Han Tieran, Fernandez Marilyn, Chou Ting-Chao, Agarwal Ram P
Division of Hematology-Oncology, Sylvester Comprehensive Cancer Center, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, 33101, USA.
J Cancer Res Clin Oncol. 2005 Sep;131(9):609-16. doi: 10.1007/s00432-005-0012-5. Epub 2005 Oct 20.
This report presents a quantitative analysis of the synergistic interaction of arabinosylcytosine (araC) and cladribine (CdA) in human H9-lymphoid cell lines sensitive and resistant to araC (H9-araC cells). H9-araC cells obtained by cultivation of H9 cells in the presence of 0.5 microM arabinosylcytosine (araC) had lower deoxycytidine kinase (dCK) than the parental cell line. The IC50 values of araC and CdA calculated by using median-effect analysis and CalcuSyn software were: 0.55 microM and 1.16 microM for CdA and 0.0058 microM and 3.5 microM for araC in H9 and H9-araC cells, respectively. These values were reduced to 0.10 microM and 0.38 microM for CdA and to 0.004 microM and to 0.77 microM for araC when the drugs were used in combination. Computerized simulation of dose reduction index (DRI) indicated that at 50-99% growth inhibition levels, the doses of araC could be reduced by 2.0 to 11.9-fold and 2.9 to 5.3-fold and the doses of CdA by 5.9 and 183.7-fold and 3.1 to 164.8-fold in H9 and H9-araC cells, respectively, when the drugs are used in combination. Assessment by combination index (CI) analysis showed that the combination exhibited moderate to strong synergistic lympho-cytotoxic effects. CdA metabolic studies (influx and activation) in the presence of deoxyadenosine, deoxycytidine, or araC suggested that CdA enters cells by a deoxyadenosine-inhibitable transport system, which is different than that of araC and deoxycytidine transport system. Thus, in addition to the known mechanisms, other mechanisms might be involved in the metabolism of CdA. The demonstration that araC and CdA combinations exert synergistic cytotoxicity even in the resistant cells raises hope that such a combination may be useful in tumors that were found resistant to these drugs.
本报告对阿糖胞苷（araC）和克拉屈滨（CdA）在对araC敏感和耐药的人H9淋巴细胞系（H9 - araC细胞）中的协同相互作用进行了定量分析。通过在0.5微摩尔阿糖胞苷（araC）存在下培养H9细胞获得的H9 - araC细胞，其脱氧胞苷激酶（dCK）低于亲代细胞系。使用中位效应分析和CalcuSyn软件计算的araC和CdA的IC50值分别为：H9细胞中CdA为0.55微摩尔和1.16微摩尔，araC为0.0058微摩尔和3.5微摩尔；H9 - araC细胞中CdA为0.10微摩尔和0.38微摩尔，araC为0.004微摩尔和0.77微摩尔。当联合使用这两种药物时，剂量降低指数（DRI）的计算机模拟表明，在50 - 99%的生长抑制水平下，H9细胞和H
9 - araC细胞中araC的剂量可分别降低2.0至11.9倍和2.9至5.3倍，CdA的剂量可分别降低5.9和183.7倍以及3.1至164.8倍。联合指数（CI）分析评估表明，该联合用药表现出中度至强的协同淋巴细胞毒性作用。在脱氧腺苷、脱氧胞苷或araC存在下进行的CdA代谢研究（内流和激活）表明，CdA通过一种可被脱氧腺苷抑制的转运系统进入细胞，这与araC和脱氧胞苷的转运系统不同。因此，除了已知机制外，CdA的代谢可能还涉及其他机制。araC和CdA联合用药即使在耐药细胞中也能发挥协同细胞毒性作用，这一发现让人希望这种联合用药可能对那些对这些药物耐药的肿瘤有用。
