During the past years of the support, we demonstrated that the cocarcinogenic effect of a choline-deficient (CD) diet in the induction of liver tumors by several carcinogens is primarily mediated through its promoting action. Several agents or the conditions which modify the promoting efficacy of the CD diet have been idenfified, and the modifiers were used to nalyze the mechanisms of action of the CD diet as a promoter. We postulated that in liver tumor promoting two components are involved; a stimulation of the proliferation of initiated cells and a suppression of the proliferation of non-initiated cells. In the renewal application, we will test the validity of this concept with the promotion regimen of a CD diet plus barbiturates on the initiated liver. Several other modifiers of the CD diet promotion will be explored, such as altering the quality of fat in the diet, butylated hydroxytoluene and a hypolipedemic drug, and attempts will be made to characterize factor(s) responsible for the modifications, including a possible presence of separate stages of the liver tumor promotion. The nature of regressing putative preneoplastic foci will be investigated, and roles of the promoting agents in the resurgence of foci will be evaluated. Finally, the dietary modification of choline deficiency will be applied to investigate the sequential changes of methapyrilene carcinogenesis, and to analyze whether cholangiocarcinomas and hepato-cellular carcinomas develop through common preneoplastic precursor lesions. It is hoped that the proposed studies will provide newer information relevant to the mechanisms of tumor promotion in the liver and its nutritional modifications.
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