In vitro evaluation of dimethane sulfonate analogues with potential alkylating activity and selective renal cell carcinoma cytotoxicity.
In vitro evaluation of dimethane sulfonate analogues with potential alkylating activity and selective renal cell carcinoma cytotoxicity.
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发表时间：
2004-07
影响因子：
5.7
通讯作者：
S. Mertins;T. Myers;S. Holbeck;Wilma Y. Medina-Pérez;E. Wang;G. Kohlhagen;Y. Pommier;S. Bates
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作者：
S. Mertins;T. Myers;S. Holbeck;Wilma Y. Medina-Pérez;E. Wang;G. Kohlhagen;Y. Pommier;S. Bates
我们确定了五个结构相关的二甲烷磺酸盐在肾癌细胞系中具有假定的选择性细胞毒性。这些化合物具有与预测的烷基化基团连接的疏水部分。与国家癌症研究所抗癌药物筛选标准试剂数据库的比较分析发现测试化合物的IC 50与烷基化剂的IC 50之间存在显著相关性（例如，r = 0.68，P < 0.00001）。在这份报告中，我们研究了这些化合物是否具有与常规烷基化剂相似的活性。在细胞毒性研究中，苯丁酸氮芥耐药的步行者大鼠癌细胞对测试化合物的交叉耐药是对苯丁酸氮芥耐药的14倍。为了确定对细胞周期进程的影响，在药物处理之前用溴脱氧尿苷标记肾细胞癌（RCC）系109。在用IC 90剂量的NSC 268965处理的细胞中发生完全细胞周期停滞。在药物暴露18小时后，RCC系109中p53蛋白水平增加多达5.7倍，乳腺癌系MCF-7中增加多达20.4倍。最后，DNA-蛋白质交联被发现后6小时的预处理与所有的化合物。因此，二甲磺酸盐类似物具有某些烷化剂的预期性质，但与常规烷化剂不同，似乎具有抗RCC的活性。
We identified five structurally related dimethane sulfonates with putative selective cytotoxicity in renal cancer cell lines. These compounds have a hydrophobic moiety linked to a predicted alkylating group. A COMPARE analysis with the National Cancer Institute Anticancer Drug Screen standard agent database found significant correlations between the IC50 of the test compounds and the IC50 of alkylating agents (e.g., r = 0.68, P < 0.00001 for chlorambucil). In this report, we examined whether these compounds had activities similar to those of conventional alkylating agents. In cytotoxicity studies, chlorambucil-resistant Walker rat carcinoma cells were 4- to 11-fold cross-resistant to the test compounds compared with 14-fold resistant to chlorambucil. To determine effects on cell cycle progression, renal cell carcinoma (RCC) line 109 was labeled with bromodeoxyuridine prior to drug treatment. Complete cell cycle arrest occurred in cells treated with an IC90 dose of NSC 268965. p53 protein levels increased as much as 5.7-fold in RCC line 109 and as much as 20.4-fold in breast cancer line MCF-7 following an 18-hour drug exposure. Finally, DNA-protein cross-links were found following a 6-hour pretreatment with all compounds. Thus, the dimethane sulfonate analogues have properties expected of some alkylating agents but, unlike conventional alkylating agents, appear to possess activity against RCC.