glutaminase and Leukemia--Myeloid

We treated 13 adult patients with acute leukemia or chronic myelocytic leukemia (CML) in blast phase using succinylated Acinetobacter glutaminase-asparaginase (SAGA) administered on a daily dose schedule. SAGA reduced the peripheral blast count in two patients with acute lymphoblastic leukemia and two with blastic CML; however, no patient achieved either complete or partial remission. Marked central nervous system toxic effects (encephalopathy and coma) were observed, limiting treatment in patients whose disease appeared responsive; this effect finally prompted early discontinuance of the trial. Other toxic effects observed included nausea, hyperglycemia, and respiratory alkalosis. Hypersensitivity reactions to the enzyme were not seen. Pharmacologic analyses showed that prolonged blood glutamine depletion was achieved only by daily enzyme administration; however, we noted the importance of performing amino acid analysis on blood which was deproteinized immediately following phlebotomy. Our results demonstrate excessive central nervous system toxicity when glutaminase-asparaginase is administered on a daily schedule. Because of this effect, we propose that future trials of similar enzymes be limited to short courses of enzyme therapy, possibly with the addition of antimetabolites or amino acid analogs, which could enhance the antitumor effect without increasing toxicity.

Topics: Acinetobacter; Adult; Antineoplastic Agents; Asparaginase; Clinical Trials as Topic; Drug Administration Schedule; Follow-Up Studies; Glutaminase; Humans; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid; Leukemia, Myeloid, Acute

Well-coupled mitochondria of hematopoietic tumors were isolated from mouse erythroleukemia and rat chloroma tumors grown in male DBA/2J mice and Long-Evans rats, respectively. We used erythroleukemia and chloroma mitochondria to determine their ability to utilize glutamine as an energy source for adenosine triphosphate formation. Oxypolarographic tests showed the following. (a) Presence of a prominent glutaminase activity in erythroleukemia and chloroma mitochondria is evidenced by their active glutamine-supported respiratory state 3. (b) Glutamine oxidation is mediated through a nicotinamide adenine dinucleotide-linked reaction inhibited by rotenone. (c) Under similar conditions, mitochondria isolated from rabbit bone marrow have shown a feeble glutamine oxidation activity, while in mitochondria from rat liver the activity was not detectable and in those from rat kidney it was prominent as expected. (d) The determination of apparent Km and Vmax values for substrate-supported adenosine triphosphate formation has shown 8- to 10-fold lower Km values for glutamine oxidation as compared to that of glutamate, with virtually the same Vmax for each substrate in each mitochondria. These results clearly show the presence of a high glutamine oxidation activity in erythroleukemia and chloroma mitochondria and suggest that one of the glutamine hydrolysis products in those mitochondria may have an important role in supplying adenosine triphosphate in the corresponding malignant cells.

Topics: Adenosine Triphosphate; Animals; Cell Fractionation; Glutamates; Glutaminase; Glutamine; Kinetics; Leukemia, Erythroblastic, Acute; Leukemia, Myeloid; Male; Mice; Mitochondria; Neoplasms, Experimental; Polarography; Rabbits; Rats; Rotenone

Topics: Asparaginase; Carbon Radioisotopes; Diagnosis, Differential; Glutaminase; Humans; Leukemia, Lymphoid; Leukemia, Myeloid; Lymphocytes

Topics: Acute Disease; Asparaginase; Cytarabine; Daunorubicin; Glutaminase; Humans; Leukemia; Leukemia, Myeloid; Vinblastine; Vincristine