Factors which may influence the effectiveness of l-asparaginases as tumor inhibitors.

TLDR: The purpose of the present paper is to show in further detail the relationship between the tumor inhibitory activities and in vitro enzyme kinet, and how certain other properties of the E. coli asparaginase which prolong its action in vivo may augment its ability to inhibit tumors.

Abstract: A NUMBER of tumors of experimental animals and of man are strongly inhibited in vivo by certain l-asparaginases (Broome, 1961, 1963, 1965, 1968a; Mashburn and Wriston, 1964). However, preparations of the enzyme from different sources vary greatly in tumor inhibitory activity. In previous work we have demonstrated 2 factors which may determine this: first, the rate of removal of the asparaginase from the blood of treated animals, and secondly the avidity of the enzyme for asparagine (Broome, 1965; Schwartz, Reeves and Broome, 1966). Thus, yeast asparaginase which almost completely disappeared from mouse blood within 30 minutes of injection, failed to inhibit tumors, while guinea-pig serum asparaginase with a half-life in the blood of 11 to 19 hours, was highly effective (Broome, 1965). This explanation cannot, however, account for observations with the inducible asparaginase of E. coli, for it is normally cleared from the blood with a half-life which varies in different preparations from 55 minutes to 3 hours. Yet this enzyme, when tested either 1 day after tumor implantation or when palpable tumors are present, produces a greater tumor inhibition in relation to conventional in vitro enzyme assays than serum asparaginase of the guinea-pig or agouti (Schwartz, Reeves and Broome, 1966; Mashburn et al., 1967). Its effectiveness in vivo has been related to a particularly high avidity for asparagine (Schwartz, Reeves and Broome, 1966). The purpose of the present paper is to show in further detail the relationship between the tumor inhibitory activities and in vitro enzyme kinet.ics of asparaginases from E. coli and a agouti serum, and in addition to show how certain other properties of the E. coli asparaginase which prolong its action in vivo may augment its ability to inhibit tumors.