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Effects of Threonine Deaminase on Growth and Viability of Mammalian Cells in Tissue Culture and Its Selective Cytotoxicity toward Leukemia Cells¹

Department of Biochemistry, Cornell University Medical College, New York, New York 10021

The purpose of this work was to investigate the effects of threonine deprivation on the growth and viability of malignant and nonmalignant cells in vitro. Threonine deaminase was added to the culture media of two mouse leukemias (RADA1 and EARAD1), mouse L-cells, and human GM 38 fibroblasts. This enzyme irreversibly deaminates threonine to -ketobutyrate and ammonia, products that cannot be utilized by the cell for the resynthesis of threonine. Growth inhibition was observed in all cases, but only the two leukemia cell lines were killed in 24 to 48 hr after treatment. In the threonine-deficient medium, L-cells and GM 38 fibroblasts showed little or no loss of viability after 3 and 5 days, respectively. The inhibition of cell division and loss of viability were related to the ability of threonine deaminase to reduce threonine levels in the medium. However, addition of threonine deaminase to the cultures was more effective than simply using a threonine-free medium. Protein and RNA synthesis in RADA1 cells ceased 5 hr after treatment with the enzyme, while DNA synthesis gradually decreased between 5 and 24 hr. When the threonine-depleted medium was replaced by complete medium, inhibited L-cells resumed cell division, while fibroblasts did not. When the fibroblasts were trypsinized and replated in fresh medium, the cells resumed normal growth. These findings demonstrate that certain leukemia cells are more sensitive to threonine deprivation than some nonmalignant cells and suggest the possibility that threonine deaminase may have therapeutic uses in the treatment of cancer.

¹ This work was supported in part by NIH Grant CA-13259.

² Present address: Department of Pathology, Tufts Univeristy School of Medicine, Boston, Mass. 02111.

³ To whom requests for reprints should be addressed.

Received 12/ 6/76. Accepted 4/27/77.