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Inhibition of Immune Responses by Glutamine Antagonism: Effect of Azotomycin on Lymphocyte Blastogenesis¹

Departments of Developmental Therapeutics [E. M. H.] and Biomathematics [B. W. B.], The University of Texas M. D. Anderson Hospital and Tumor Institute at Houston, Houston, Texas 77025

The effects of the glutamine antagonist azotomycin on the immune response in vitro was studied by measuring the effect of the drug on the blastogenic responses of human lymphocytes to mitogens. Doses of 1.0 µg/ml or greater completely inhibited responses to phytohemagglutinin, streptolysin O, and allogenic leukocytes. Both thymidine-³H incorporation and morphological manifestations of blastogenesis were inhibited. Inhibition could be achieved without cytotoxicity, as demonstrated by stable viable cell counts and restoration of responses by washing the drug from the cultures. Specificity of action was proved by complete reversal of inhibition by L-glutamine. Addition of a wide range of L-asparaginase doses markedly increased the inhibition produced by azotomycin. Certain dosage combinations were synergistic. This study suggests that, depending upon pharmacological factors, azotomycin, either alone or in combination with L-asparaginase, may produce potent immunosuppression in vivo.

¹ Presented in part at The 61st Annual Meeting of The American Association for Cancer Research, Philadelphia, Pa., April 9–11, 1970. Supported in part by Contract PH 43 68 949 from the Collaborative Research Program, Transplantation Immunology Branch, National Institute of Allergy and Infectious Diseases, NIH, and Grants CA 05831, FR 05511, and CA 11430 from the USPHS.

Received 12/ 7/70. Accepted 2/23/71.

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