DON, CONV and DONV-III. Pharmacologic and toxicologic studies.

The pharmacologie, toxicologic and oncolytic properties of the ketoamino acids DON (l-DON; 6-diazo-5-oxo-l-norleucine), CONV (l-CONV; 5-chloro-4-oxo-l-norvaline; 2-amino-5-chloro-levulinic acid) and DONV (l-DONV; 5-diazo-4-oxo-l-norvaline) were examined. DON was found to be the most active therapeutic agent of the three drugs against leukemia 1210 and also the most potent cytocidal agent against KB tumor cells in culture. The acute ld₅₀ values of the agents were dissimilar: CONV was the most toxic drug of the three after single intraperitoneal injections, and DONV the least toxic. Only DON showed evidence of prominent cumulative toxicity. In studies with isolated cells of leukemia 5178Y rendered resistant to l-asparaginase (L5178Y/AR), all three agents appeared to compete both with l-asparagine and with l-glutamine for transport into the cell. DONV competed most effectively with l-glutamine and CONV most effectively with l-asparagine. In mice, all three drugs were cleared from the plasma and excreted into the urine at a rapid rate. None was bound to the proteins of mouse plasma. After an intraperitoneal injection of 100 mg/kg, the concentration of DONV in the pancreas was approximately ten times that of CONV or DON; after comparable intravenous injections, only DONV could be identified in this tissue. Although the metabolism of all three ketoamino acids was found to be minor in degree, evidence is presented that they can be degraded in vitro by organ homogenates and also that purified enzymes can catalyze their transamination. In addition, DON was a good substrate for renal γ-glutamyl transferase (EC 2.3.2.2). In the case of DONV, some conversion to CO₂ by isolated tumor cells also was observed. From these and previous studies it is concluded that, of these analogs of l-glutamine and l-asparagine, DON is the most “l-glutamine-like” agent of the three, DONV the most “l-asparagine-like,” while CONV has important attributes of both amino acids.