Shewach D S, Mitchell B S
Department of Pharmacology, University of Michigan Medical Center, Ann Arbor 48109.
Cancer Res. 1989 Dec 1;49(23):6498-502.
9-beta-D-Arabinofuranosylguanine (araG) is a nucleoside analogue that elicits cytotoxicity through the intracellular accumulation of its 5'-triphosphate, araGTP, araG is selectively toxic to cultured T-lymphoblasts due to their ability to accumulate higher levels of the cytotoxic metabolite, araGTP, relative to B- and null lymphoblastoid cells. In an effort to determine whether this selectivity may occur in leukemic cells in vivo, we have investigated the metabolism of araG in MOLT-4 T-lymphoblasts. MGL-8 B-lymphoblasts, HL-60 promyelocytes, and HUT-102 mature T-cells and compared it to that in freshly isolated leukemic cells from patients. MOLT-4 T-lymphoblasts were 50- to 380-fold more sensitive to growth inhibition with araG and accumulated 80-fold higher levels of araGTP than any of the other cell lines studied. Incubation of peripheral blood from patients with leukemia with araG for 4 h demonstrated that T-acute lymphocytic leukemia cells accumulated significantly higher median levels of araGTP than did acute myelogenous leukemia or chronic lymphocytic leukemia cells (187 versus 72 and 31 pmol of araGTP per 10(7) cells, respectively), araGTP accumulation was not dependent on the rate of degradation of araG during the incubation. In contrast, araG did not exhibit similar selective growth inhibition, nor did the accumulation of 1-beta-D-arabinofuranosylcytosine 5'-triphosphate in the freshly isolated leukemic cells differ significantly among T-acute lymphocytic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, and non-T-, non-B-cell acute lymphocytic leukemia cells. These results demonstrate that the selective metabolism of araG observed in cultured cell lines was representative of the metabolism in freshly isolated leukemic cells. Furthermore, degradation of araG did not limit the accumulation of araGTP in the leukemic cells. These results indicate that araG may be valuable as a selectively acting chemotherapeutic agent in T-lymphoblastic malignancies.
9-β-D-阿拉伯呋喃糖基鸟嘌呤（araG）是一种核苷类似物，其通过细胞内积累其5'-三磷酸（araGTP）引发细胞毒性。由于相对于B淋巴细胞和无淋巴细胞系，培养的T淋巴细胞能够积累更高水平的细胞毒性代谢物araGTP，因此araG对培养的T淋巴细胞具有选择性毒性。为了确定这种选择性是否可能在体内白血病细胞中发生，我们研究了araG在MOLT-4 T淋巴细胞、MGL-8 B淋巴细胞、HL-60早幼粒细胞和HUT-102成熟T细胞中的代谢，并将其与来自患者的新鲜分离的白血病细胞中的代谢进行比较。MOLT-4 T淋巴细胞对araG诱导的生长抑制的敏感性比其他任何研究的细胞系高50至380倍，并且积累的araGTP水平比其他细胞系高80倍。用araG孵育白血病患者的外周血4小时表明，T急性淋巴细胞白血病细胞积累的araGTP中位数水平明显高于急性髓性白血病或慢性淋巴细胞白血病细胞（分别为每10^7个细胞187 pmol与72和31 pmol的araGTP），araGTP的积累不依赖于孵育期间araG的降解速率。相比之下，araG没有表现出类似的选择性生长抑制，新鲜分离的白血病细胞中1-β-D-阿拉伯呋喃糖基胞嘧啶5'-三磷酸的积累在T急性淋巴细胞白血病、急性髓性白血病、慢性淋巴细胞白血病和非T、非B细胞急性淋巴细胞白血病细胞之间也没有显著差异。这些结果表明，在培养细胞系中观察到的araG的选择性代谢代表了新鲜分离的白血病细胞中的代谢。此外，araG的降解并不限制白血病细胞中araGTP的积累。这些结果表明，araG作为一种在T淋巴细胞恶性肿瘤中具有选择性作用的化疗药物可能具有价值。
