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Tumor-Targeted Delivery of 6-Diazo-5-oxo-l-norleucine (DON) Using Substituted Acetylated Lysine Prodrugs
L. Tenora, J. Alt, RP. Dash, AJ. Gadiano, K. Novotná, V. Veeravalli, J. Lam, QR. Kirkpatrick, KM. Lemberg, P. Majer, R. Rais, BS. Slusher,
Language English Country United States
Document type Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
Grant support
R01 CA193895
NCI NIH HHS - United States
R01 CA229451
NCI NIH HHS - United States
R01 NS103927
NINDS NIH HHS - United States
- MeSH
- Acetylation MeSH
- Diazooxonorleucine administration & dosage pharmacokinetics MeSH
- Carboxylic Ester Hydrolases genetics MeSH
- Drug Delivery Systems * MeSH
- Humans MeSH
- Lysine chemistry MeSH
- Mice, Knockout MeSH
- Mice MeSH
- Cell Line, Tumor MeSH
- Area Under Curve MeSH
- Swine MeSH
- Prodrugs chemistry MeSH
- Antineoplastic Agents administration & dosage MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
6-Diazo-5-oxo-l-norleucine (DON) is a glutamine antagonist with robust anticancer efficacy; however, its therapeutic potential was hampered by its biodistribution and toxicity to normal tissues, specifically gastrointestinal (GI) tissues. To circumvent DON's toxicity, we synthesized a series of tumor-targeted DON prodrugs designed to circulate inert in plasma and preferentially activate over DON in tumor. Our best prodrug 6 (isopropyl 2-(6-acetamido-2-(adamantane-1-carboxamido)hexanamido)-6-diazo-5-oxohexanoate) showed stability in plasma, liver, and intestinal homogenates yet was readily cleaved to DON in P493B lymphoma cells, exhibiting a 55-fold enhanced tumor cell-to-plasma ratio versus that of DON and resulting in a dose-dependent inhibition of cell proliferation. Using carboxylesterase 1 knockout mice that were shown to mimic human prodrug metabolism, systemic administration of 6 delivered 11-fold higher DON exposure to tumor (target tissue; AUC0- t = 5.1 nmol h/g) versus GI tissues (toxicity tissue; AUC0- t = 0.45 nmol h/g). In summary, these studies describe the discovery of a glutamine antagonist prodrug that provides selective tumor exposure.
References provided by Crossref.org
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