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Inhibition of tumor promotion and hepatocellular growth by dietary restriction in mice
Division of Toxicology, Department of Pharmacology and Toxicology, Indiana University School of Medicine 1001 Walnut Street MRF 003, Indianapolis, IN 46202, USA
1To whom correspondence should be addressed
The effects of dietary restriction on the growth of hepatic focal lesions in phenobarbital (PB) promoted mice were examined. Dietary restriction which can inhibit many age-related diseases in rodents including hepatic cancer also decreases cell proliferation and increases apoptosis in the liver. In contrast, PB, a non-genotoxic rodent hepatocarcinogen, enhances the growth of hepatic focal lesions in mice and rats by increasing cell proliferation and inhibiting apoptosis. The present study examined the impact of dietary restriction on PB-induced hepatic tumor 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 diet/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/1) treatment to ad libitum-fed mice (group 2) enhanced focal lesion volume, number, and labeling index compared with group 1. In addition, PB treatment (group 2) inhibited apoptosis in normal and focal hepatocytes compared with untreated control mice (group 1). In contrast, in dietary restricted mice treated with PB (group 4) a significantly lower focal lesion volume, number and labeling index were seen compared with the ad libitumfed/PB treatment group (group 2). PB treatment in dietary 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 growth of preneoplastic focal lesions was inhibited. These results show that dietary restriction can ablate the tumor promotional effects of PB in hepatic focal lesions and suggest that inhibition of focal lesion DNA synthesis and enhancement of apoptosis may be a mechanism for this effect.
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