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Pathway Description
Nelarabine Action Pathway
Homo sapiens
Drug Action Pathway
Nelarabine is an antineoplastic agent from the nucleoside analog drug class. This drug is indicated in the treatment of T-cell lymphoblastic leukemia, particularly T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL), in both adult and pediatric patients whose disease has not responded to or has relapsed following at least two chemotherapy regimens. At the structure level of this molecule, it is a prodrug of the cytotoxic deoxyguanosine analog 9-ß-D-arabinofuranosylguanine (ara-G). Before entering the cells, it is metabolized by adenosine deaminase (ADA) to ara-G. The molecule then enters the cell to be phosphorylated three times, resulting in the formation of ara-G triphosphate (ara-GTP). Ara-GTP is the molecule with the cytotoxic activity. Since T lymphoblasts have a higher expression of deoxycytidine kinase, ara-G accumulates in higher quantities in T cells over B cells, thus showing higher toxicity to T lymphoblasts. Since ara-GTP accumulates in leukemic blasts, it will incorporate the DNA to exert its S phase-specific cytotoxic effects. This activity leads to the apoptosis of the cell. As a nucleoside analog, ara-GTP competes with endogenous deoxyGTP (dGTP) for incorporation into DNA. The mechanism of action that leads to apoptosis is not well understood. It is thought that the inclusion of ara-GTP into the DNA strand can impair proper DNA repair processes, leading to inhibition of DNA elongation, apoptosis, and cellular destruction. It is anticipated that overdosage of this drug result in severe neurotoxicity, myelosuppression, and potential death. Nelarabine is administered as an intravenous injection.
References
Nelarabine Pathway References
Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, Sajed T, Johnson D, Li C, Sayeeda Z, Assempour N, Iynkkaran I, Liu Y, Maciejewski A, Gale N, Wilson A, Chin L, Cummings R, Le D, Pon A, Knox C, Wilson M: DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2018 Jan 4;46(D1):D1074-D1082. doi: 10.1093/nar/gkx1037.
Pubmed: 29126136
Buie LW, Epstein SS, Lindley CM: Nelarabine: a novel purine antimetabolite antineoplastic agent. Clin Ther. 2007 Sep;29(9):1887-99. doi: 10.1016/j.clinthera.2007.09.002.
Pubmed: 18035189
DeAngelo DJ: Nelarabine for the treatment of patients with relapsed or refractory T-cell acute lymphoblastic leukemia or lymphoblastic lymphoma. Hematol Oncol Clin North Am. 2009 Oct;23(5):1121-35, vii-viii. doi: 10.1016/j.hoc.2009.07.008.
Pubmed: 19825456
Sanford M, Lyseng-Williamson KA: Nelarabine. Drugs. 2008;68(4):439-47. doi: 10.2165/00003495-200868040-00004.
Pubmed: 18318562
Roecker AM, Allison JC, Kisor DF: Nelarabine: efficacy in the treatment of clinical malignancies. Future Oncol. 2006 Aug;2(4):441-8. doi: 10.2217/14796694.2.4.441.
Pubmed: 16922610
Curbo S, Karlsson A: Nelarabine: a new purine analog in the treatment of hematologic malignancies. Rev Recent Clin Trials. 2006 Sep;1(3):185-92. doi: 10.2174/157488706778250104.
Pubmed: 18473971
Zwaan CM, Kowalczyk J, Schmitt C, Bielorai B, Russo MW, Woessner M, Ranganathan S, Leverger G: Safety and efficacy of nelarabine in children and young adults with relapsed or refractory T-lineage acute lymphoblastic leukaemia or T-lineage lymphoblastic lymphoma: results of a phase 4 study. Br J Haematol. 2017 Oct;179(2):284-293. doi: 10.1111/bjh.14874. Epub 2017 Aug 2.
Pubmed: 28771663
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