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Enhancement of Antitumor Activity of Glutamine Antagonists 6-Diazo-5-oxo-L-norleucine and Acivicin in Cell Culture by Glutaminase-Asparaginase¹

Memorial Sloan-Kettering Cancer Center, New York, New York 10021

Mouse P388 and L1210 leukemia cells grown in vitro were found to be 4 to 10 times more sensitive to 6-diazo-5-oxo-L-norleucine and 3 to 5 times more sensitive to Acivicin than were 3T3 and C57BL x DBA/2 F₁ embryonic fibroblasts. The combined actions of succinylated Acinetobacter glutaminase-asparaginase and 6-diazo-5-oxo-L-norleucine or Acivicin produced synergistic inhibition of nucleic acid synthesis in P388 tumor cells.

An uptake system for Acivicin is described. Its properties in P388 and 3T3 cells are similar in their strong temperature dependence, utilization of the "L" transport system, presumably competitive inhibition by glutamine, similar K_m's (about 200 µM), and potent inhibition by p-chloromercuribenzene sulfonate, Na⁺. However, Acivicin uptake was inhibited in 3T3 (but not in P388) cells by KCN or 2,4-dinitrophenol. At equilibrium in P388 cells, the intracellular level of Acivicin was approximately 57-fold greater than was the extracellular concentration. The accumulated Acivicin was not metabolized by P388 cells, nor does exchange of ³H label into water occur. Rapid efflux of Acivicin occurred with both cell lines at 37°, but efflux from 3T3 cells was greatly diminished at 0°. The rate of efflux was accelerated by including glutamine or unlabeled Acivicin in the extracellular medium.

¹ Supported by USPHS Grants CA-15860 and CA-08748 from the National Cancer Institute, Department of Health, Education and Welfare.

² To whom requests for reprints should be addressed.

Received 7/ 7/80. Accepted 12/30/80.

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