T细胞选择性核苷类似物奈拉滨

奈拉滨为T细胞选择性核苷类似物，为9-β—D-阿糖呋喃糖乌嘌呤（ara—G）的水溶性前体药物，ara—G在白血病的原始细胞中转化为ara—G的三磷酸盐（ara—GTP），从而抑制DNA合成，导致细胞死亡。主要用于治疗病情复发或对药物无应答的T细胞急性淋巴细胞性白血病（T—ALL）和T细胞淋巴瘤（T—LBL）患者。现对其作用机制、药效学、药动学和临床评价做一介绍。     

In vitro cytotoxicity of nelarabine, clofarabine and flavopiridol in paediatric acute lymphoblastic leukaemia

The in vitro efficacies of three new drugs--clofarabine (CLOF), nelarabine (NEL) and flavopiridol (FP) - were assessed in a panel of acute lymphoblastic leukaemia (ALL) cell lines. The 50% inhibitory concentration (IC50) for CLOF across all lines was 188-fold lower than that of NEL. B-lineage, but not T-lineage lines, were >7-fold more sensitive to CLOF than cytosine arabinoside (ARAC). NEL IC50 was 25-fold and 113-fold higher than ARAC in T- and B-lineage, respectively. T-ALL cells were eightfold more sensitive to NEL than B-lineage but there was considerable overlap. FP was more potent in vitro than glucocorticoids and thiopurines and at doses that recent phase I experience predicts will translate into clinical efficacy. Potential cross-resistance of CLOF, NEL and FP was observed with many front-line ALL therapeutics but not methotrexate or thiopurines. Methotrexate sensitivity was inversely related to that of NEL and FP. Whilst NEL was particularly effective in T-ALL, a subset of patients with B-lineage ALL might also be sensitive. CLOF appeared to be marginally more effective in B-lineage than T-ALL and has a distinct resistance profile that may prove useful in combination with other compounds. FP should be widely effective in ALL if sufficient plasma levels can be achieved clinically.     

Towards the development of a rapid,portable, surface enhanced Raman spectroscopy based cleaning verification system for the drug nelarabine

Objectives Cleaning verification is a scientific and economic problem for the pharmaceutical industry. A large amount of potential manufacturing time is lost to the process of cleaning verification. This involves the analysis of residues on spoiled manufacturing equipment, with high‐performance liquid chromatography (HPLC) being the predominantly employed analytical technique. The aim of this study was to develop a portable cleaning verification system for nelarabine using surface enhanced Raman spectroscopy (SERS). Methods SERS was conducted using a portable Raman spectrometer and a commercially available SERS substrate to develop a rapid and portable cleaning verification system for nelarabine. Samples of standard solutions and swab extracts were deposited onto the SERS active surfaces, allowed to dry and then subjected to spectroscopic analysis. Key findings Nelarabine was amenable to analysis by SERS and the necessary levels of sensitivity were achievable. It is possible to use this technology for a semi‐quantitative limits test. Replicate precision, however, was poor due to the heterogeneous drying pattern of nelarabine on the SERS active surface. Understanding and improving the drying process in order to produce a consistent SERS signal for quantitative analysis is desirable. Conclusions This work shows the potential application of SERS for cleaning verification analysis. SERS may not replace HPLC as the definitive analytical technique, but it could be used in conjunction with HPLC so that swabbing is only carried out once the portable SERS equipment has demonstrated that the manufacturing equipment is below the threshold contamination level.     

Salvage therapy with nelarabine,etoposide, and cyclophosphamide in relapsed/refractory paediatric T‐cell lymphoblastic leukaemia and lymphoma

A combination of 5 d of nelarabine (AraG) with 5 d of etoposide (VP) and cyclophosphamide (CPM) and prophylactic intrathecal chemotherapy was used as salvage therapy in seven children with refractory or relapsed T‐cell leukaemia or lymphoma. The most common side effects attributable to the AraG included Grade 2 and 3 sensory and motor neuropathy and musculoskeletal pain. Haematological toxicity was greater for the combination than AraG alone, although median time to neutrophil and platelet recovery was consistent with other salvage therapies. All patients had some response to the combined therapy and five of the seven went into complete remission after one or two courses of AraG/VP/CPM. Our experience supports the safety of giving AraG as salvage therapy in synchrony with etoposide and cyclophosphamide, although neurological toxicity must be closely monitored.     

Novel purine nucleoside analogues for T-cell-lineage acute lymphoblastic leukaemia and lymphoma

Purine nucleoside phosphorylase (PNP) deficiency is a rare, inherited immunodeficiency disorder in which the specific molecular defect was identified. Clinically, a lack of PNP manifests as profound T-cell deficiency with minor or variable changes in the humoral system. Biochemically, the absence of PNP results in an increase in plasma deoxyguanosine (dGuo) and a T-cell-specific increase in intracellular deoxyguanosine triphosphate (dGTP). This observation has been the impetus for the search for either inhibitors of the enzyme or PNP-resistant dGuo analogues as potential anti-T-cell-lineage agents over the past 30 years. Forodesine (an inhibitor of PNP) and nelarabine (a PNP-resistant dGuo analogue) proved to be T-cell selective when tested in clinic. This review summarises the preclinical, clinical and pharmacokinetic investigations with these novel agents.     

GC测定奈拉滨中有机溶剂残留量

目的建立奈拉滨中有机溶剂残留量的气相色谱分析方法。方法色谱柱为SE-54石英毛细管柱（30 m×0.53 mm,1.0μm）,氢火焰离子化检测器（FID）,载气为氮气,流速40 mL.min 1。进样口温度：200℃,检测器温度：250℃,分流比为50∶1,柱温为程序升温：初始温度40℃保持5 min,以50℃.min 1升至200℃保持5 min。外标法进行定量,并对分离条件进行了研究。结果甲醇、乙腈、二氯甲烷、乙酸乙酯的线性范围分别为14.93～746.4 ng（r=0.999 4）,1.950～97.45 ng（r=0.999 8）,2.980～149.0 ng（r=0.999 6）,25.12～1 256 ng（r=0.999 8）;平均回收率（n=9）分别为100.6%（RSD=1.87%）,101.0%（RSD=2.27%）,99.7%（RSD=3.41%）,100.4%（RSD=1.52%）。结论该方法快速、准确、灵敏度高、重复性好,可作为奈拉滨中有机溶剂残留量的测定方法。     

Nelarabine in the treatment of refractory T-cell malignant diseases

T-cell haematological malignancies are uncommon, difficult to treat and, with the exception of T-cell acute lymphoblastic leukaemia, often associated with a poor prognosis. Nelarabine (2-amino-9-β-d-arabinosyl-6-methoxy-9H-guanine), a synthesised guanosine nucleoside and water-soluble prodrug of ara-G (9-β-d-arabinofuranosylguanine), has recently been approved by the FDA for the treatment of relapsed/refractory T-cell acute lymphoblastic leukaemia and T-cell lymphoblastic lymphoma in adults and children. Similar to other nucleoside analogues, nelarabine acts by inhibiting DNA synthesis and inducing apoptosis in susceptible cells. Ara-G itself is a water-insoluble molecule, making its clinical use difficult. However, nelarabine is water soluble and rapidly converted to ara-G in vivo. Interestingly, it has been demonstrated that ara-GTP accumulates more readily in T-cells than in B-cells, and this discovery created interest in the development of nelarabine for the treatment of T-cell malignancies. The results of early-phase clinical trials evaluating the use of nelarabine in adults and children with refractory T-cell malignancies have been promising. This article describes the development, pharmacology, toxicity and clinical activity of nelarabine, as well as discusses its potential role in the treatment of T-cell haematological malignancies.