Some tumor cells have a nearly absolute requirement for exogenously supplied asparagine. Others, however, can fulfill their needs by endogenous biosynthesis. Those that require asparagine to be supplied are uniquely susceptible to treatment by the enzyme that hydrolizes asparagine, namely 1-asparaginase. While treatment of various types of tumors with 1-asparaginase has proven to be effective under certain circumstances, only a very small number of tumors are amenable to this treatment. Because of this limitation, we have begun a detailed description of the metabolic differences between those cells that are sensitive to 1-asparaginase and those that are resistant. When this is accomplished, we hope to be able to diagnose those cell types that are either sensitive or resistant and, in addition, propose new adjuvants to 1-asparaginase therapy that might make it more broadly useful. We have characterized the enzyme responsible for the cellular synthesis of asparagine. We have studied its physical and kinetic properties and are in the process of trying to describe the method by which it is controlled. In addition, we are studying the metabolism of asparagine in both 1-asparaginase-sensitive and -resistant tumor cells. We have found that a major role for asparagine in tumor cells is for the production of glycine. It appears that the nitrogen of asparagine is a major source for the nitrogen of glycine. The carbon of the asparagine appears to be used for the formation of oxaloacetate by a series of reactions that do not require cellular asparaginase. In addition, it seems that the metabolism of asparagine is required in order that glutamate and glutamine can be utilized for cellular energy production. The enzymes of these various pathways are being characterized so that we can predict control mechanisms for the metabolism of asparagine and the other amino acids. (B)
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