INHIBITORY EFFECT OF TRANSIENT ADMINISTRATION OF FLUTAMIDE (SCH-13521, 4'-NITRO-3'-TRIFLUOROMETHYLISOBUTYRANILIDE) ON DIETHYL-NITROSAMINE (DEN) INDUCED LIVER-TUMORS IN MALE B6C3F1 MICE

In order to understand the role of androgen in DEN induced liver tumorigenesis in mice, we studied the influence of anti-androgenic compound, flutamide (SCH 13521, 4'-Nitro-3'-trifluoromethylisobutyranilide) on liver tumors, in B6C3F1 male mice. At 6 weeks of age mice were treated with DEN, (0.2 muM/g body weight). Transient administration of flutamide (0.5 mg/g food) in diet to male mice for (i) three weeks immediately after diethylnitrosamine (DEN) treatment, for (ii) three weeks starting at the age of 25 weeks and (iii) starting at 25 weeks of age until end of experiment inhibited liver tumors incidence to 63%, 50% and 53%, respectively, compared to that of DEN alone, 81.3% (significantly different). However, continuous administration of this drug throughout the experimental period (58 weeks) produced 96.9% liver tumor incidence. The time-dependent sacrifice of DEN alone treated mice at 25, 30, 38, 44 and 58 weeks of age produced liver tumor incidence of 0, 12.5, 31.5, 43.8 and 81.3%, respectively (r = 0.99). Mean tumor number and size were also correlatively increased with the prolongation of latency and highest value was noted at 58 weeks of age. Implantation of testosterone pellet after castration significantly increased cytosolic androgen receptor levels but decreased in mice treated with flutamide. Three weeks administration of flutamide to male B6C3F1 mice enhanced nuclear BrdU incorporated cells in the liver. Our results suggested that flutamide reduces cytosolic androgen receptor levels and increases DNA synthesis. These factors may in part be responsible for the liver tumor inhibitory effect of flutamide in male mice.