Richard Christina, Matthews Donald, Duivenvoorden Wilhelmina, Yau Jonathan, Wright Paul S, Th'ng John P H
Thunder Bay Regional Health Sciences Centre, Thunder Bay, Ontario, Canada.
Clin Cancer Res. 2005 May 1;11(9):3523-9. doi: 10.1158/1078-0432.CCR-04-2507.
We examined the efficacy of flavopiridol, a cyclin-dependent kinase inhibitor that is undergoing clinical trials, on primary cancer cells isolated from the ascites or pleural fluids of patients with metastatic cancers.
Metastasized cancer cells were isolated from the pleural fluids (n = 20) or ascites (n = 15) of patients, most of whom were refractory to chemotherapy. These primary cancer cells were used within 2 weeks of isolation without selecting for proliferative capacities. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide viability assay was used to characterize the response of these cancer cells to commonly used chemotherapeutic agents, and their response to flavopiridol was compared with rapidly dividing cultured cell lines.
The primary cancer cells displayed phenotypes that were different from established cell lines; they had very low replication rates, dividing every 1 to 2 weeks, and underwent replicative senescence within five passages. These primary tumor cells retained their resistance to chemotherapeutic drugs exhibited by the respective patients but did not show cross-resistance to other agents. However, these cancer cells showed sensitivity to flavopiridol with an average LD50 of 50 nmol/L (range, 21.5-69 nmol/L), similar to the LD50 in established cell lines. Because senescent cells also showed similar sensitivity to flavopiridol, it suggests that the mechanism of action is not dependent on the activity of cyclin-dependent kinases that regulate the progression of the cell cycle.
Using cancer cells isolated from the ascites or pleural fluids, this study shows the potential of flavopiridol against cancer cells that have developed resistance to conventional chemotherapeutic agents.
我们研究了正在进行临床试验的细胞周期蛋白依赖性激酶抑制剂黄酮哌啶醇对从转移性癌症患者腹水或胸水中分离出的原发性癌细胞的疗效。
从患者的胸水（n = 20）或腹水（n = 15）中分离出转移癌细胞，这些患者大多对化疗耐药。这些原发性癌细胞在分离后2周内使用，未选择增殖能力。采用3-（4,5-二甲基噻唑-2-基）-2,5-二苯基四氮唑溴盐活力测定法来表征这些癌细胞对常用化疗药物的反应，并将它们对黄酮哌啶醇的反应与快速分裂的培养细胞系进行比较。
原发性癌细胞表现出与已建立的细胞系不同的表型；它们的复制率非常低，每1至2周分裂一次，并在五代内经历复制性衰老。这些原发性肿瘤细胞保留了各自患者所表现出的对化疗药物的耐药性，但对其他药物没有交叉耐药性。然而，这些癌细胞对黄酮哌啶醇敏感，平均半数致死剂量（LD50）为50 nmol/L（范围为21.5 - 69 nmol/L），与已建立细胞系中的LD50相似。由于衰老细胞对黄酮哌啶醇也表现出类似的敏感性，这表明其作用机制不依赖于调节细胞周期进程的细胞周期蛋白依赖性激酶的活性。
本研究使用从腹水或胸水中分离出的癌细胞，表明了黄酮哌啶醇对已对传统化疗药物产生耐药性的癌细胞的治疗潜力。
