Bhalla K, Cole J, MacLaughlin W, Baker M, Arlin Z, Graham G, Grant S
Blood. 1986 Nov;68(5):1136-41.
We have examined the effect of supraphysiologic concentrations of the naturally occurring nucleoside deoxycytidine (dCyd) on the in vitro growth of normal (CFU-GM) and leukemic (L-CFU) myeloid progenitor cells. Bone marrow samples obtained from 34 consecutive patients undergoing routine diagnostic bone marrow aspirations for nonmalignant hematologic disorders exhibited nearly a twofold increment in CFU-GM when continuously cultured in the presence of 10(-4) mol/L dCyd. Higher dCyd concentrations were associated with a smaller degree of enhancement of colony formation. In contrast, the growth of leukemic blast progenitors obtained from patients with acute nonlymphocytic leukemia were not enhanced by any of the dCyd concentrations tested. Coadministration of 10(-3) mol/L tetrahydrouridine (THU), a cytidine deaminase inhibitor, failed to alter the relative inability of dCyd to enhance L-CFU colony growth. The stimulatory effect of dCyd on normal CFU-GM was not mediated by the adherent mononuclear cell population of the marrow, nor was it restricted to the subpopulation of CFU-GM in S phase at the time of initial exposure. Moreover, treatment of normal bone marrow cells with dCyd at concentrations ranging from 10(-6) to 5 X 10(-3) mol/L for 24 hours had only a minor effect on the fraction of CFU-GM in S phase. Coadministration of 10(-4) mol/L dCyd was able to reverse the inhibitory effects of several putative regulators of normal myelopoiesis, including leukemia inhibitory activity (LIA), acidic isoferritins (AIF), and prostaglandin E1 (PGE1). Leukemic myeloblasts exposed to 10(-4) mol/L dCyd exhibited substantial expansion of intracellular pools of dCyd triphosphate (dCTP), demonstrating that inability to metabolize dCyd could not be solely responsible for the absence of growth potentiation in these cells. These studies suggest that supraphysiologic concentrations of dCyd may confer a selective in vitro growth advantage upon normal v leukemic myeloid progenitor cells, and may free the former from the inhibitory effects of several potential negative regulators of myelopoiesis.
我们研究了超生理浓度的天然核苷脱氧胞苷（dCyd）对正常髓系祖细胞（CFU - GM）和白血病髓系祖细胞（L - CFU）体外生长的影响。从34例因非恶性血液系统疾病接受常规诊断性骨髓穿刺的连续患者获取的骨髓样本，当在10⁻⁴mol/L dCyd存在下连续培养时，CFU - GM呈现近两倍的增加。更高的dCyd浓度与集落形成的增强程度较小相关。相反，从急性非淋巴细胞白血病患者获得的白血病原始祖细胞的生长在任何测试的dCyd浓度下均未增强。联合给予10⁻³mol/L四氢尿苷（THU），一种胞苷脱氨酶抑制剂，未能改变dCyd相对无法增强L - CFU集落生长的情况。dCyd对正常CFU - GM的刺激作用不是由骨髓中的黏附单核细胞群体介导的，也不限于初始暴露时处于S期的CFU - GM亚群。此外，用浓度范围为10⁻⁶至5×10⁻³mol/L的dCyd处理正常骨髓细胞24小时，对处于S期的CFU - GM比例仅有轻微影响。联合给予10⁻⁴mol/L dCyd能够逆转几种正常髓系造血假定调节因子的抑制作用，包括白血病抑制活性（LIA）、酸性异铁蛋白（AIF）和前列腺素E1（PGE1）。暴露于10⁻⁴mol/L dCyd的白血病成髓细胞表现出细胞内三磷酸脱氧胞苷（dCTP）池的大量扩增，表明无法代谢dCyd不能完全解释这些细胞中缺乏生长增强的原因。这些研究表明，超生理浓度的dCyd可能赋予正常与白血病髓系祖细胞选择性的体外生长优势，并可能使前者免受几种潜在的髓系造血负调节因子的抑制作用。
