DIFFERENTIAL CYTOTOXICITY OF 19 ANTICANCER AGENTS IN WILD-TYPE AND ETOPOSIDE RESISTANT SMALL-CELL LUNG-CANCER CELL-LINES
DIFFERENTIAL CYTOTOXICITY OF 19 ANTICANCER AGENTS IN WILD-TYPE AND ETOPOSIDE RESISTANT SMALL-CELL LUNG-CANCER CELL-LINES
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DOI：
10.1038/bjc.1993.58
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发表时间：
1993-02-01
影响因子：
8.8
通讯作者：
VINDELOV, L
中科院分区：
文献类型：
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作者：
JENSEN, PB;CHRISTENSEN, IJ;VINDELOV, L
使用一组六种“野生型”和三种VP-16抗性小细胞肺癌（SCLC）细胞系来评估使用克隆形成测定的体外敏感性测试在多大程度上可以有助于将细胞毒性药物联合收割机组合到具有改善的针对SCLC的功效的方案中。抗性品系包括（a）H69/DAU 4。其是典型的多药耐药（MDR），具有P-糖蛋白外排泵（B）NYH/VM，其表现出改变的拓扑异构酶II（topo II）活性，和（c）H69/VP，其对长春新碱交叉耐药，表现出与H69/DAU 4相同的药物积累减少，但不具有P-糖蛋白。在该小组中比较了19种抗癌药物。MDR细胞系表现出，正如预期的那样，交叉耐药的所有拓扑异构酶II药物，但也有不同的模式的附属敏感性BCNU，顺铂，阿糖胞苷，羟基脲，和拓扑异构酶I抑制剂喜树碱。相关性分析显示，药物类似物之间（例如VP-16/VM-26 0.99，长春新碱/长春地辛0.89）以及具有相似作用机制的药物之间（例如BCNU/顺铂0.89，VP-16/多柔比星0.92）具有较高的相关系数（CC），而不同药物类别显示出较低甚至为负的CC（例如BCNU/VP-16 -0.21）。当19种药物模式的CC对VP-16的CC对BCNU作图时，观察到作用于微管、拓扑异构酶II、烷化剂和抗代谢物的药物之间的聚类。在该图中，喜树碱和阿糖胞苷模式是有希望的，因为它们缺乏对烷化剂和拓扑异构酶II药物的交叉抗性。因此，这组细胞上的差异细胞毒性模式可以（1）提供有关药物作用机制的信息，（2）能够选择和组合非交叉耐药药物，以及（3）显示新药在已建立的药物中“适合”的位置。
A panel of six 'wild type' and three VP-16 resistant small cell lung cancer (SCLC) cell lines is used to evaluate to what extent in vitro sensitivity testing using a clonogenic assay can contribute to combine cytotoxic drugs to regimens with improved efficacy against SCLC. The resistant lines include (a) H69/DAU4. which is classical multidrug resistant (MDR) with a P-glycoprotein efflux pump (b) NYH/VM, which exhibits an altered topoisomerase II (topo II) activity and (c) H69/VP, which is cross-resistant to vincristine, exhibits a reduced drug accumulation as H69/DAU4 but is without P-glycoprotein. 19 anticancer agents were compared in the panel. The MDR lines demonstrated, as expected, cross-resistance to all topo II drugs, but also different patterns of collateral sensitivity to BCNU, cisplatin, ara-C, hydroxyurea, and to the topo I inhibitor camptothecin.The complete panel of nine cell lines clearly demonstrated diverse sensitivity patterns to drugs with different modes of action. Correlation analysis showed high correlation coefficients (CC) among drug analogues (e.g. VP-16/VM-26 0.99, vincristine/vindesine 0.89), and between drugs with similar mechanisms of action (e.g. BCNU/Cisplatin 0.89, VP-16/Doxorubicin 0.92), whereas different drug classes demonstrated low or even negative CC (e.g. BCNU/VP-16 -0.21). When the CC of the 19 drug patterns to VP-16 were plotted against the CC to BCNU, clustering was observed between drugs acting on microtubules, on topo II, alkylating agents, and antimetabolites. In this plot, camptothecin and ara-C patterns were promising by virtue of their lack of cross-resistance to alkylating agents and topo II drugs. Thus, the differential cytotoxicity patterns on this panel of cells can (1) give information about drug mechanism of action, (2) enable the selection and combination of non-cross-resistant drugs, and (3) show where new drugs 'fit in' among established agents.