Wiley J S, Jones S P, Sawyer W H, Paterson A R
J Clin Invest. 1982 Feb;69(2):479-89. doi: 10.1172/jci110472.
Although cytosine arabinoside (araC) can induce a remission in a majority of patients presenting with acute myeloblastic leukemia (AML), a minority fail to respond and moreover the drug has less effect in acute lymphoblastic leukemia (ALL). The carrier-mediated influx of araC into purified blasts from patients with AML, ALL, and acute undifferentiated leukemia (AUL) has been compared to that of normal lymphocytes and polymorphs. Blasts showed a larger mediated influx of araC than mature cells, since mean influxes for myeloblasts and lymphoblasts were 6- and 2.3-fold greater than polymorphs and lymphocytes, respectively. Also, the mean influx for myeloblasts was fourfold greater than the mean for lymphoblasts. The number of nucleoside transport sites was estimated for each cell type by measuring the equilibrium binding of [(3)H]nitrobenzylthioinosine (NBMPR), which inhibits nucleoside fluxes by binding with high affinity to specific sites on the transport mechanism. The mean binding site numbers for myeloblasts and lymphoblasts were 5- and 2.8-fold greater, respectively, than for the mature cells of the same maturation series. The mean number of NBMPR binding sites for myeloblasts was fourfold greater than for lymphoblasts. Patients with AUL were heterogeneous since blasts from some gave values within the myeloblastic range and others within the lymphoblastic range. The araC influx correlated closely with the number of NBMPR binding sites measured in the same cells on the same day. Transport parameters were measured on blasts from 15 patients with AML or AUL who were then treated with standard induction therapy containing araC. Eight patients entered complete remission, while seven failed therapy, among whom were the three patients with the lowest araC influx (<0.4 pmol/10(7) cells per min) and NBMPR binding (<3,000 sites/cell) for the treated group. In summary, myeloblasts have both higher araC transport rates and more nucleoside transport sites than lymphoblasts and this factor may contribute to the greater sensitivity of AML to this drug. AraC transport varied >10-fold between leukemic blasts and normal leukocytes, but transport capacity related directly to the number of nucleoside transport sites on the cell. Finally, low araC transport rates or few NBMPR binding sites on blasts were observed in a subset of patients with acute leukemia who failed to achieve remission with drug combinations containing araC.
尽管阿糖胞苷（araC）可使大多数急性髓细胞白血病（AML）患者获得缓解，但少数患者对此无反应，而且该药物对急性淋巴细胞白血病（ALL）的疗效较差。已将araC通过载体介导进入AML、ALL和急性未分化白血病（AUL）患者纯化母细胞的情况与正常淋巴细胞和多形核白细胞进行了比较。母细胞显示出比成熟细胞更大的araC介导内流，因为原粒细胞和淋巴细胞的平均内流分别比多形核白细胞和淋巴细胞大6倍和2.3倍。此外，原粒细胞的平均内流比淋巴细胞的平均内流大4倍。通过测量[(3)H]硝基苄硫肌苷（NBMPR）的平衡结合来估计每种细胞类型的核苷转运位点数量，NBMPR通过与转运机制上的特定位点高亲和力结合来抑制核苷通量。原粒细胞和淋巴细胞的平均结合位点数分别比同一成熟系列的成熟细胞大5倍和2.8倍。原粒细胞的NBMPR结合位点平均数比淋巴细胞大4倍。AUL患者具有异质性，因为一些患者的母细胞给出的值在髓细胞范围内，而另一些在淋巴细胞范围内。araC内流与同一天在同一细胞中测量的NBMPR结合位点数量密切相关。对15例AML或AUL患者的母细胞进行了转运参数测量，这些患者随后接受了含araC的标准诱导治疗。8例患者进入完全缓解，7例治疗失败，其中3例是治疗组中araC内流最低（<0.4 pmol/10(7)细胞/分钟）且NBMPR结合最少（<3000位点/细胞）的患者。总之，原粒细胞比淋巴细胞具有更高的araC转运速率和更多的核苷转运位点，这一因素可能导致AML对该药物的敏感性更高。白血病母细胞和正常白细胞之间的araC转运差异超过10倍，但转运能力与细胞上核苷转运位点的数量直接相关。最后，在一部分使用含araC的药物组合未能实现缓解的急性白血病患者中，观察到母细胞上araC转运速率低或NBMPR结合位点少。
