Suppression of rat liver tumorigenesis by 25-hydroxycholesterol and all-trans retinoic acid: differentiation therapy for hepatocellular carcinoma.
To determine whether differentiation therapy is useful in treating patients with hepatoma, we assayed the effects of 25-hydroxycholesterol (25-OH) and/or all-trans retinoic acid (ATRA) on rat AH136B ascites hepatoma cells. Flow cytometric DNA analysis showed that treatment of cells with 25-OH alone induced entry into the sub-G1 phase in a dose-dependent manner. While ATRA alone was ineffective, it enhanced the activity of 25-OH. Condensed and fragmented nuclei occurred mainly in cells treated with 25-OH (4 microg/ml). When cells treated with 25-OH (4 microg/ml), or 25-OH (4 microg/ml) + ATRA (1 microM) were transplanted into Donryu rats, we found that tumor development was completely inhibited; in contrast, rats administered the methanol-treated AH136B cells developed tumors. These findings suggest that AH136B cells in the sub-G1 phase can not recover tumorigenicity, and that the administration of a 3-hydroxy-3-methylglutaryl CoA reductase inhibitor, such as 25-OH, and ATRA may be effective in treating patients with hepatoma.
Yokoyama
S
S
Department of Surgery II, Kumamoto University School of Medicine, Kumamoto 860-0811, Japan.
Nozawa
F
F
Mugita
N
N
Ogawa
M
M
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000175:diagnosis / Q000188:drug therapy*; D017690:Cell Transplantation; D003937:Diagnosis, Differential; D006888:Hydroxycholesterols / Q000008:administration & dosage; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D008114:Liver Neoplasms, Experimental / Q000175:diagnosis / Q000188:drug therapy*; D008297:Male; D051381:Rats; D014212:Tretinoin / Q000008:administration & dosage; D014407:Tumor Cells, Cultured
D006888:Hydroxycholesterols; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D014212:Tretinoin; C007997:25-hydroxycholesterol