title: The ex vivo production of ammonia predicts L-asparaginase biological activity in children with acute lymphoblastic leukemia.
abstract: Patients with acute lymphoblastic leukemia (ALL), who develop antiasparaginase antibodies without clinical allergic reactions ("silent inactivation") during L: -asparaginase (L: -Asp) treatment, have poor outcomes. Ammonia is produced by hydrolysis of asparagine by L: -Asp. We postulated that plasma ammonia level might reflect the biological activity of L: -Asp. Five children with ALL treated according to the Tokyo Children's Cancer Study Group (TCCSG) protocol were enrolled. Plasma ammonia levels were analyzed immediately and 1 h after incubation at room temperature and "ex vivo ammonia production" was defined as increase in ammonia concentration. Ex vivo ammonia production well correlated with L: -Asp activity (r = 0.882, P < 0.01, n = 23). It always exceeded 170 microg/dL (170-345 microg/dL) in induction therapy. We found 3 patients whose ammonia production was negligible during later phases of therapy. Antiasparaginase antibody was detected and L: -Asp activity decreased in these patients. Ex vivo ammonia production is a surrogate marker of L: -Asp biological activity.
authors.affiliation: Department of Pediatrics, St. Luke's International Hospital, 9-1 Akashi-cho, Chuo-ku, Tokyo, 104-8560, Japan.|Department of Pharmacy, St. Luke's International Hospital, Tokyo, Japan.|Department of Practical Pharmacy, Keio University, Tokyo, Japan.
authors.forename: Shizuka
authors.initials: S
authors.lastname: Watanabe
authors.affiliation: Department of Pediatrics, St. Luke's International Hospital, 9-1 Akashi-cho, Chuo-ku, Tokyo, 104-8560, Japan.|Department of Practical Pharmacy, Keio University, Tokyo, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Miyake
authors.affiliation: Department of Pediatrics, St. Luke's International Hospital, 9-1 Akashi-cho, Chuo-ku, Tokyo, 104-8560, Japan.
authors.forename: Chitose
authors.initials: C
authors.lastname: Ogawa
authors.affiliation: Department of Pediatrics, St. Luke's International Hospital, 9-1 Akashi-cho, Chuo-ku, Tokyo, 104-8560, Japan.|Department of Practical Pharmacy, Keio University, Tokyo, Japan.
authors.forename: Haruna
authors.initials: H
authors.lastname: Matsumoto
authors.affiliation: Department of Pediatrics, St. Luke's International Hospital, 9-1 Akashi-cho, Chuo-ku, Tokyo, 104-8560, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Department of Pediatrics, St. Luke's International Hospital, 9-1 Akashi-cho, Chuo-ku, Tokyo, 104-8560, Japan.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Hirabayashi
authors.affiliation: Department of Pediatrics, St. Luke's International Hospital, 9-1 Akashi-cho, Chuo-ku, Tokyo, 104-8560, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Hasegawa
authors.affiliation: Department of Pharmacy, International University of Health and Welfare, Tokyo, Japan.
authors.forename: Tadao
authors.initials: T
authors.lastname: Inoue
authors.affiliation: Department of Practical Pharmacy, Keio University, Tokyo, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Kizu
authors.affiliation: First Department of Pediatrics, Toho University, Tokyo, Japan.
authors.forename: Reiko
authors.initials: R
authors.lastname: Machida
authors.affiliation: First Department of Pediatrics, Toho University, Tokyo, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Ohara
authors.affiliation: Department of Pediatrics, St. Luke's International Hospital, 9-1 Akashi-cho, Chuo-ku, Tokyo, 104-8560, Japan.
authors.forename: Ryota
authors.initials: R
authors.lastname: Hosoya
authors.affiliation: Department of Pediatrics, St. Luke's International Hospital, 9-1 Akashi-cho, Chuo-ku, Tokyo, 104-8560, Japan. manabe-luke@umin.ac.jp.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Manabe
mesh_terms: D000641:Ammonia / Q000097:blood*; D000970:Antineoplastic Agents / Q000276:immunology / Q000627:therapeutic use*; D001215:Asparaginase / Q000276:immunology / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D002648:Child; D002675:Child, Preschool; D016903:Drug Monitoring / Q000379:methods*; D019008:Drug Resistance, Neoplasm / Q000276:immunology; D005260:Female; D006801:Humans; D006868:Hydrolysis; D007074:Immunoglobulin G / Q000097:blood; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood* / Q000188:drug therapy* / Q000276:immunology; D011237:Predictive Value of Tests; D011446:Prospective Studies
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D007074:Immunoglobulin G; D000641:Ammonia; D001215:Asparaginase