ORAL ANTILYMPHOCYTE ACTIVITY AND INDUCTION OF APOPTOSIS BY 2-CHLORO-2'-ARABINO-FLUORO-2'-DEOXYADENOSINE
ORAL ANTILYMPHOCYTE ACTIVITY AND INDUCTION OF APOPTOSIS BY 2-CHLORO-2'-ARABINO-FLUORO-2'-DEOXYADENOSINE
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DOI：
10.1073/pnas.89.7.2970
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发表时间：
1992-04-01
影响因子：
11.1
通讯作者：
COTTAM, HB
中科院分区：
文献类型：
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作者：
CARSON, DA;WASSON, DB;COTTAM, HB
2-氯脱氧腺苷(CDA)在慢性淋巴细胞白血病、毛细胞白血病和低度恶性淋巴瘤中很活跃。在一定程度上，这种活性谱可能归因于CDA对未分裂的淋巴细胞和单核细胞的选择性毒性。然而，CDA在酸性pH下不稳定，可被细菌核苷磷酸化酶降解。本实验证明CDA的2‘-阿拉伯氟衍生物CAFdA对静止的淋巴细胞和巨噬细胞也有直接毒性作用。与CDA不同，CAFdA在pH=2时稳定，不被大肠杆菌核苷磷酸化酶降解。细胞死亡发生在DNA链断裂之前，并可通过添加脱氧胞苷来防止。最初的DNA损伤启动了以细胞凋亡为特征的寡核小体DNA片段化模式。突变的淋巴母细胞缺乏脱氧胞苷酶，胞浆5‘-核苷酸酶升高，或继而核糖核苷酸还原酶活性增加而扩大的脱氧核酸池，对CAFdA和CDA毒性都具有交叉抗药性。口服CAFdA(饮用水中1 mg/ml)一周后，平均血药浓度为0.56mU-M，消除了90%移植到严重联合免疫缺陷(SCID)小鼠体内的慢性淋巴细胞白血病细胞。在相同的条件下，CDA的活性要低得多。总而言之，这些结果表明，CAFdA可以作为一种口服药物，用于治疗惰性淋巴增生性疾病和自身免疫性疾病，在这些疾病中，淋巴细胞和单核细胞需要耗尽。
2-Chlorodeoxyadenosine (CdA) is active in chronic lymphocytic leukemia, hairy-cell leukemia, and low-grade lymphomas. In part, this spectrum of activity may be attributable to the selective toxicity of CdA to nondividing lymphocytes and monocytes. However, CdA is unstable at acidic pH and is degraded by bacterial nucleoside phosphorylases. The present experiments demonstrate that the 2'-arabino-fluoro derivative of CdA, designated CAFdA, is also directly toxic to quiescent lymphocytes and macrophages. Unlike CdA, CAFdA was stable at pH 2 and resisted degradation by Escherichia coli nucleoside phosphorylase. Cell killing was preceded by the formation of DNA strand breaks and could be prevented by supplementation of the medium with deoxycytidine. The initial DNA damage initiated the pattern of oligonucleosomal DNA fragmentation characteristic of apoptosis. Mutant lymphoblasts, deficient in deoxycytidine kinase, with elevated cytoplasmic 5'-nucleotidase, or with expanded deoxynucleotide pools secondary to increased ribonucleotide reductase activity, were cross-resistant to both CAFdA and CdA toxicity. One-week oral treatment with CAFdA (1 mg/ml in drinking water) achieved an average plasma concentration of 0.56-mu-M and eliminated 90% of chronic lymphocytic leukemia cells transplanted into severe combined immunodeficiency (scid) mice. Under the same conditions, CdA was much less active. Collectively, these results suggest that CAFdA could be effective as an oral agent in indolent lymphoproliferative diseases and in autoimmune diseases where lymphocyte and monocyte depletion is desirable.