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Pegylated Arginine Deiminase Treatment of Patients With Metastatic Melanoma: Results From Phase I and II Studies
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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“Recombinant pegylated arginine deiminase (ADI-PEG20) has been tested in clinical trials to treat melanoma and hepatocellular carcinoma with some therapeutic benefit (Ascierto et al., 2005; Izzo et al., 2004; Ott et al., 2013; Szlosarek et al., 2013; Yang et al., 2010).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Ascierto et al., 2005
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Metadata
- 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
- Venue
- Journal of Clinical Oncology
- Published
- 2005-10-20
- Volume
- 23
- Issue
- 30
- Pages
- 7660-7668
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- 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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