Human recombinant arginase I(Co)-PEG5000 [HuArgI(Co)-PEG5000]-induced arginine depletion is selectively cytotoxic to human acute myeloid leukemia cells

Tanios, Rita Farid; Bekdash, Amira; Kassab, Elias; Stone, Everett; Georgiou, George; Frankel, Arthur E.; Abi-Habib, Ralph J.

doi:10.1016/j.leukres.2013.08.007

Cited by 48 publications

(67 citation statements)

References 26 publications

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“…30 This arginase may be less immunogenic than ADI-PEG 20 as it is a human protein. However, arginase I cobalt has a narrow therapeutic window, causing bone marrow necrosis and death in mice at higher doses.…”

Section: Discussionmentioning

confidence: 99%

Arginine deprivation using pegylated arginine deiminase has activity against primary acute myeloid leukemia cells in vivo

Miraki-Moud

Ghazaly

Ariza‐McNaughton

et al. 2015

Blood

115

103

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Key Points• Most AMLs lack ASS1, which allows synthesis of arginine, and so depend on exogenous sources.• Depletion of arginine via ADI-PEG 20 reduces the burden of primary AML in vivo and in vitro.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. (Blood. 2015;125(26): 4060-4068)

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Section: Discussionmentioning

confidence: 99%

Arginine deprivation using pegylated arginine deiminase has activity against primary acute myeloid leukemia cells in vivo

Miraki-Moud

Ghazaly

Ariza‐McNaughton

et al. 2015

Blood

115

103

View full text Add to dashboard Cite

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“…Animal toxicity testing indicates that citrulline supplementation is required since arginase, unlike ADI, produces ornithine which cannot be recycled readily to citrulline [95]. Several studies confirm that HuArg I [Co]-PEG5K displays tumor cytotoxicity in vitro and is active in xenograft tumor models [96,97]. …”

Section: Arginine Deprivation: Preclinical Datamentioning

confidence: 99%

Targeting Arginine-Dependent Cancers with Arginine-Degrading Enzymes: Opportunities and Challenges

2013

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Arginine deprivation is a novel antimetabolite strategy for the treatment of arginine-dependent cancers that exploits differential expression and regulation of key urea cycle enzymes. Several studies have focused on inactivation of argininosuccinate synthetase 1 (ASS1) in a range of malignancies, including melanoma, hepatocellular carcinoma (HCC), mesothelial and urological cancers, sarcomas, and lymphomas. Epigenetic silencing has been identified as a key mechanism for loss of the tumor suppressor role of ASS1 leading to tumoral dependence on exogenous arginine. More recently, dysregulation of argininosuccinate lyase has been documented in a subset of arginine auxotrophic glioblastoma multiforme, HCC and in fumarate hydratase-mutant renal cancers. Clinical trials of several arginine depletors are ongoing, including pegylated arginine deiminase (ADI-PEG20, Polaris Group) and bioengineered forms of human arginase. ADI-PEG20 is furthest along the path of clinical development from combinatorial phase 1 to phase 3 trials and is described in more detail. The challenge will be to identify tumors sensitive to drugs such as ADI-PEG20 and integrate these agents into multimodality drug regimens using imaging and tissue/fluid-based biomarkers as predictors of response. Lastly, resistance pathways to arginine deprivation require further study to optimize arginine-targeted therapies in the oncology clinic.

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“…Acute myeloid leukemia cell lines were found sensitive toward Co-hArgI–PEG-mediated arginine deprivation with very low (58–722 PM) IC 50 values, suggesting a very high potential of Co-hArgI–PEG-mediated arginine depletion in acute myeloid leukemia cells. 136 Moreover, Co-hArgI–PEG-mediated arginine deprivation has been demonstrated to induce caspase-independent, non-apoptotic cell death in human glioblastoma cells. 137 Alternative method to extend the plasma half-life of recombinant human arginase also has been established.…”

Section: Arginasementioning

confidence: 99%

Arginine dependence of tumor cells: targeting a chink in cancer’s armor

et al. 2016

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Arginine, one among the 20 most common natural amino acids, has a pivotal role in cellular physiology as it is being involved in numerous cellular metabolic and signaling pathways. Dependence on arginine is diverse for both tumor and normal cells. Because of decreased expression of argininosuccinate synthetase and/or ornithine transcarbamoylase, several types of tumor are auxotrophic for arginine. Deprivation of arginine exploits a significant vulnerability of these tumor cells and leads to their rapid demise. Hence, enzyme-mediated arginine depletion is a potential strategy for the selective destruction of tumor cells. Arginase, arginine deiminase and arginine decarboxylase are potential enzymes that may be used for arginine deprivation therapy. These arginine catabolizing enzymes not only reduce tumor growth but also make them susceptible to concomitantly administered anti-cancer therapeutics. Most of these enzymes are currently under clinical investigations and if successful will potentially be advanced as anti-cancer modalities.

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Human recombinant arginase I(Co)-PEG5000 [HuArgI(Co)-PEG5000]-induced arginine depletion is selectively cytotoxic to human acute myeloid leukemia cells

Cited by 48 publications

References 26 publications

Arginine deprivation using pegylated arginine deiminase has activity against primary acute myeloid leukemia cells in vivo

Arginine deprivation using pegylated arginine deiminase has activity against primary acute myeloid leukemia cells in vivo

Targeting Arginine-Dependent Cancers with Arginine-Degrading Enzymes: Opportunities and Challenges

Arginine dependence of tumor cells: targeting a chink in cancer’s armor

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