The present proposal stems from our recent finding that initiated rats exposed for 13 months to orotic acid a pyrimidine nucleotide precursor developed 100% hepatocellular carcinoma with many metastases to lungs. Of the many mechanisms considered, creation of altered nucleotide pools that occurs following orotic acid feeding appears attractive because such an altered state can induce both genomic as well as membrane perturbations. Alterations at genomic and at membrane levels are considered to play important roles in tumorigenic process. In the present proposal experiments are designed to characterize the Orotic Acid Model in greater detail. For e.g. what is the minimum time of exposure to orotic acid required to develop hepatocellular carcinoma? Are the hyperplastic nodules developed in this model similar to those developed in other models? Can an imbalance of nucleotide pools caused by other means promote liver carcinogenesis? What types of genomic perturbations can be caused by an imbalance of nucleotides? Preliminary experiments carried out revealed that in addition to arotic acid feeding, thymine or thymidine also promoted the appearance of Gamma-glutamyl transferase positive foci induced by 1,2-dimethylhydrazine. In another preliminary experiment it was observed that one type of DNA damage caused by feeding arotic acid is the induction of alkali labile lesions. Some attractive features of this model are, orotic acid is a normal cellular constituent and present in the 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 creating several metabolic disturbances such as an essential amino acid deficiency and disturbances in urea cycle and unfortunately disturbances of this kind are not uncommon in human population at large.

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National Cancer Institute (NCI)
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Chemical Pathology Study Section (CPA)
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University of Toronto
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M5 1S8
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