PROMOTION OF LIVER CARCINOGENESIS BY OROTIC ACID

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The present proposal stems from our recent observations that orotic acid, a precursor of pyrimidine nucleotides is not only an excellent liver tumor promoter but also has the potential to be a multiorgan tumor promoter. Unlike most of the tumor promoters, orotic acid does not induce cell proliferation either in the liver or in the colon, the 2 organs examined. A new hypothesis was postulated i.e. an imbalance in nucleotide pools such as the one that occurs following orotic acid feeding appears to play an important role in the promotion phase of the carcinogenic process. In the present proposal experiments are designed to characterize the Orotic Acid Model of liver tumor promotion in greater detail. In order to study the mechanism of tumor promotion, in the present proposal experiments are designed to obtain far fewer nodules but with increased probability of progressing to cancer. For example rats will be initiated with diethylnitrosamine and will be exposed to 1% orotic acid 5 or 10 weeks after initiation rather than 1 week after initiation. In a preliminary experiments such a protocol resulted in 1 or 2 nodules per rat with 100% incidence of nodules at the end of 20-40 weeks, and with 1 hepatocellular carcinoma. To test the multiorgan tumor potential of orotic acid, the effect of orotic acid on the intestinal carcinogenesis initiated with azoxymethane and on the urinary bladder carcinogenesis initiated with N-butyl-N-(4-hydroxybutyl) nitrosamine will be tested. Preliminary results indicated that orotic acid does indeed promote intestinal carcinogenesis initiated with azoxymethane. Some attractive features of this model that have human relevance are, orotic acid is a normal cellular constituent and present in the cow's milk in considerable quantities. Increased orotic acid in milk, serum and urine occurs in some hereditary disorders and such and increase can also be achieved by metabolic disturbances and dietary means such as high protein or amino acids intake. Unfortunately, disturbances of this kind and high protein intake are not uncommon in human population at large.