Anti-tumor effects of 25-hydroxycholesterol and low-dose recombinant tumor necrosis factor-alpha on rat liver tumorigenesis: modulated differentiation therapy for hepatocellular carcinoma.
Previously, we have demonstrated that treatment of rat AH136B ascites hepatoma cells with 25-hydroxycholesterol (25-OH) induces apoptosis. In this study, to elucidate whether modulated differentiation therapy may be useful in treating patients with hepatoma, we assayed the effects of 25-OH and/or tumor necrosis factor-alpha (TNF) on rat AH136B ascites hepatoma cells in vivo. Here we show that a high concentration of TNF (250 U/ml) mediated a stronger cytocidal effect than a low concentration of TNF (25 U/ml) in vitro. Flow cytometric DNA analysis also showed that treatment of cells with the high concentration of TNF (250 U/ml) increased the percentage of AH136B cells in the G0/G1 phase, while 25 U/ml of TNF did not cause any marked change in cell kinetics. In in vivo experiments, 25-OH (80 microg/rat) and TNF (500 U/rat) were administered after transplanting AH136B cells into Donryu rats intraperitoneally. We found that tumor development was completely inhibited by this treatment in 3 of 9 rats, and their 40-day survival rate was 44%; in contrast, rats administered 25-OH (80 microg/rat) alone or TNF (500 U/ml) alone developed peritonitis carcinomatosa, and died within 13 days of inoculation. These findings suggest that local combined treatment with 25-hydroxycholesterol and low-dose TNF can induce synergistic anti-tumor effects.
Yokoyama
S
S
Department of Surgery II, Kumamoto University School of Medicine, Kumamoto 860-0811, Japan.
Nozawa
F
F
Tanaka
S
S
Muneyuki
S
S
Ogawa
M
M
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000517:prevention & control*; D006888:Hydroxycholesterols / Q000008:administration & dosage*; D008113:Liver Neoplasms / Q000517:prevention & control*; D008297:Male; D009368:Neoplasm Transplantation; D051381:Rats; D011994:Recombinant Proteins / Q000008:administration & dosage*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage*
D006888:Hydroxycholesterols; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C007997:25-hydroxycholesterol