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Combination Therapy of Animal Tumors with L-Asparaginase and Antagonists of Glutamine or Glutamic Acid¹

Divisions of Experimental Chemotherapy and Special Studies, Sloan-Kettering Institute for Cancer Research, New York, New York 10021

Treatment of the 1-day-old Ehrlich ascites tumor with combinations of selected doses of L-asparaginase and the L-glutamine antagonist, 6-diazo-5-oxo-L-norleucine, or of the L-glutamine acid antagonist, DL-methionine-DL-sulfoximine, produced significantly more growth inhibition without a marked increase in host toxicity than did treatment with L-asparaginase administered alone. In the 3-day-old tumor treated with the combination of L-asparaginase and 6-diazo-5-oxo-L-norleucine, there was a significant enhancement of growth inhibition as compared with the effect of either drug used alone. A less significant increase of growth inhibition was obtained with combination of L-asparaginase and L-glutamyl--hydrazide as compared with the effect of this chemical administered alone.

Combinations of L-asparaginase and 6-diazo-5-oxo-L-norleucine produced increased antitumor effects in mouse melanoma B16 and to a lesser degree in the solid form of Ehrlich tumor and Walker carcinosarcoma 256 of the rat.

Enhanced antitumor activity was seen when 2-deoxy-D-glucose was included with L-asparaginase, azaserine, DL-methionine-DL-sulfoximine, and their combinations in treatment of the Ehrlich ascites tumor.

¹ Supported in part by Grant CA-08748 from the National Cancer Institute, USPHS, and the Elsa U. Pardee Foundation. A portion of these data has been presented at the 60th Annual Meeting of the American Association for Cancer Research, March 23 to 25, 1969 (26).

Received 8/14/69. Accepted 10/23/69.