Grant S, Bhalla K, McCrady C
Division of Hematology/Oncology, Medical College of Virginia, Richmond 23298.
Leuk Res. 1991;15(4):205-13. doi: 10.1016/0145-2126(91)90122-a.
The interaction between 2'-deoxycytidine (dCyd) and 1-beta-D-arabinofuranosylcytosine (ara-C), administered at pharmacologically achievable concentrations, was examined in four continuously cultured human leukemia cell lines, HL-60, KG-1, K-562, and CCRF-CEM. In three of the cell lines (HL-60, K-562, and CCRF-CEM), co-administration of 20 or 50 microM dCyd with 10 microM ara-C reduced ara-CTP formation by at least 90% and incorporation of ara-C into DNA by at least 80%. In contrast, KG-1 cells exhibited substantially smaller reductions in both ara-CTP formation and incorporation of ara-C into DNA under identical conditions. KG-1 cells were distinguished by the highest activity of the enzyme cytidine deaminase of the four lines assayed, and exhibited the smallest increments in the intracellular accumulation of both dCyd and deoxycytidine triphosphate (dCTP) in response to exogenous dCyd. Co-administration of 1 mM tetrahydrouridine (THU) or 0.5 mM deoxy-tetrahydrouridine (dTHU) had little effect on the ability of dCyd to antagonize ara-C metabolism in HL-60, KG-1 and K-562 cells. In contrast, these deaminase inhibitors substantially increased the intracellular accumulation of dCTP as well as the ability of dCyd to antagonize ara-CTP formation and incorporation of ara-C into DNA in KG-1 cells. THU and dTHU also permitted dCyd to antagonize ara-C growth inhibitory effects in KG-1 cells to the extent observed in the other leukemic cell lines. These studies suggest that the intracellular deamination of exogenous deoxycytidine may influence the degree to which this nucleoside antagonizes ara-C metabolism and toxicity in some leukemic cells. They also raise the possibility that deaminase inhibitors may be employed to modulate, and perhaps to improve, the therapeutic selectivity of pharmacologically relevant concentrations of ara-C and dCyd in the treatment of acute leukemia in man.
在四种连续培养的人白血病细胞系HL-60、KG-1、K-562和CCRF-CEM中，研究了以药理学可达到的浓度给予的2'-脱氧胞苷（dCyd）和1-β-D-阿拉伯呋喃糖基胞嘧啶（ara-C）之间的相互作用。在其中三种细胞系（HL-60、K-562和CCRF-CEM）中，将20或50微摩尔/升的dCyd与10微摩尔/升的ara-C共同给药，可使ara-CTP的形成减少至少90%，并使ara-C掺入DNA的量减少至少80%。相比之下，在相同条件下，KG-1细胞的ara-CTP形成和ara-C掺入DNA的减少幅度要小得多。在所检测的四种细胞系中，KG-1细胞的胞苷脱氨酶活性最高，并且对外源dCyd的反应中，dCyd和脱氧胞苷三磷酸（dCTP）的细胞内积累增量最小。在HL-60、KG-1和K-562细胞中，共同给予1毫摩尔/升的四氢尿苷（THU）或0.5毫摩尔/升的脱氧四氢尿苷（dTHU）对dCyd拮抗ara-C代谢的能力几乎没有影响。相比之下，这些脱氨酶抑制剂显著增加了KG-1细胞中dCTP的细胞内积累，以及dCyd拮抗ara-CTP形成和ara-C掺入DNA的能力。THU和dTHU还使dCyd能够在KG-1细胞中拮抗ara-C的生长抑制作用，达到在其他白血病细胞系中观察到的程度。这些研究表明，外源性脱氧胞苷的细胞内脱氨作用可能会影响这种核苷在某些白血病细胞中拮抗ara-C代谢和毒性的程度。它们还提出了一种可能性，即脱氨酶抑制剂可用于调节，甚至可能改善药理学相关浓度的ara-C和dCyd在治疗人类急性白血病中的治疗选择性。
