Schiller M, Hohenlöchter B, Schulze-Westhoff P, Zimmermann M, Ritter J, Jürgens H, Boos J
Klinik und Poliklinik für Kinderheilkunde, Westfälische Wilhelms-Universität Münster.
Klin Padiatr. 1996 Jul-Aug;208(4):151-9. doi: 10.1055/s-2008-1046466.
Cellular uptake and intracellular phosphorylation to the nucleotide cytosine arabinoside-triphosphate (Ara-CTP) is the precondition for the cytostatic effect of cytarabine. The pharmacokinetics of Ara-CTP in leukemic cells was reported to be of clinical importance in adult nonlymphoblastic leukemia. Therefore, the role of intracellular Ara-CTP formation and retention was investigated in blast cells from children with acute lymphoblastic leukemia (ALL).
At the time of diagnosis, peripheral or bone marrow blast cells from 41 children with ALL and 13 with relapsed ALL were incubated in Ara-C containing medium (1 hour, 1 or 3 micrograms/ml) followed by reincubation in Ara-C free medium (3 h). Intracellular Ara CTP formation and Ara-CTP retention were determined.
Ara-CTP formation did not show marked differences between the different immunological subtypes. Ara-CTP retention, however, was significantly lower in T-ALL (37 +/- 15%, n = 8) compared to non-T-ALL (67 +/- 25%, n = 33; p < 0.003). Ara-CTP retention was also significantly different in children with and without persistence of peripheral blast cells after one week of prednison treatment (71 +/- 30%, n = 9 and 53 +/- 19%, n = 21; p = 0.031) as well as in children with and without complete bone marrow remission on day 15 of the ALL-BFM treatment protocol (66 +/- 17%, n = 19 and 43 +/- 18%, n = 11; p = 0.018). Ara-CTP retention was inversely correlated with the risk groups defined by the ALL-BFM treatment protocols (standard 79 +/- 29, intermediate 59 +/- 25, high risk 47 +/- 21%). A trend towards lower Ara-CTP retention was observed in relapsed leukemias (relapsed non-T-ALL 51 +/- 17%, p = 0.061). The difference in the probability of event free survival (following risk group adapted treatment according to ALL-BFM trials) between children with high (> or = 72%; 0.92 +/- 0.08) and low (< 72%: 0.58 +/- 0.15) Ara-CTP retention up to now did not reach statistical significance (p = 0.12).
The more rapid decrease of cellular Ara-CTP in T-cell leukemia and children at higher clinical risk groups provide a pharmacokinetic rationale for prolonged infusion duration as an alternative to the intensification by dose escalation alone.
细胞摄取并将其磷酸化为核苷酸阿糖胞苷三磷酸（Ara-CTP）是阿糖胞苷发挥细胞抑制作用的前提条件。据报道，Ara-CTP在白血病细胞中的药代动力学在成人非淋巴细胞白血病中具有临床重要性。因此，研究了急性淋巴细胞白血病（ALL）患儿原始细胞中细胞内Ara-CTP形成和保留的作用。
在诊断时，将41例ALL患儿和13例复发ALL患儿的外周血或骨髓原始细胞在含阿糖胞苷的培养基（1小时，1或3微克/毫升）中孵育，然后在不含阿糖胞苷的培养基中再孵育3小时。测定细胞内Ara-CTP的形成和Ara-CTP的保留情况。
不同免疫亚型之间Ara-CTP的形成没有显著差异。然而，与非T-ALL（67±25%，n = 33；p < 0.003）相比，T-ALL中Ara-CTP的保留率显著较低（37±15%，n = 8）。在泼尼松治疗一周后外周血原始细胞持续存在和不存在的患儿中，Ara-CTP的保留率也有显著差异（71±30%，n = 9和53±19%，n = 21；p = 0.031），在ALL-BFM治疗方案第15天时骨髓完全缓解和未完全缓解的患儿中也是如此（66±17%，n = 19和43±18%，n = 11；p = 0.018）。Ara-CTP的保留率与ALL-BFM治疗方案定义的风险组呈负相关（标准组79±29，中间组59±25，高危组47±21%）。在复发白血病中观察到Ara-CTP保留率有降低趋势（复发非T-ALL 51±17%，p = 0.061）。到目前为止，Ara-CTP保留率高（≥72%：0.92±0.08）和低（<72%：0.58±0.15）的患儿之间无事件生存期概率的差异（根据ALL-BFM试验进行风险组适应性治疗后）尚未达到统计学意义（p = 0.12）。
T细胞白血病和临床高危组患儿细胞内Ara-CTP的更快下降为延长输注时间提供了药代动力学依据，作为仅通过剂量递增强化的替代方法。
原文中“标准组79±29”这里的29疑似有误，未进行修改直接翻译了。
