Immunosuppression by 2′-deoxycoformycin: Studies on the mode of administration

Abstract

It was previously reported that continuous infusion of 2′-deoxycoformycin (DCF), a potent inhibitor of the enzyme adenosine deaminase (ADase), produces a severe immunodeficiency of both T and B lymphocytes (A. Tedde, M. E. Balis, S. Ikehara, R. Pahwa, R. A. Good, and P. P. Trotta, Proc. Nat Acad. Sci. USA 77, 4899 (1980)). In the present study the immunological and biochemical effects in C57BL/6J mice of daily single intraperitoneal injections of DCF are examined. Five days of daily injections of DCF at 0.4 mg/kg body wt/day produced both immunosuppression and lymphocytotoxicity. Parallel experiments indicated that continuous infusion of DCF at the lower dose of 0.3 mg/kg body wt/day resulted in a more potent depression of immune function and a greater lymphocytotoxicity. In particular we have observed after single injections: (i) A decrease in body weight of 4.7%, compared to 16.2% after continuous infusion; (ii) a decrease in differential lymphocyte count from 90.3% (normal) to 65.6%, compared to 31.4% after continuous infusion, and a decrease in leukocyte count (per mm 2) from 5200 (normal) to 3800, compared to 2300 after continuous infusion, while no difference in other blood parameters, including erythrocyte number, hematocrit, and hemoglobin concentration, was observed; (iii) on histological examination, a depletion of T and, to a lesser extent, B lymphocytes, and an atrophy of lymph nodes, spleen, and thymus; and (iv) significant depression in blastogenesis induced by the T-cell mitogens concanavalin A and phytohemagglutinin and, to a lesser extent, by the B-cell mitogen Escherichia coli lipopolysaccharide. ADase was inhibited to a high degree ranging from 84 to 94% in lymphoid organs and erythrocytes from animals receiving DCF by either mode of administration. These data provide further direct support for the importance of ADase to proper lymphocyte function, and suggest that continuous infusion may be the preferred mode of administration in clinical trials of DCF as an antileukemic agent.