生物活性

• 靶点	DNA Synthesis IC50:0.067-2.15μM

• 描述Ara-G triphosphate (ara-GTP) competes with deoxyguanosine triphosphate for incorporation into DNA. Once incorporated, it inhibits DNA synthesis and leads to high molecular weight DNA fragmentation and cell death. Nelarabine is an anticancer prodrug of arabinofura-nosylguanine (ara-G), which is metabolized in cells to the cytotoxic metabolite ara-GTP^[3]. Ara-GTP appears to have the main cytotoxic effect in T-cell malignancies^[4]. Nelarabine's cytotoxic and immune system modulatory effects are not restricted to T-leukaemic cells, but also affect bone marrow and other tissues^[5]. Both nelarabine and ara-G are widely distributed throughout the body, with the highest radioactivity levels after a single infusion of 14C-nelarabine detected in kidney, gall bladder, liver and spleen, and lower levels detected in the CNS{European Medicines Agency. Atriance: scientific discussion[online] |http://www.emea.europa.eu/humandocs/Humans/EPAR/atriance/atriance.htm [Accessed 2007 Dec 6}. in vitro studies show that neither nelarabine nor ara-G are substantially bound to plasma proteins(<25%) and that binding is independent of plasma concentrations up to 600 uM, nelarabine or ara-G had no significant effects on hepatic cytochrome P450 (CYP) isoenzymes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6 or 3A4, indicating that nelarabine is unlikely to have clinically important interactions with drugs metabolized by these CYP isoenzymes^[6]. With nelarabine being administered as an infusion, the maximum concentration (Cmax) of nelarabine occurred at the end of the infusion. The nelarabine Cmax and area under the curve from time zero to infinity (AUC0–∞) were proportional to the dose over the dose range of 5–75 mg/kg^[7].
• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT02551718	Acute Leukemia of Ambiguous Li... more >>neage Recurrent Adult Acute Lymphoblastic Leukemia Recurrent Adult Acute Myeloid Leukemia Recurrent Childhood Acute Lymphoblastic Leukemia Recurrent Childhood Acute Myeloid Leukemia Refractory Acute Myeloid Leukemia Refractory Adult Acute Lymphoblastic Leukemia Refractory Childhood Acute Lymphoblastic Leukemia Collapse <<	Not Applicable	Recruiting	-	United States, Washington ... more >> Fred Hutch/University of Washington Cancer Consortium Recruiting Seattle, Washington, United States, 98109 Contact: Pamela S. Becker    206-616-1589    pbecker@u.washington.edu    Principal Investigator: Pamela S. Becker Collapse <<
  NCT02518750	Acute Lymphoblastic Leukemia ... more >> Lymphoma, Non-Hodgkin's Leukemia, T-Cell Leukemia, B-Cell Collapse <<	Phase 2	Terminated(Due to slow accrual... more >>) Collapse <<	-	United States, Tennessee ... more >> St. Jude Children's Research Hospital Memphis, Tennessee, United States, 38105 Collapse <<
  NCT03117751	Acute Lymphoblastic Leukemia ... more >> Acute Lymphoblastic Lymphoma Collapse <<	Phase 2 Phase 3	Recruiting	March 31, 2028	United States, Tennessee ... more >> St. Jude Children's Research Hospital Recruiting Memphis, Tennessee, United States, 38105 Contact: Hiroto Inaba, MD, PhD    866-278-5833    referralinfo@stjude.org    Principal Investigator: Hiroto Inaba, MD, PhD Collapse <<

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• 参考文献

• [1] Beesley AH, Palmer ML, et al. In vitro cytotoxicity of nelarabine, clofarabine and flavopiridol in paediatric acute lymphoblastic leukaemia. Br J Haematol. 2007 Apr;137(2):109-16.

  [2] Kline J, Larson RA. Nelarabine in the treatment of refractory T-cell malignant diseases. Expert Opin Pharmacother. 2006 Sep;7(13):1791-9.

  [3] Mark Sanford,et al. Drugs. 2008;68(4):439-47.

  [4] Kisor DF. Nelarabine: a nucleoside analog with efficacy in T- cell and other leukemias. Ann Pharmacother 2005 Jun; 39 (6):1056-63

  [5] GlaxoSmithKline. Arranon® (nelarabine): US prescribing information[online]

  [6] European Medicines Agency. Atriance (nelarabine): summary of product information[online]

  [7] Kisor DF, et al.Pharmacokinetics of nelarabine and 9-β-D-arabinofuranosyl guanine in pediatric and adult patients during a phase I study of nelarabine for the treatment of refractory hematologic malignancies. J Clin Oncol 2000;18:995-1003

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