Ara-G
(Synonyms: 9-Β-D-糖呋喃鸟嘌呤) 目录号 : GC45385
An anticancer nucleoside analog
Cas No.:38819-10-2
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >95.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Ara-G is an analog of the nucleoside guanosine and an active metabolite of nelarabine .1,2 Ara-G accumulates in T lymphoblasts and malignant T-lymphoid cells, where it is phosphorylated to produce ara-GTP and incorporated into the DNA.3,1 Ara-G inhibits DNA replication by 92% after 30 minutes when used at a concentration of 50 μM in CEM cells, which are used as a model for human T lymphoblasts.1 It also halts the cell cycle at the sub-G1 phase and induces apoptosis in CEM cells.3 Syngeneic bone marrow containing 6C3HED tumor cells treated with ara-G (100 mM) ex vivo prior to transplantation increases survival of lethally irradiated mice and induces reconstitution of lymphoid, myeloid, and erythroid cell linages.4
References
1. Leanza, L., Miazzi, C., Ferraro, P., et al. Activation of guanine-β-D-arabinofuranoside and deoxyguanosine to triphosphates by a common pathway blocks T lymphoblasts at different checkpoints. Exp. Cell Res. 316(20), 3443-3453 (2010).
2. Lambe, C.U., Averett, D.R., Paff, M.T., et al. 2-Amino-6-methoxypurine arabinoside: An agent for T-cell malignancies. Cancer Res. 55(15), 3352-3356 (1995).
3. Rodriguez, C.O., Jr., Stellrecht, C.M., and Gandhi, V. Mechanisms for T-cell selective cytotoxicity of arabinosylguanine. Blood 102(5), 1842-1848 (2003).
4. Kurtzberg, J. Guanine arabinoside as a bone marrow-purging agent. Ann. N.Y. Acad. Sci 685(1), 225-236 (1993).
| Cas No. | 38819-10-2 | SDF | |
| 别名 | 9-Β-D-糖呋喃鸟嘌呤 | ||
| Canonical SMILES | O[C@H]1[C@H](O)[C@H](N2C=NC3=C2NC(N)=NC3=O)O[C@@H]1CO | ||
| 分子式 | C10H13N5O5 | 分子量 | 283.2 |
| 溶解度 | DMF: 3 mg/ml,DMSO: 5 mg/ml,Ethanol: Partially soluble,PBS (pH 7.2): 0.3 mg/ml | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 3.5311 mL | 17.6554 mL | 35.3107 mL |
| 5 mM | 0.7062 mL | 3.5311 mL | 7.0621 mL |
| 10 mM | 0.3531 mL | 1.7655 mL | 3.5311 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Neurotoxicity Associated with Treatment of Acute Lymphoblastic Leukemia Chemotherapy and Immunotherapy
Int J Mol Sci 2022 May 15;23(10):5515.PMID:35628334DOI:10.3390/ijms23105515.
Immunotherapy is a milestone in the treatment of poor-prognosis pediatric acute lymphoblastic leukemia (ALL) and is expected to improve treatment outcomes and reduce doses of conventional chemotherapy without compromising the effectiveness of the therapy. However, both chemotherapy and immunotherapy cause side effects, including neurological ones. Acute neurological complications occur in 3.6-11% of children treated for ALL. The most neurotoxical chemotherapeutics are L-asparaginase (L-ASP), methotrexate (MTX), vincristine (VCR), and nelarabine (Ara-G). Neurotoxicity associated with methotrexate (MTX-NT) occurs in 3-7% of children treated for ALL and is characterized by seizures, stroke-like symptoms, speech disturbances, and encephalopathy. Recent studies indicate that specific polymorphisms in genes related to neurogenesis may have a predisposition to MTX toxicity. One of the most common complications associated with CAR T-cell therapy is immune effector cell-associated neurotoxicity syndrome (ICANS). Mechanisms of neurotoxicity in CAR T-cell therapy are still unknown and may be due to disruption of the blood-brain barrier and the effects of elevated cytokine levels on the central nervous system (CNS). In this review, we present an analysis of the current knowledge on the mechanisms of neurotoxicity of standard chemotherapy and the targeted therapy in children with ALL.
Hyper-CVAD plus nelarabine in newly diagnosed adult T-cell acute lymphoblastic leukemia and T-lymphoblastic lymphoma
Am J Hematol 2018 Jan;93(1):91-99.PMID:29047158DOI:10.1002/ajh.24947.
Nelarabine, a water soluble prodrug of 9-β-D-arabinofuranosylguanine (Ara-G), is a T-cell specific purine nucleoside analogue. Given its activity in relapsed and refractory T acute lymphoblastic leukemia (T-ALL) and T lymphoblastic lymphoma (T-LBL), we sought to define its role in the frontline treatment of adult patients. Therefore, we conducted a single arm phase 2 study to determine the safety and efficacy of nelarabine in combination with hyper-CVAD in newly diagnosed patients. For induction/consolidation, patients received eight cycles of hyper-CVAD alternating with high-dose methotrexate and cytarabine plus two cycles of nelarabine given at a dose of 650 mg/m2 intravenously daily for 5 days. This was followed by thirty months of POMP maintenance chemotherapy with two additional cycles of nelarabine given instead of cycles 6 and 7 of POMP maintenance. Sixty-seven patients, including 40 with T-ALL and 26 with T-LBL, were enrolled. Complete response rates in both T-ALL and T-LBL were 87% and 100% respectively. Grade 3 to 4 neurotoxic adverse events were reported in 5 patients. There were 21 relapses (31%) including 2 after allogeneic stem cell transplantation. Median duration of follow-up was 42.5 months. The 3-year complete remission duration (CRD) and overall survival (OS) rates were 66% and 65%, respectively. Compared to our historic hyper-CVAD data, there was no survival benefit with the addition of nelarabine. In conclusion, hyper-CVAD plus nelarabine was well tolerated and active in the frontline treatment of adult T-ALL/LBL patients.
Nelarabine
Drugs 2008;68(4):439-47.PMID:18318562DOI:10.2165/00003495-200868040-00004.
Nelarabine is an anticancer prodrug of arabinofuranosylguanine (Ara-G), which is metabolized in cells to the cytotoxic metabolite Ara-G triphosphate (ara-GTP). 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. In paediatric and adult patients with T-cell acute lymphoblastic leukaemia or T-cell lymphoblastic lymphoma, nelarabine induced a complete response, with or without complete haematological recovery, in approximately one-fifth of patients who had not responded to, or had relapsed following treatment with, two or more prior chemotherapy regimens. The median overall survival time was 13.1 and 20.6 weeks in paediatric and adult patients, with corresponding 1-year survival rates of 14% and 29%. Treatment-emergent adverse events were common, but non-haematological events were mostly of mild or moderate severity. Neurological events, which may be severe and irreversible, were the most likely adverse events to limit treatment.
In vitro efficacy of forodesine and nelarabine (Ara-G) in pediatric leukemia
Blood 2011 Aug 25;118(8):2184-90.PMID:21730354DOI:10.1182/blood-2011-02-337840.
Forodesine and nelarabine (the pro-drug of Ara-G) are 2 nucleoside analogues with promising anti-leukemic activity. To better understand which pediatric patients might benefit from forodesine or nelarabine (Ara-G) therapy, we investigated the in vitro sensitivity to these drugs in 96 diagnostic pediatric leukemia patient samples and the mRNA expression levels of different enzymes involved in nucleoside metabolism. Forodesine and Ara-G cytotoxicities were higher in T-cell acute lymphoblastic leukemia (T-ALL) samples than in B-cell precursor (BCP)-ALL and acute myeloid leukemia (AML) samples. Resistance to forodesine did not preclude Ara-G sensitivity and vice versa, indicating that both drugs rely on different resistance mechanisms. Differences in sensitivity could be partly explained by significantly higher accumulation of intracellular dGTP in forodesine-sensitive samples compared with resistant samples, and higher mRNA levels of dGK but not dCK. The mRNA levels of the transporters ENT1 and ENT2 were higher in ara-G-sensitive than -resistant samples. We conclude that especially T-ALL, but also BCP-ALL, pediatric patients may benefit from forodesine or nelarabine (Ara-G) treatment.
Nelarabine: a nucleoside analog with efficacy in T-cell and other leukemias
Ann Pharmacother 2005 Jun;39(6):1056-63.PMID:15870141DOI:10.1345/aph.1E453.
Objective: To present the pharmacology and pharmacokinetics of nelarabine, 9-beta-D-arabinofuranosylguanine (Ara-G) and intraleukemic cellular pharmacokinetics of 9-beta-D-arabinofuranosylguanine triphosphate (ara-GTP) generated from the administration of nelarabine, and clinical and safety information relative to nelarabine use in the treatment of hematologic malignancies. Data sources: MEDLINE (1966-December 2004) was searched using the English-language key terms 2-amino-6-methoxypurine arabinoside, 506U78, and nelarabine. Data were also obtained from published abstracts. Study selection and data extraction: Clinical studies evaluating the pharmacokinetics of nelarabine, Ara-G, and cellular ara-GTP and use of nelarabine, alone or in combination with other agents for the treatment of hematologic malignancies, were included in this review. Data synthesis: Nelarabine is the water-soluble, 6-methoxy analog of 9-beta-D-ara-G. Nelarabine is readily converted to Ara-G by endogenous adenosine deaminase. The half-life of nelarabine is approximately 15 minutes compared with 2-4 hours for Ara-G. The clearance of Ara-G is higher in children than in adults (0.312 vs 0.213 L x h(-1) x kg(-1)). Intracellular ara-GTP elimination is slow relative to nelarabine and Ara-G. In pediatric and adult patients, neurologic toxicity is dose limiting. Severe myelosuppression was not consistently observed. Major responses were seen in patients with T-cell malignancies. Patients who responded had significantly higher intracellular ara-GTP concentrations compared with those who did not respond. Conclusions: Nelarabine is an effective Ara-G prodrug. Nelarabine has significant activity against malignant T-cells and appears to be an important addition to treatments of various leukemias.