BUDR DEPENDENCE, MALIGNANCY, AND DIFFERENTIATION

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Experiments were carried out to test for the presence of transfectable oncogenes controlled by 5-bromodeoxyuridine (BrdU) in BrdU-dependent mutants of a Syrian hamster melanoma line. In this line, the transformed phenotype is expressed only in the presence of high concentrations of BrdU. In a related approach, tests were begun to search for transfectable oncogenes in tumors with hereditary disposition, for example, neurofibromatosis (NF). The relationship between chromosomal breakage events and the perturbation of nucleotide metabolism was analyzed in tests on the human fragile X syndrome, which is associated with mental retardation and whose expression in cultured cells is induced by the perturbation of thymidine biosynthesis. Hybrids were isolated from crosses between Chinese hamster cells and lymphoblastoid cells from male patients with the fragile X syndrome. The hybrids expressed the fragile site in approximately 10% of metaphases. Clones resistant to the toxic effects of 5-fluorouracil have been isolated from Chinese hamster fibroblasts. A primary lesion in these mutants appears to be an altered CTP synthetase activity that is no longer sensitive to negative regulation by CTP. Experiments on the toxicity of 5-hydroxymethyldeoxyuridine (hmdU) were performed. It was found that a major metabolite of hmdU is the free pyrimidine hydroxymethyluracil (hmUra), which is not toxic, and also that resistance to hmdU toxicity is correlated with an increased ability to degrade the nucleoside to hmUra. (P)