatocellular carcinomas (HCC) in experimental rats.


METHODS
Diethylnitrosamine was administered for 12 weeks to all rats (n = 36). Rats were divided into three groups of 12 rats each. One group was injected with OK-Lipo from week 5 (OK-5w group) and another from week 9 (OK-9w group). A control group was injected with saline from week 5 (Non-OK group). At week 13, five rats from each group were used for histological analysis and immunofluorescence assays (surface phenotypic and intracellular cytokine analysis of the mononuclear cells in the liver, spleen and peripheral blood). The remaining rats were observed for the remainder of their survival period.


RESULTS
The mean survival times of Non-OK, OK-5w, and OK-9w groups differed significantly (98.0 +/- 5.3 days, 116.0 +/- 5.8 days, and 106.0 +/- 5.4 days, respectively, P < 0.01). Histological examination revealed many apoptotic tumor cells, infiltration of lymphocytes and macrophages in the OK-5w group. The two-color immunofluorescence assay showed that the proportion of natural killer (NK) cells and IFN-gamma-producing cells in the liver were significantly higher in the OK-5w group.


CONCLUSIONS
These findings showed that systemic administration of OK-Lipo contributed to prolonging the survival of rats with HCC. OK-Lipo induced NK cells and IFN-gamma-producing cells specifically in the liver and these cells seemed to reduce hepatocarcinogenesis and tumor growth.
Uehara
Kazuhiro
K
Department of Internal Medicine III, Niigata University School of Medicine, Japan.
Ichida
Takafumi
T
Sugahara
Satoshi
S
Ishikawa
Toru
T
Yamagiwa
Satoshi
S
Yoshida
Yuhei
Y
Nomoto
Minoru
M
Katoh
Masashi
M
Satoh
Hiroshi
H
Watanabe
Hisami
H
Abo
Toru
T
Asakura
Hitoshi
H
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000401:mortality; D004195:Disease Models, Animal; D007371:Interferon-gamma / Q000187:drug effects* / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D008099:Liver / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000401:mortality; D016131:Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology; D008297:Male; D010844:Picibanil / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D016019:Survival Analysis
D010844:Picibanil; D007371:Interferon-gamma