Canitrot Y, Frit P, Salles B
Institut de Pharmacologie et de Biologie Structurale, UPR CNRS 9062, Toulouse, France.
Biochem Biophys Res Commun. 1997 May 29;234(3):573-7. doi: 10.1006/bbrc.1997.6674.
Apoptosis is a major determinant of the effectiveness of antitumor chemotherapy since most of the drugs used in cancer treatment provoke cell death by this process. We selected L1210/0.7R (7-fold) and L1210/3R (16-fold) murine leukemia cells resistant to cisplatin (CDDP) by adaptation of parental L1210/S cells to increasing drug concentration. L1210/0.7R exhibited a decreased apoptosis response to CDDP compared to parental L1210/S, while it was totally defective in L1210/3R as analyzed by cell morphology, DNA fragmentation, and poly(ADP-ribose) polymerase cleavage. This default in apoptosis did not result from differential expression of the antiapoptotic protein bcl-2 or from altered expression of p53. L1210/3R was resistant to other cross-linking agents and sensitive to topoisomerase II inhibitors and microtubule poisons. Whatever the drug sensitivity phenotype to these agents, L1210/3R was totally defective in apoptosis in response to drug treatment, showing that apoptosis control cannot be directly involved in the resistance process of these cell lines.
细胞凋亡是抗肿瘤化疗效果的主要决定因素，因为癌症治疗中使用的大多数药物都是通过这一过程引发细胞死亡。我们通过将亲本L1210/S细胞适应不断增加的药物浓度，筛选出了对顺铂（CDDP）耐药的L1210/0.7R（7倍）和L1210/3R（16倍）小鼠白血病细胞。与亲本L1210/S相比，L1210/0.7R对CDDP的细胞凋亡反应降低，而通过细胞形态学、DNA片段化和聚（ADP-核糖）聚合酶裂解分析，L1210/3R的细胞凋亡完全缺陷。这种细胞凋亡缺陷并非由抗凋亡蛋白bcl-2的差异表达或p53表达改变所致。L1210/3R对其他交联剂耐药，对拓扑异构酶II抑制剂和微管毒物敏感。无论对这些药物的敏感性表型如何，L1210/3R在药物治疗后的细胞凋亡中完全缺陷，表明细胞凋亡控制不能直接参与这些细胞系的耐药过程。
