A. DeFELICE,a, M. Rosenberg, J. Matias
Jun 1, 1988
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Annals of the New York Academy of Sciences
Abstract
Methionine, an essential amino acid, functions as a methyl donor for numerous biosynthetic processes which require transmethylation reactions. It has recently been shown that the rate of transmethylation proceeds faster in many types of cancer cells in comparison to normal cells.' Other investigators studying the methionine adenosyltransferase (MAT) reactions in extracts of tumor and normal tissues have suggested the use of inhibitors of the MAT reaction as a means of inhibiting cancer growth? We explored this possibility by supplementing the normal growth media of Lewis lung carcinoma (LLC) and B16-Fl0 melanoma cells with various structural analogues of methionine. The data in FIGURE 1 (see inset) show that the addition of L-ethionine at a concentration of 500 pg/ml inhibited the proliferation of LLC cells grown in a media which contained 38.5 pg/ml of methionine. This inhibition occurred at an ethi0nine:methionine ratio of 13:l. Viability of the ethionine-treated cells was high (85-90%). The absence of vacuolization, the lack of cell detachment from the substrate, and the maintenance of the typical cellular morphologic pattern suggest that ethionine may act by inhibiting cellular proliferation rather than through a direct toxic effect. A dose-response study on L-ethionine showed that the antiproliferative effects were evident even at a concentration of 250 p g / d for LLC cells. In contrast, a similar degree of growth inhibition of B16-Fl0 melanoma cells occurred at a much higher concentration (FIG. 1). Methionine is unique because it is the only amino acid that the body can use in either the Lor D-form. Thus, it is surprising to find that the L-isomer was 100% more potent than D-ethionine. Using preparations of the MAT enzymes, it has been