Deoxycoformycin toxicity in mice after long-term treatment.

Deoxycoformycin, a tight-binding inhibitor of the enzyme adenosine deaminase, is a potent lymphocytotoxic agent. To examine the effect of deoxycoformycin on mouse tissues the drug was administered IP either by single or by repeated injections at one of two dose levels (0.2 or 10.0 mg/kg). Treatment with repeated injections at the higher dose caused retardation of growth and increases in lung and splenic mass. Body temperature, hematocrit, and total leukocyte count remained constant. Single injections at the lower dose caused complete inhibition of adenosine deaminase in liver and blood, and partial inhibition in jejunum and spleen, but at the higher dose complete inhibition of the enzyme in all tissues was obtained. Dosage appeared to have no effect on the rate of recovery of the deoxycoformycin-inhibited enzyme but marked tissue differences were observed. The enzymic activity recovered rapidly in jejunum (100% in 1 day) but slowly in other tissues (after 28 days, about 60% in spleen and liver; about 85% in kidney and blood, and 100% in lungs). These observations suggest that the recovery of inhibited enzyme depends largely upon the rate of proliferation of cells and protein synthesis. These tissue differences in recovery rates may play a role in the pharmacological and chemotherapeutic behavior of this drug.