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Role of Asparagine Synthetase and Asparagyl-transfer RNA Synthetase in the Cell-killing Activity of Asparaginase in Chinese Hamster Ovary Cell Mutants¹

Department of Medical Biophysics, University of Toronto, and the Ontario Cancer Institute, Toronto, Ontario M4X 1K9, Canada

The cell-killing activity of asparaginase on three classes of Chinese hamster ovary cell mutants was examined: a mutant which overproduces asparagine synthetase (AH5); mutants defective in asparagine synthetase (N3 and N4); and mutants conditionally defective in asparagyl-transfer RNA synthetase (Asn 3, Asn 7, and Asn 9). The overproducer was more resistant to the cell-killing activity of asparaginase than wild-type Chinese hamster ovary cells, while mutants defective in asparagine synthetase were more sensitive. Surprisingly, the asparagyl-transfer RNA synthetase mutants were even more sensitive to asparaginase than the asparagine synthetase mutants. In a preliminary survey of four human lymphoid cell lines (RPMI 8402, RPMI 8392, B46M, and Molt-4F) which showed dramatically different asparaginase sensitivity, however, sensitivity to the cell-killing activity of asparaginase was correlated with reduced levels of asparagine synthetase and not with reduced levels of asparagyl-transfer RNA synthetase.

¹ Supported by grants from the National Cancer Institute of Canada and Grant MT 1877 from the Medical Research Council of Canada.

² Research student of the National Cancer Institute of Canada.

³ To whom requests for reprints should be addressed.

Received 9/30/80. Accepted 5/ 7/81.