Rixe O, Ortuzar W, Alvarez M, Parker R, Reed E, Paull K, Fojo T
Division of Clinical Sciences, NCI, NIH, Bethesda, MD 20892, USA.
Biochem Pharmacol. 1996 Dec 24;52(12):1855-65. doi: 10.1016/s0006-2952(97)81490-6.
The present study was designed to explore the activity of platinum compounds in cisplatin-resistant cell lines, the unselected cell lines of the National Cancer Institute's Anticancer Drug Screen, and the potential for use in combination. The activities of four platinum compounds in cisplatin-resistant KB and A2780 cells were investigated. The cells were highly resistant to cisplatin and cross-resistant to carboplatin, but less than one-tenth as resistant to oxaliplatin and tetraplatin. Cellular accumulation of all platinum compounds was decreased in both resistant cell lines. When the activities of cisplatin and oxaliplatin were evaluated in the National Cancer Institute's Anticancer Drug Screen, marked differences were observed. Evaluation of the activity profile using the COMPARE program revealed a different pattern for both agents: the cisplatin activity profile was similar to those of other diamine-platinum compounds, alkylating agents including melphalan, and camptothecin analogs, whereas the activity profile of oxaliplatin resembled those of other "dach" (diaminocyclohexane) platinum compounds and of acridine derivatives. The sensitivity profiles are influenced by the target(s)/mechanism(s) of action and the mechanism(s) of resistance of a drug. The dissimilarity in profiles suggests that these two platinum compounds have a different target(s)/mechanism(s) of action, a different mechanism(s) of resistance, or most likely both. Studies evaluating combinations of cisplatin/oxaliplatin suggest that the activities of these two agents are at least additive and possibly synergistic. Oxaliplatin has a different spectrum of activity and low cross-resistance to cisplatin and should be valuable in cisplatin refractory patients or in combination with cisplatin.
本研究旨在探索铂类化合物在顺铂耐药细胞系、美国国立癌症研究所抗癌药物筛选的未选择细胞系中的活性以及联合使用的潜力。研究了四种铂类化合物在顺铂耐药的KB和A2780细胞中的活性。这些细胞对顺铂高度耐药且对卡铂交叉耐药，但对奥沙利铂和四铂的耐药性不到十分之一。在两种耐药细胞系中，所有铂类化合物的细胞蓄积均减少。在美国国立癌症研究所抗癌药物筛选中评估顺铂和奥沙利铂的活性时，观察到显著差异。使用COMPARE程序评估活性谱显示这两种药物的模式不同：顺铂的活性谱与其他二胺铂化合物、包括美法仑在内的烷化剂以及喜树碱类似物的活性谱相似，而奥沙利铂的活性谱与其他“达可”（二氨基环己烷）铂化合物和吖啶衍生物的活性谱相似。敏感性谱受药物的作用靶点/机制和耐药机制影响。谱的差异表明这两种铂类化合物具有不同的作用靶点/机制、不同的耐药机制，或者很可能两者都不同。评估顺铂/奥沙利铂联合使用的研究表明，这两种药物的活性至少相加，甚至可能协同。奥沙利铂具有不同的活性谱且对顺铂的交叉耐药性低，在顺铂难治性患者或与顺铂联合使用时应该很有价值。
