Differential sensitivity of human leukemic T cell lines and B cell lines to growth inhibition by deoxyadenosine.
Differential sensitivity of human leukemic T cell lines and B cell lines to growth inhibition by deoxyadenosine.
复制标题
人白血病 T 细胞系和 B 细胞系对脱氧腺苷生长抑制的不同敏感性。
作者：
D. A. Carson;Jonathan Kaye;J. Seegmiller
先前的实验已经表明，与酶腺苷脱氨酶（ADA）（腺苷氨基水解酶; EC 3.5.4.4）和嘌呤核苷磷酸化酶（PNP）（嘌呤-核苷正磷酸核糖基转移酶; EC 2.4.2.1）的遗传缺陷相关的淋巴特异性毒性是由毒性嘌呤脱氧核糖核苷酸介导的，所述毒性嘌呤脱氧核糖核苷酸选择性地捕获在富含嘌呤脱氧核糖核苷激酶的淋巴组织中。然而，这一假说并不能完全解释ADA尤其是PNP缺乏症中T细胞功能相对于B细胞功能的更大损害。在本实验中，我们比较了脱氧腺苷和腺苷，ADA的天然底物，对三个白血病T细胞系和三个B细胞系在长期组织培养的抑制作用。白血病T细胞系比B细胞系对脱氧腺苷的毒性作用敏感20倍，但对腺苷不敏感。在ADA抑制剂盐酸阿克罗-9-（2-羟基-3-壬基）腺嘌呤存在的情况下，2.6 µM脱氧腺苷可抑制白血病T细胞生长50%。T细胞系对脱氧腺苷的敏感性增加与细胞内三磷酸脱氧腺苷（deoxyATP）的积累有关，并且与DNA而不是RNA合成的抑制有关。在T和B细胞系中，通过向培养基中加入脱氧胞苷可以逆转脱氧腺苷的毒性。在测试的其他有毒化合物中，白血病T细胞对胸苷（一种已知的核糖核苷酸还原酶抑制剂）的敏感性是B细胞的几倍。因此，白血病T细胞在体外似乎是非常敏感的核糖核苷酸还原酶抑制剂的毒性作用。不是腺苷脱氨酶或嘌呤核苷磷酸化酶底物的嘌呤脱氧核糖核苷类似物和不是胸苷磷酸化酶底物的胸苷类似物可能具有作为T细胞选择性化疗剂的潜在价值。
Previous experiments have suggested that the lymphospecific toxicity associated with inherited deficiencies of the enzymes adenosine deaminase (ADA) (adenosine aminohydrolase; EC 3.5.4.4) and purine nucleoside phosphorylase (PNP) (purine-nucleoside orthophosphate ribosyltransferase; EC 2.4.2.1) is mediated by toxic purine deoxyribonucleotides, which are selectively trapped in lymphoid tissues enriched in purine deoxyribonucleoside kinase. This hypothesis, however, does not fully explain the greater impairment of T as opposed to B cell functions seen in ADA and particularly PNP deficiency. In the present experiments we have compared the inhibitory effects of deoxyadenosine and adenosine, the natural substrates of ADA, on three leukemic T cell lines and three B cell lines in long-term tissue culture. The leukemic T cell lines were 20-fold more sensitive than the B cell lines to the toxic effects of deoxyadenosine, but not adenosine. In the presence of the ADA inhibitor erythro-9-(2-hydroxy-3-nonyl) adenine hydrochloride, 2.6 µM deoxyadenosine inhibited leukemic T cell growth by 50%. The increased sensitivity of the T cell lines to deoxyadenosine was associated with the accumulation of intracellular deoxyadenosine triphosphate (deoxyATP), and with inhibition of DNA but not RNA synthesis. In both the T and B cell lines, deoxyadenosine toxicity could be reversed by the addition of deoxycytidine to the culture medium. Among other toxic compounds tested, the leukemic T cells were several-fold more sensitive than the B cells to thymidine, a known ribonucleotide reductase inhibitor. Thus leukemic T cells in vitro appear to be very susceptible to the toxic effects of ribonucleotide reductase inhibitors. Purine deoxyribonucleoside analogs that are not substrates for adenosine deaminase or purine nucleoside phosphorylase, and thymidine analogs that are not substrates for thymidine phosphorylase, may have potential value as T cell-selective chemotherapeutic agents.