Arginine deprivation using pegylated arginine deiminase has activity against primary acute myeloid leukemia cells in vivo
| Autor: | Marianne Grantham, Andrew Clear, John S. Bomalaski, Farideh Miraki-Moud, Katharine A. Hodby, Linda Ariza-McNaughton, John G. Gribben, Essam Ghazaly, Fernando Anjos-Afonso, Peter W. Szlosarek, David Taussig, Jamie Cavenagh, Dominique Bonnet, Fareeda Sohrabi, Konstantinos Liapis |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
Myeloid
Arginine Hydrolases Blotting Western Immunology Antineoplastic Agents Mice SCID Argininosuccinate Synthase Pharmacology Biology Real-Time Polymerase Chain Reaction Biochemistry Mass Spectrometry Polyethylene Glycols Mice Mice Inbred NOD In vivo hemic and lymphatic diseases medicine Extracellular Animals Humans neoplasms Cells Cultured Chromatography High Pressure Liquid Myeloid leukemia Cell Biology Hematology medicine.disease Immunohistochemistry Xenograft Model Antitumor Assays In vitro Leukemia Myeloid Acute Leukemia medicine.anatomical_structure Cytarabine medicine.drug |
| Zdroj: | Blood. 125:4060-4068 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2014-10-608133 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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