title: Arginine deprivation using pegylated arginine deiminase has activity against primary acute myeloid leukemia cells in vivo.
abstract: The strategy of enzymatic degradation of amino acids to deprive malignant cells of important nutrients is an established component of induction therapy of acute lymphoblastic leukemia. Here we show that acute myeloid leukemia (AML) cells from most patients with AML are deficient in a critical enzyme required for arginine synthesis, argininosuccinate synthetase-1 (ASS1). Thus, these ASS1-deficient AML cells are dependent on importing extracellular arginine. We therefore investigated the effect of plasma arginine deprivation using pegylated arginine deiminase (ADI-PEG 20) against primary AMLs in a xenograft model and in vitro. ADI-PEG 20 alone induced responses in 19 of 38 AMLs in vitro and 3 of 6 AMLs in vivo, leading to caspase activation in sensitive AMLs. ADI-PEG 20-resistant AMLs showed higher relative expression of ASS1 than sensitive AMLs. This suggests that the resistant AMLs survive by producing arginine through this metabolic pathway and ASS1 expression could be used as a biomarker for response. Sensitive AMLs showed more avid uptake of arginine from the extracellular environment consistent with their auxotrophy for arginine. The combination of ADI-PEG 20 and cytarabine chemotherapy was more effective than either treatment alone resulting in responses in 6 of 6 AMLs tested in vivo. Our data show that arginine deprivation is a reasonable strategy in AML that paves the way for clinical trials.
authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom;
authors.forename: Farideh
authors.initials: F
authors.lastname: Miraki-Moud
authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom;
authors.forename: Essam
authors.initials: E
authors.lastname: Ghazaly
authors.affiliation: Haematopoietic Stem Cell Laboratory, Cancer Research UK London Research Institute, Lincoln's Inn Fields, London, United Kingdom;
authors.forename: Linda
authors.initials: L
authors.lastname: Ariza-McNaughton
authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom;
authors.forename: Katharine A
authors.initials: KA
authors.lastname: Hodby
authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom;
authors.forename: Andrew
authors.initials: A
authors.lastname: Clear
authors.affiliation: Haematopoietic Stem Cell Laboratory, Cancer Research UK London Research Institute, Lincoln's Inn Fields, London, United Kingdom;
authors.forename: Fernando
authors.initials: F
authors.lastname: Anjos-Afonso
authors.affiliation: Department of Haemato-Oncology, Royal Marsden Hospital, Sutton, United Kingdom;
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Liapis
authors.affiliation: Cytogenetics Department, Barts Health National Health Service Trust, Royal London Hospital, London, United Kingdom;
authors.forename: Marianne
authors.initials: M
authors.lastname: Grantham
authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom;
authors.forename: Fareeda
authors.initials: F
authors.lastname: Sohrabi
authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom;
authors.forename: Jamie
authors.initials: J
authors.lastname: Cavenagh
authors.affiliation: Polaris Pharmaceuticals Inc., San Diego, CA;
authors.forename: John S
authors.initials: JS
authors.lastname: Bomalaski
authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom;
authors.forename: John G
authors.initials: JG
authors.lastname: Gribben
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom; and.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Szlosarek
authors.affiliation: Haematopoietic Stem Cell Laboratory, Cancer Research UK London Research Institute, Lincoln's Inn Fields, London, United Kingdom;
authors.forename: Dominique
authors.initials: D
authors.lastname: Bonnet
authors.affiliation: Department of Haemato-Oncology, Royal Marsden Hospital, Sutton, United Kingdom; The Institute of Cancer Research, London, United Kingdom.
authors.forename: David C
authors.initials: DC
authors.lastname: Taussig
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001120:Arginine / Q000378:metabolism; D001124:Argininosuccinate Synthase / Q000096:biosynthesis / Q000235:genetics; D015153:Blotting, Western; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D006867:Hydrolases / Q000494:pharmacology*; D007150:Immunohistochemistry; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism*; D013058:Mass Spectrometry; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D011092:Polyethylene Glycols / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D011092:Polyethylene Glycols; D001120:Arginine; D006867:Hydrolases; C512527:ADI PEG20; D001124:Argininosuccinate Synthase