Biochemical and pharmacological studies with asparaginase in man.

The biochemical and pharmacological effects oÃEscherichia coli asparagjnase were studied in 45 patients with leukemia and solid tumors. The drug was given in three different schedules: as a single dose, daily, or weekly. After i.v. injec tion, the peak activity obtained was dose related; the initial clearance of the enzyme from plasma followed first-order kinetics, and a half-life was about 14 to 22 hr. Daily adminis tration of the enzyme caused cumulation in serum. Enzyme activity was detectable 13 to 22 days after single injections. Plasma asparagjne and aspartic acid levels in leukemia were compared with levels in 20 normal individuals. Three of 10 patients with acute lymphocytic leukemia had marked aber ration in their amino acid levels. Patients with acute myelocytic leukemia as a group had lowered levels of asparagine. After enzyme administration, plasma asparagine fell precipi tously to nearly unmeasureable levels. Asparagine reappeared in plasma 23 to 33 days after single injections. Even 0.2 i.u./kg as a skin test dose produced a substantial fall of plasma asparagine. Asparaginase produced multiple manifestations of toxicity involving brain, liver, pancreas, kidney, fingernail, and hypersensitivity reactions. Asparagine was given as a "rescue"