Ahmad I, Al-Katib A M, Beck F W, Mohammad R M
Department of Medicine, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
Clin Cancer Res. 2000 Apr;6(4):1328-32.
Bryostatin 1 (Bryo-1) has been shown to differentiate chronic lymphocytic leukemia (CLL) cells to the hairy cell leukemia phenotype. The purine analogue 2-chlorodeoxyadenosine (2-CdA) exhibits enhanced activity in patients with hairy cell leukemia compared to those with CLL. Here we present a case report of a patient diagnosed with resistant CLL and treated sequentially with Bryo-1 followed by 2-CdA for three cycles. Molecular and biochemical parameters relative to the sequential treatment with these agents in vivo were comparable to those found in the WSU-CLL cell line in vitro (R. M. Mohammad et al., Clin. Cancer Res., 4: 445-453, 1998; R. M. Mohammad et al., Biol. Chem., 379: 1253-1261, 1998). There was a significant reduction of lymphocyte count from 37.1 x 10(3)/microl before the treatment to 3.4 x 10(3)/microl after treatment, and partial remission was achieved 2 months after the treatment. The percentage of morphologically differentiated lymphocytes was increased from 3% before treatment to 92% with the first cycle of Bryo-1. Similarly, expression of CD22, a marker of differentiation, increased from 38% to 97% and was maintained at a high level for the duration of the treatment. Analysis of the molecular markers of apoptosis in isolated peripheral blood lymphocytes revealed an increase in the Bax:Bcl-2 ratio after treatment with Bryo-1 in cycles 2 and 3, with associated poly(ADP-ribose) polymerase cleavage after Bryo-1 and 2-CdA treatment. The deoxycytidine kinase: cytosolic 5'-nucleotidase activity ratio increased modestly after Bryo-1 treatment, indicating increased sensitivity of the peripheral blood lymphocytes to 2-CdA. In summary, we found that sequential treatment with Bryo-1 and 2-CdA caused a significant reduction in peripheral blood lymphocytes (CLL cells) with simultaneous induction of differentiation and the initiation of the Bax: Bcl-2 apoptotic pathway.
苔藓抑素1（Bryo-1）已被证明可将慢性淋巴细胞白血病（CLL）细胞分化为毛细胞白血病表型。与CLL患者相比，嘌呤类似物2-氯脱氧腺苷（2-CdA）在毛细胞白血病患者中表现出更强的活性。在此，我们报告一例诊断为耐药CLL的患者，先后接受了三个周期的Bryo-1治疗，随后接受2-CdA治疗。体内这些药物序贯治疗相关的分子和生化参数与体外WSU-CLL细胞系中的参数相当（R.M. Mohammad等人，《临床癌症研究》，4: 445 - 453，1998；R.M. Mohammad等人，《生物化学》，379: 1253 - 1261，1998）。治疗前淋巴细胞计数从37.1×10³/微升显著降至治疗后的3.4×10³/微升，治疗2个月后实现部分缓解。形态学上分化的淋巴细胞百分比从治疗前的3%增加到Bryo-1第一个周期后的92%。同样，分化标志物CD22的表达从38%增加到97%，并在治疗期间维持在高水平。对分离的外周血淋巴细胞凋亡分子标志物的分析显示，在第2和第3周期用Bryo-1治疗后，Bax:Bcl-2比值增加，在Bryo-1和2-CdA治疗后伴有聚（ADP-核糖）聚合酶裂解。Bryo-1治疗后脱氧胞苷激酶:胞质5'-核苷酸酶活性比值略有增加，表明外周血淋巴细胞对2-CdA的敏感性增加。总之，我们发现Bryo-1和2-CdA序贯治疗导致外周血淋巴细胞（CLL细胞）显著减少，同时诱导分化并启动Bax:Bcl-2凋亡途径。
