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Alternative Tumor-Targeting Strategies
Published in David E. Thurston, Ilona Pysz, 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.
Placental Nutrient Metabolism and Transport
Published in Emilio Herrera, Robert H. Knopp, Perinatal Biochemistry, 2020
A second example of placental cycling of amino acids is demonstrated by measurements from umbilical and fetal hepatic plasma concentrations of amino acids in fetal sheep showing reciprocal relationships between three sets of amino acids.89 Glutamine and glycine are taken up in net by the fetus from the placenta and by the liver from the umbilical vein whereas their metabolic products, glutamate and serine, respectively, are produced in net by the fetal liver and taken up in net by the placenta. A similar but less definite relationship has been found for net hepatic uptake of asparagine and release of aspartate with a reciprocal exchange across the umbilical circulation in the placenta. Preliminary studies in sheep indicate that for serine as much as 20 to 30% of fetal hepatic serine production may be derived from glycine and approximately 20% of the glycine taken up by the fetal liver is accounted for by serine production.90 These data indicate that the interorgan cycling of glycine and serine between the placenta and the fetal liver is quantitatively significant, contributing importantly to energy and protein balance in the fetal-placental unit. Furthermore, these preliminary studies showed that fetal serine production and uptake by the placenta from the umbilical circulation was much larger at midgestation than near term suggesting an active developmental regulation of this interorgan cycling.
Enzymatic Amino Acid Deprivation Therapies Targeting Cancer
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Carla S. S. Teixeira, Henrique S. Fernandes, Sérgio F. Sousa, Nuno M. F. S. A. Cerqueira
l-Asparagine (l-ASN) is a non-essential amino acid that is synthesized in humans by the asparagine synthetase enzyme (Lomelino et al., 2017). However, l-ASN is indispensable for the synthesis of several proteins, in particular, the ones that are glycosylated through N-glycosylation (Cherepanova and Gilmore, 2016) Moreover, this amino acid is involved in the control of some cell functions in the nervous system, and also in the metabolism of ammonia to enable the elimination of this toxic metabolic by-product (Erecinska et al., 1991; Chen and Chen, 1992).
A comprehensive strategy to address shortage of Erwinia asparaginase in pediatric acute lymphoblastic leukemia
Published in Expert Review of Clinical Pharmacology, 2023
Anshul Vagrecha, Vincent Tao, Rosemarie Corless, Cassandra Colon, Arlene Redner, Mark Atlas
Currently, the established standard of care for children with ALL who develop a significant drug HSR with PEG is a switch to EA. However, the current drug shortage of the previous EA preparations risks the omission of asparagine therapy for these patients. A recent COG report demonstrated that pediatric ALL patients not receiving asparaginase therapy have a lower disease-free survival.3 The supply of EA has been unreliable for many years now. Currently, a recombinant form of EA was approved under emergency designation by the US FDA due to the lack of alternatives for these patients. This approval was based on an ongoing Phase 2/3, single arm, open label, dose confirmation study. It is yet to be approved in other countries, and only the intramuscular route has been approved so far. Hence, alternative treatment strategies are needed, especially in treatment settings when EA is unavailable.
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)