Alternative Tumor-Targeting Strategies
David E. Thurston, Ilona Pysz in Chemistry and Pharmacology of Anticancer Drugs, 2021
Asparaginase (CristanaspaseTM; ErwinaseTM) therapy takes advantage of the fact that certain types of tumor cells (in particular lymphoblastic leukemia cells) are unable to synthesize their own asparagine. Healthy cells, on the other hand, can synthesize their own asparagine, thus providing a basis for the observed selectivity. Systemic administration of the enzyme asparaginase causes a significant reduction in systemic concentrations of asparagine by converting it to aspartic acid and ammonia, thus removing it from the protein synthesis cycle (Figure 10.13). This starves the cancer cells of asparagine, eventually leading to cell death while healthy cells continue to synthesize their own. Catabolism of asparagine to aspartic acid and ammonia by the asparaginase enzyme.
Short-Lived Positron Emitting Radionuclides
Frank Helus, Lelio G. Colombetti in Radionuclides Production, 2019
As discussed before, an advantage of enzymatic methods is that very often the natural stereoisomers of the prepared compounds are obtained. A recent improvement in the preparation is the application of immobilized enzymes. Gelbard described the preparation of l-13N-glutamate by this technique. The procedure to immobilize the enzyme used, is included.260 Baumgartner developed a remote, semiautomated procedure not only for l-13N-glutamate but also for l-glutamine, labeled either in the α or ω positron.261 The semiautomated procedure for l-13N-alanine is reported earlier by the same group.262 Nitrogen-13 labeled l-glutamic acid is used as intermediate in the preparation of two aromatic amino acids. l-13N-tyrosine and l-13N-phenylalanine are prepared by transamination of the appropriate α-keto acid with glutamate oxalacetate transaminase isolated from a pig heart.263 The enzymatic synthesis of 13N-asparagine is described in an abstract by Majumdar.134 A new nonenzymatic preparation is reported by Elmaleh.264 The β-carboxylic group of the protected l-aspartic acid is activated with N-hydroxysuccinimide. This intermediate compound is refluxed with 13N-ammonia, hydrolyzed and after chromatography l-13N-asparagine is obtained in good yields.
Antineoplastic Agents
Frank A. Barile in Barile’s Clinical Toxicology, 2019
The enzyme L-asparaginase produces tumor cell death through the activation of apoptosis. In particular, the drug deprives the cell of asparagine. This amino acid is crucial for protein synthesis because the enzyme catalyzes the hydrolysis of circulating asparagine to aspartic acid and ammonia. Consequently, L-asparaginase stops the progression of cells through the cell cycle. Its unique mechanism of action supports its inclusion with other antitumor drugs as part of a chemotherapeutic program, especially in the treatment of acute lymphoblastic leukemia and other lymphoid malignancies. The drug is conveniently administered I.V. or intramuscularly (I.M.) in a variety of regimens and schedules but poses a serious toxicity threat due to its bacterial origin—that is, antigenicity. Hypersensitivity and anaphylactic reactions occur in 5 to 20% of patients, most notably when administered intermittently. Other toxicities related to its mechanism of action include hyperglycemia, coagulopathies, immunosuppression, and hemorrhage, all of which are potentially fatal.
Broad Anti-Cancer Activity Produced by Targeted Nutrients Deprivation (TND) of Multiple Non-Essential Amino Acids
Published in Nutrition and Cancer, 2022
Zehui Li, Shuang Zhou, Xiaodong Yang, Xiyan Li, Grace Xiaolu Yang, John Chant, Michael Snyder, Xin Wang
As mentioned previously, multiple studies lend support to the notion that amino acid deprivation might be a promising therapeutic approach in certain tumor types. In humans, injected asparaginase to reduce asparagine levels in the bloodstream is used for the treatment of ALL (Egler, Ahuja et al. 2016). Small molecule inhibitor-based approaches are also being taken to interrupt amino acid metabolism. CB-839, a small molecule glutaminase inhibitor, prolonged progression free survival when combined with everolimus in a Phase II clinical trial for the treatment of renal cell carcinoma (27, 28). The glutaminase inhibitor blocks the conversion of glutamine to glutamic acid, thereby preventing cells from utilizing glutamine as an alternate energy source to glucose under metabolic stress conditions.
Multifunctional magnetic nanoparticles for MRI-guided co-delivery of erlotinib and L-asparaginase to ovarian cancer
Published in Journal of Microencapsulation, 2022
Seraj Mohaghegh, Ali Tarighatnia, Yadollah Omidi, Jaleh Barar, Ayuob Aghanejad, Khosro Adibkia
Erlotinib (ERL), a tyrosine kinase inhibitor, is used for the treatment of inoperable or metastatic pancreatic cancer and metastatic non-small cell lung cancer (Asgari et al.2011). Nowadays, the potential of ERL has been investigated in treating various tumours such as glioblastoma, ovarian cancer and head and neck cancers (Raizer et al.2016, Anisuzzaman et al.2017). On the other hand, L-asparaginase (L-ASPN) has been approved for the treatment of acute lymphoblastic leukaemia (ALL) to deprive tumour cells with the asparagine amino acid formation. The results of some studies suggested that the proliferation of ovarian cancer cells having low to moderate levels of asparagine synthetase (ASNS) may be affected by the diminution of extracellular asparagine. This may propose L-ASPN as a potential drug in the treatment of OC when used in combination with ERL-loaded NSs (Abdolahinia et al.2019, Ajoolabady et al.2020).
Novel systemic treatment approaches for metastatic pancreatic cancer
Published in Expert Opinion on Investigational Drugs, 2022
Klara Dorman, Volker Heinemann, Sebastian Kobold, Michael von Bergwelt-Baildon, Stefan Boeck
The chemotherapeutic drug asparaginase hydrolyzes asparagine to aspartic acid and ammonia, this way depriving cells of circulating asparagine, an amino acid important for cell growth and proliferation. Most cells are able to produce asparagine themselves through the asparagine synthetase (ASNS), however tumors with low ASNS expression, such as PDAC, might benefit from asparaginase therapy [34]. Despite the effectiveness of asparaginase as a chemotherapeutic treatment in acute lymphoblastic leukemia, associated toxicities such as hepatotoxicity, pancreatitis, thrombosis and hypersensitivity limit the broader use [34,35]. Encapsulating asparaginase within erythrocytes (eryaspase) leads to prolonged half-life and good tolerability of the drug. A randomized phase IIb trial showed that eryaspase combined with gemcitabine or mFOLFOX-6 was associated with improved overall survival and progression-free survival, warranting further investigation in the currently ongoing phase III trial Trybeca-1 as a second-line therapy (NCT03665441, Table 1) [36] as well as a phase I trial combining eryaspase with FOLFIRINOX in a first-line setting (NCT04292743)
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