Selective extracellular arginine deprivation by a single injection of cellular non-uptake arginine deiminase nanocapsules for sustained tumor inhibition

Nanoscale ◽  
2020 ◽  
Vol 12 (47) ◽  
pp. 24030-24043
Author(s):  
Hongzhao Qi ◽  
Yin Wang ◽  
Xubo Yuan ◽  
Peifeng Li ◽  
Lijun Yang
Keyword(s):  
Single Injection ◽  
Arginine Deiminase ◽  
Cellular Interaction ◽  
Argininosuccinate Synthetase ◽  
Tumor Inhibition ◽  
Arginine Deprivation

Arginine deiminase nanocapsules possessing extremely weak cellular interaction could selectively deprive extracellular arginine to treat argininosuccinate synthetase-deficient tumors efficiently.

ATOMIC-Meso: A randomized phase 2/3 trial of ADI-PEG20 or placebo with pemetrexed and cisplatin in patients with argininosuccinate synthetase 1-deficient non-epithelioid mesothelioma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS8582-TPS8582 ◽  
Author(s):  
Peter Wojciech Szlosarek ◽  
Paul Baas ◽  
Giovanni Luca Ceresoli ◽  
Dean Anthony Fennell ◽  
David Gilligan ◽  
...  
Keyword(s):  
Malignant Pleural Mesothelioma ◽  
Primary Endpoint ◽  
Phase 1 ◽  
Arginine Deiminase ◽  
Pleural Mesothelioma ◽  
Phase 2 ◽  
Argininosuccinate Synthetase ◽  
Phase 3 ◽  
Double Blind ◽  
Arginine Deprivation

TPS8582 Background: Argininosuccinate synthetase 1 (ASS1)-deficient malignant pleural mesothelioma (MPM) is sensitive to arginine deprivation therapy with pegylated arginine deiminase (ADI-PEG20), which also enhances the cytotoxicity of pemetrexed. The TRAP Phase 1 trial (NCT02029690) of ADI-PEG 20 combined with 1st-line pemetrexed (PEM) and cisplatin (CDDP) chemotherapy revealed a 94% disease control rate in non-epithelioid (biphasic and sarcomatoid) MPM subtypes characterized by a 75% rate of ASS1 loss. Thus, we plan to assess the efficacy of ADI-PEG20 or placebo combined with PEM and CDDP in patients (pts) with poor prognosis MPM in a randomized, placebo-controlled, double-blind phase 2/3 global trial. Methods: Up to 386 good performance (ECOG 0-1) pts with non-epithelioid malignant pleural mesothelioma will be enrolled in a phase 2/3 adaptive, biomarker-driven study design. Biopsies will be required prior to randomization: ASS1-agnostic pts will be enrolled initially (phase 2 stage) with an option to restrict enrolment to ASS1-deficient MPM (phase 3 stage). Pts will be randomized to receive weekly ADI-PEG20 (36 mg/m2 IM) or placebo with standard doses of PEM and CDDP for a maximum of 18 weeks (6 cycles) of treatment. Pts who develop CDDP toxicity may be switched to carboplatin. Pts will be assessed every 6 weeks using modified RECIST (RECIST 1.1 allowed for pts with significant extrathoracic disease). The primary endpoint for the phase 2 stage will be overall response rate (ORR) with secondary endpoints of overall survival (OS), safety and toxicity. The phase 2 will test ORR proportions with the placebo triplet set at 15% vs. 35% for the ADI-PEG 20 triplet, with a 1:1 randomization, 80% power. After recruitment of 176 pts, the phase 2 will convert to a phase 3 study with the primary endpoint of OS. In summary, ATOMIC-Meso is the first triplet chemotherapy study to assess the role of targeted arginine deprivation in aggressive subtypes of mesothelioma. Pt accrual has commenced across the US and Asia, with enrolment due in Europe and Australia by 2nd quarter of 2017. [Trial sponsored by Polaris Group]. Clinical trial information: NCT02709512.

scholarly journals Pancreatic cancer cell lines deficient in argininosuccinate synthetase are sensitive to arginine deprivation by arginine deiminase

2008 ◽  
Vol 123 (8) ◽  
pp. 1950-1955 ◽  
Author(s):  
Tawnya L. Bowles ◽  
Randie Kim ◽  
Joseph Galante ◽  
Colin M. Parsons ◽  
Subbulakshmi Virudachalam ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Pancreatic Cancer Cell ◽  
Cancer Cell Lines ◽  
Arginine Deiminase ◽  
Argininosuccinate Synthetase ◽  
Arginine Deprivation

Arginine Deprivation With Pegylated Arginine Deiminase Induces Death Of Acute Myeloid Leukaemia Cells In Vivo

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1458-1458
Author(s):  
Farideh Miraki-Moud ◽  
Linda Ariza-McNaughton ◽  
Essam A Ghazaly ◽  
Katharine A Hodby ◽  
Phuong Luong ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Arginine Deiminase ◽  
Amino Acid Deprivation ◽  
Argininosuccinate Synthetase ◽  
Arginine Deprivation ◽  
Plasma Arginine ◽  
Acute Myeloid

Abstract Introduction Malignant cells require amino acids for a wide range of core functions. Amino acid deprivation using enzymatic degradation has been used to induce remission in acute lymphoblastic leukemia for decades. Amino acid deprivation may also benefit patients with acute myeloid leukemia (AML). We have previously shown that AML cells lack of argininosuccinate synthetase 1(ASS1), a key enzyme in the pathway that produces arginine (1). Here we tested the effect of an arginine depleting agent, pegylated arginine deiminase (ADI-PEG 20) on primary AML cells in a xenograft model of AML. Methods NOD/SCID/interleukin 2 gamma chain null (NSG) mice were transplanted with 6 primary AML samples. 12 weeks after transplantation of AML mice received either ADI-PEG 20, cytarabine, ADI-PEG 20 plus cytarabine or vehicle. ADI was administered weekly for 4 doses and cytarabine was given for 10 consecutive days (0.2mg per day, roughly equivalent to 40mg in humans). Five weeks after treatment started, mice were killed and the percentage of AML in the bone marrow was determined by flow cytometry. Blood was collected to quantify plasma arginine using liquid chromatography-mass spectrometry/mass spectrometry. Results Plasma arginine levels were depressed following ADI-PEG 20 administration confirming that arginine depletion was achieved in vivo. In all six experiments the combination of ADI-PEG 20 and cytarabine induced a significant reduction in levels of AML compared to control (Figure 1). Critically the combination of ADI-PEG 20 and cytarabine was significantly better than cytarabine alone in three of six experiments. Conclusion Our experiments show that arginine deprivation by ADI-PEG 20 can decrease the leukemic burden in mice transplanted with primary AML cells. The combination of ADI with cytarabine had a greater effect than cytarabine alone in half the experiments. These results provide the rationale to test ADI-PEG 20 with cytarabine in clinical trials. 1. Peter W. Szlosarek, Fiona Luong, Andrew Clear, David Taussig, Simon Joel, Maria Calaminici, Silvana Debernardi, Jude Fitzgibbon, John S. Bomalaski, Arthur E. Frankel, and Dominique Bonnet. Pegylated arginine deiminase (ADI-PEG 20) as a potential novel therapy for argininosuccinate synthetase-deficient acute myeloid leukemia. Cancer Research: April 15, 2011. AACR 102nd Annual Meeting 2011, (AACR Abstract # 467) F. M-M and L. A-M contributed equally D.B., P.W.S. and D.C.T contributed equally Disclosures: Bomalaski: Polaris Group: Employment, Equity Ownership. Szlosarek:Polaris Group: Research Funding.

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

Blood ◽  
2015 ◽  
Vol 125 (26) ◽  
pp. 4060-4068 ◽  
Author(s):  
Farideh Miraki-Moud ◽  
Essam Ghazaly ◽  
Linda Ariza-McNaughton ◽  
Katharine A. Hodby ◽  
Andrew Clear ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Arginine Deiminase ◽  
Leukemia Cells ◽  
Arginine Deprivation ◽  
Key Points ◽  
Acute Myeloid Leukemia Cells ◽  
Acute Myeloid

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.

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