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Effect of L-Asparaginase on DNA Synthesis in Regenerating Liver and in Other Dividing Tissues¹

Department of Pathology, New York University School of Medicine, New York, New York 10016, and Fels Research Institute and Department of Pathology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140

L-Asparaginase strongly inhibits the growth of certain animal tumors and has been found to delay the appearance of mitosis which occurs in regenerating rat liver after partial hepatectomy. The mitotic activity of normal intestinal and lymphoid cells was not affected. The present investigation deals with the effect of this enzyme on DNA synthesis in residual hepatocytes following 70% hepatectomy, in several normally dividing mammalian cells and in certain quiescent tissues stimulated to divide.

A single, subtumoricidal dose of L-asparaginase was found to delay DNA synthesis approximately 10 hr in regenerating liver. Other dividing cells were not affected. This included intestinal and lymphoid cells as well as renal tubular cells stimulated to divide by unilateral nephrectomy or folic acid injection and salivary acinar cells stimulated by isoproterenol.

The hepatocytes recovered from the enzyme effect 10 to 12 hr after the operation and were resistant to its delaying effect if the enzyme was administered at this time. These studies suggest that some early phase of the biochemical response to 70% hepatectomy may be dependent upon an exogenous source of asparagine, which implies the participation in this response of important, newly synthesized proteins.

¹ Supported by Grant E-355 C from the American Cancer Society and by Grant 08373 from the National Cancer Institute, USPHS.

² Career Scientist of the Health Research Council of the City of New York.

Received 4/21/69. Accepted 5/21/69.