DON (6-diazo-5-oxo-L-norleucine), a
glutamine antagonist, has been subjected to limited clinical trials since 1957. Use of the
drug in adults has been curtailed due to sparse reports of effectiveness as well as its dose-limiting toxicities, i.e., severe
nausea,
vomiting and
mucositis. In earlier studies, children given DON orally in combination with
6-mercaptopurine had significant prolongation of remission of acute
leukemias during maintenance
therapy. As DON is
acid-labile and relatively unstable in
solution,
oral administration does not appear to be ideal for DON. In the trial described in this report, i.v. DON
therapy was studied, using i.v.
chlorpromazine to control
vomiting, in 20 children, 17 of whom were evaluable following treatment at DON dose levels ranging from 150 mg/m2 to 520 mg/m2.
Nausea and
vomiting, the dose-limiting toxicity for adults, was controlled with
chlorpromazine.
Mucositis, which has also been observed in adults, did not occur in the children given DON i.v. A maximum tolerated dose was not defined; however, the projected maximum tolerated dose appears to be in excess of 450 mg/m2. DON was measured in plasma using a rapid-sampling HPLC procedure. The total body clearance, plasma t1/2, and area under the plasma concentration curve (AUC) were calculated using a noncompartmental method. The
drug is rapidly cleared from plasma (t 1/2 = 3 h), and its volume of distribution is approximately twice that of total body water in children. These pharmacokinetic data, differ from that of adults reported by others. Specifically, the plasma t 1/2 for children is longer: total body clearance (Cl), and volume of distribution at steady state (Vss) are greater. In addition, no dose dependency of t 1/2, Cl or Vss was observed in this study, and the DON pharmacokinetics were linear and predictable. Five of nine children with acute
leukemia showed improvement, though insufficient for classification as partial response, and five of eight children with solid
tumors also showed improvement. Further trials using DON in combination with thiopurines or other agents appear indicated.