Christodoulopoulos G, Fotouhi N, Krajewski S, Reed J C, Alaoui-Jamali M, Panasci L
Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec, Canada.
Cancer Lett. 1997 Dec 16;121(1):59-67. doi: 10.1016/s0304-3835(97)00336-4.
Several genes have been implicated in the regulation of apoptosis including bcl-2, bax, bcl-X and p53. These genes may be important in the development of nitrogen mustard (NM) drug resistance in B-cell chronic lymphocytic leukemia (B-CLL). Using Western blot analysis, we examined the levels of Bcl-2, Bax, Bcl-X and p53 protein expression and determined whether the levels of these proteins correlated with in vitro drug resistance in CLL patients' lymphocyte samples. Our investigations suggest that in CLL, NM drug resistance develops without any detectable alteration of Bcl-2, Bax or Bcl-X. In addition, we determined the presence of p53 mutations in 14 samples in order to assess if there is an association between in vitro drug resistance and the presence of p53 mutations. Using single-stranded conformational polymorphism (SSCP) and sequencing analysis, we observed a p53 mutation in two out of seven resistant samples. The mutation occurring in both cases was a G:C --> A:T transition at codon 273 (exon 8). One of these cases was de novo resistant to the nitrogen mustards. Only one of six samples with acquired resistance to the nitrogen mustards had a p53 mutation suggesting that p53 mutations are not a prominent feature of acquired NM resistance in CLL.
包括bcl-2、bax、bcl-X和p53在内的多个基因与细胞凋亡的调控有关。这些基因可能在B细胞慢性淋巴细胞白血病（B-CLL）中氮芥（NM）耐药性的发展中起重要作用。我们使用蛋白质免疫印迹分析检测了Bcl-2、Bax、Bcl-X和p53蛋白的表达水平，并确定这些蛋白的水平是否与CLL患者淋巴细胞样本的体外耐药性相关。我们的研究表明，在CLL中，NM耐药性的产生与Bcl-2、Bax或Bcl-X没有任何可检测到的改变有关。此外，我们检测了14个样本中p53突变的存在情况，以评估体外耐药性与p53突变之间是否存在关联。通过单链构象多态性（SSCP）和测序分析，我们在7个耐药样本中的2个中观察到了p53突变。这两例中发生的突变均为密码子273（第8外显子）处的G:C --> A:T转换。其中一例对氮芥是原发性耐药。在6个对氮芥获得性耐药的样本中，只有1个有p53突变，这表明p53突变不是CLL中获得性NM耐药的突出特征。
