INHIBITION OF TUMOR PROMOTION AND HEPATOCELLULAR GROWTH BY DIETARY RESTRICTION IN MICE

The effects of dietary restriction on the growth of hepatic focal lesi ons in phenobarbital (PB) promoted mice were examined, Dietary restric tion which can inhibit many age-related diseases in rodents including hepatic cancer also decreases cell proliferation and increases apoptos is in the liver, In contrast, PB, a non-genotoxic rodent hepatocarcino gen, enhances the growth of hepatic focal lesions in mice and rats by increasing cell proliferation and inhibiting apoptosis, The present st udy examined the impact of dietary restriction on PB-induced hepatic t umor promotion, Focal lesions were produced by diethylnitrosamine (DEN ) treatment (35 mg DEN/kg body weight injections, twice per week for 8 weeks), After lesions were produced, mice were placed into one of the following four groups: NIH-07 control diet/no PB (group 1); NIH-07 di et/500 mg PB per liter of drinking water (group 2); dietary restricted NIH-07 diet/no PB (group 3); and dietary restricted NIH-7 diet/500 mg PB per liter of drinking water (group 4), In this study, PB (500 mg/l ) treatment to ad libitum-fed mice (group 2) enhanced focal lesion vol ume, number, and labeling index compared with group 1, In addition, PB treatment (group 2) inhibited apoptosis in normal and focal hepatocyt es compared with untreated control mice (group 1), In contrast, in die tary restricted mice treated with PB (group 4) a significantly lower f ocal lesion volume, number and labeling index were seen compared with the ad libitum-fed/PB treatment group (group 2), PB treatment in dieta ry restricted mice (group 4) did not inhibit focal apoptosis, in fact, the incidence of focal apoptosis was increased in these mice compared with ad libitum and PB-treated mice (group 2), In dietary restricted mice treated with PB (group 4), the ability of PB to promote the growt h of preneoplastic focal lesions was inhibited, These results show tha t dietary restriction can ablate the tumor promotional effects of PB i n hepatic focal lesions and suggest that inhibition of focal lesion DN A synthesis and enhancement of apoptosis may be a mechanism for this e ffect.