Methionine-dependence, the inability to grow when methionine is replaced by homocysteine, vitamin B-12 and folic acid, is a characteristic which is shown by a number of malignant and transformed cells and which is not evident in cells of normal origin. One possible implication of this phenomenon is that methionine-dependence is a direct manifestation of the heritable changes which accompany oncogenesis. A number of studies have been directed at determining the cause of methionine-dependence, with much emphasis placed on the involvement of methionine in methylation processes in tumor cells. We have chosen to study two other, related aspects of methionine metabolism, namely the role of methionine in polyamine biosynthesis and in taurine metabolism as they might relate to methionine-dependence. We propose to study the effects of methionine deficiency on the levels of polyamines and trauine and on the activities of the biosynthethic enzymes which produce these metabolites. In addition, we have asked if this possible relationship between methionine-dependence and polyamine (and trauine) metabolism might not be exploited as a means of treating tumors derived from cells showing methionine-dependence. We plan to approach the studies from two aspects: one is a strictly biochemical approach involving measurement of metabolite levels and enzyme activities and the use of metabolic inhibitors; the other is the use of 13C NMR spectroscopy to study the metabolic disposition of specifically 13C-labeled precursors in the methionine, polyamine and taurine pathways as a result of methionine deficiency. This latter technique is non-invasive and should provide information concerning the specific metabolic defect(s) which might be associated with methionine-dependence. We hope that these studies will give some insight into the metabolic changes which accompany oncogenesis and that they might be useful in the design of more effective modalities for the treatment of cancer.
