Cited by 239Bacterial Cancer TherapyMelanoma and MAPK PathwaysCutaneous Melanoma Detection and Management

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Pegylated Arginine Deiminase Treatment of Patients With Metastatic Melanoma: Results From Phase I and II Studies

Ascierto, Paolo A., Scala, Stefania, Castello, Giuseppe, Daponte, Antonio, Simeone, Ester, Ottaiano, Alessandro, Beneduce, Gerardo, De Rosa, Vincenzo, Izzo, Francesco, Melucci, Maria Teresa, Ensor, C. Mark, Prestayko, Archie W., Holtsberg, Frederick W., Bomalaski, John S., Clark, Mike A., Savaraj, Niramol, Feun, Lynn G., Logan, Theodore F.·2005·Journal of Clinical Oncology

DOI 10.1200/jco.2005.02.0933

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Abstract

Purpose: Individuals with metastatic melanoma have a poor prognosis. Many human melanomas are auxotrophic for arginine, and arginine is not an essential amino acid in humans. We hypothesized that this auxotrophy may be therapeutically exploited. A novel amino acid–degrading enzyme (arginine deiminase) conjugated to polyethylene glycol (ADI-SS PEG 20,000 mw) was used to lower plasma arginine in individuals with metastatic melanoma. Patients and Methods: Two cohort dose-escalation studies were performed. A phase I study in the United States enrolled 15 patients, and a phase I to II study in Italy enrolled 24 patients. The Italian patients also received two subsequent cycles of treatment, each consisting of four once-weekly injections of 160 U/m 2. The goals of these studies were to determine pharmacokinetics (PK), pharmacodynamics (PD), safety, and the antitumor activity of ADI-SS PEG 20,000 mw. Results: PK and PD studies indicated that a dose of 160 U/m 2 lowered plasma arginine from a resting level of approximately 130 μmol/L to less than 2 μmol/L for at least 7 days; nitric oxide levels also were lowered. There were no grade 3 or 4 toxicities directly attributable to the drug. Six of 24 phase I to II patients responded to treatment (five partial responses and one complete response; 25% response rate) and also had prolonged survival. Conclusion: Elimination of all detectable plasma arginine in patients with metastatic melanoma was well tolerated and may be effective in the treatment of this cancer. Further testing of ADI-SS PEG 20,000 mw in a larger population of individuals with metastatic melanoma is warranted.

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Additional file 6 of Intracellular expression of arginine deiminase activates the mitochondrial apoptosis pathway by inhibiting cytosolic ferritin and inducing chromatin autophagy
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Additional file 5 of Intracellular expression of arginine deiminase activates the mitochondrial apoptosis pathway by inhibiting cytosolic ferritin and inducing chromatin autophagy
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Additional file 4 of Intracellular expression of arginine deiminase activates the mitochondrial apoptosis pathway by inhibiting cytosolic ferritin and inducing chromatin autophagy
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Additional file 3 of Intracellular expression of arginine deiminase activates the mitochondrial apoptosis pathway by inhibiting cytosolic ferritin and inducing chromatin autophagy
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Additional file 8 of Intracellular expression of arginine deiminase activates the mitochondrial apoptosis pathway by inhibiting cytosolic ferritin and inducing chromatin autophagy
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Additional file 2 of Intracellular expression of arginine deiminase activates the mitochondrial apoptosis pathway by inhibiting cytosolic ferritin and inducing chromatin autophagy
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Additional file 9 of Intracellular expression of arginine deiminase activates the mitochondrial apoptosis pathway by inhibiting cytosolic ferritin and inducing chromatin autophagy
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Additional file 1 of Intracellular expression of arginine deiminase activates the mitochondrial apoptosis pathway by inhibiting cytosolic ferritin and inducing chromatin autophagy
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Additional file 7 of Intracellular expression of arginine deiminase activates the mitochondrial apoptosis pathway by inhibiting cytosolic ferritin and inducing chromatin autophagy
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Additional file 2 of The addition of arginine deiminase potentiates Mithramycin A-induced cell death in patient-derived glioblastoma cells via ATF4 and cytochrome C
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Authors: Ascierto, P. A., Scala, S., Castello, G., Daponte, A., Simeone, E., Ottaiano, A., Beneduce, G., De Rosa, V., Izzo, F., Melucci, M. T., Ensor, C. M., Prestayko, A. W., Holtsberg, F. W., Bomalaski, J. S., Clark, M. A., Savaraj, N., Feun, L. G., & Logan, T. F.
Affiliations: University of Kentucky (US)
From the Pascale National Cancer Institute, Naples, Italy; Phoenix Pharmacologics, Inc; University of Kentucky, Lexington, KY; Hematology and Oncology Division, University of Miami; Miami Veterans Affairs Medical Center, Miami, FL; and Hematology and Oncology Division, Indiana University, Indianapolis, IN.
ORCID: Ascierto, Paolo A.
Scala, Stefania
Castello, Giuseppe
Daponte, Antonio
Simeone, Ester
Ottaiano, Alessandro
Izzo, Francesco
Melucci, Maria Teresa
Holtsberg, Frederick W.
Bomalaski, John S.
Savaraj, Niramol
Feun, Lynn G.
Logan, Theodore F.
Venue: Journal of Clinical Oncology
Publisher: American Society of Clinical Oncology (ASCO)
Published: 2005-10-20
Volume: 23
Issue: 30
Pages: 7660-7668
ISSN: 0732-183X (ISSN-L)
1527-7755
DOI: 10.1200/jco.2005.02.0933
OpenAlex: W2167874373
Cited by: 238
References: 53
Citations by year: 2025: 8 · 2024: 7 · 2023: 10 · 2022: 10 · 2021: 13 · 2020: 17 · 2019: 8 · 2018: 10 · 2017: 13 · 2016: 15 · 2015: 16 · 2014: 15 · 2013: 14 · 2012: 19
FWCI: 5.98
Type: journal article
Language: en
Open access: closed
Locations: Journal of Clinical Oncology (publishedVersion)
PubMed (publishedVersion)
Funders: National Cancer Institute
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Bacterial Cancer Therapy
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
Health Sciences › Medicine › Oncology › Cutaneous Melanoma Detection and Management
Keywords: metastatic melanoma, arginine deiminase, pegylated arginine deiminase, arginine auxotrophy, nitric oxide, enzyme conjugation, pharmacokinetics, pharmacodynamics, anticancer activity, dose escalation, safety and tolerability
MeSH terms: Adult, Aged, Aged, 80 and over, Arginine, Female, Humans, Hydrolases, Italy, Male, Melanoma, Middle Aged, Nitric Oxide, Polyethylene Glycols, Skin Neoplasms, United States, Survival Rate, Treatment Outcome, Maximum Tolerated Dose

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Pegylated Arginine Deiminase Treatment of Patients With Metastatic Melanoma: Results From Phase I and II Studies

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