POTENTIATION OF CISPLATIN CYTOTOXICITY IN HUMAN OVARIAN-CARCINOMA CELL-LINES BY TRIFLUOPERAZINE, A CALMODULIN INHIBITOR
POTENTIATION OF CISPLATIN CYTOTOXICITY IN HUMAN OVARIAN-CARCINOMA CELL-LINES BY TRIFLUOPERAZINE, A CALMODULIN INHIBITOR
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DOI：
10.1016/0090-8258(92)90201-s
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发表时间：
1992-07-01
影响因子：
4.7
通讯作者：
HAMILTON, TC
中科院分区：
文献类型：
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作者：
PEREZ, RP;HANDEL, LM;HAMILTON, TC
卵巢癌的化疗常常受到顺铂 (CDDP) 耐药性的限制。增强的 DNA 修复是可能在人卵巢癌细胞系中协同产生耐药性的几种机制之一。已发表的报告表明，钙调蛋白抑制剂，例如三氟拉嗪 (TFP)，可能会抑制 DNA 修复的一个或多个步骤。单独使用 TFP 或与 CDDP 联合使用的效果是通过对六种人卵巢癌细胞系进行克隆形成测定来确定的，这些细胞系来自未经治疗的患者（其中一些在体外被选择为顺铂耐药）和来自临床上对顺铂化疗耐药的患者。 TFP 在所有细胞系中产生剂量依赖性细胞毒性。此外，TFP (10μM) 在六种细胞系中的三种（A2780、2780-CP8 和 2780-C30）中使 CDDP 细胞毒性增强约两倍。通过中值效应分析，TFP 和 CDDP 在 6 个细胞系中的 4 个中具有累加或协同细胞毒性，而在其余细胞系中则具有明显的拮抗作用。这些结果表明，TFP 可能会增强 CDDP 在某些（但不是全部）人卵巢癌细胞系中的细胞毒性。三氟拉嗪单独或与顺铂联合治疗卵巢癌的潜在效用仍有待在异种移植模型和临床试验中确定。
Chemotherapy for ovarian cancer is frequently limited by cisplatin (CDDP) resistance. Enhanced DNA repair is one of several mechanisms which may cooperate to produce resistance in human ovarian carcinoma cell lines. Published reports suggest that calmodulin inhibitors, such as trifluoperazine (TFP), may inhibit one or more steps in DNA repair. The effects of TFP alone or in combination with CDDP were determined by clonogenic assay of six human ovarian carcinoma cell lines, derived from untreated patients (some of which were selected for cisplatin resistancein vitro) and from patients clinically refractory to cisplatin-based chemotherapy. TFP produced dose-dependent cytotoxicity in all cell lines. In addition, TFP (10μM) produced approximately two-fold enhancement of CDDP cytotoxicity in three of the six cell lines (A2780, 2780-CP8, and 2780-C30). TFP and CDDP had additive or synergistic cytotoxicity in four of the six cell lines by median effects analysis, while clear antagonism was apparent in the remaining cell lines. These results suggest that TFP may enhance CDDP cytotoxicity in some, but not all, human ovarian carcinoma cell lines. The potential utility of trifluoperazine in ovarian cancer, either alone or in combination with cisplatin, remains to be defined in xenograft models and in clinical trials.