Kasahara K, Fujimura M, Bando T, Shibata K, Shirasaki H, Matsuda T
The Third Department of Internal Medicine, Kanazawa University School of Medicine, Japan.
Br J Cancer. 1996 Nov;74(10):1553-8. doi: 10.1038/bjc.1996.588.
We examined the effect of selective thromboxane A2 (TXA2) receptor antagonists, calcium 5(Z)-1R, 2S, 3S, 4S-7-[3-phenylsulphonylaminobicyclo [2.2.1] hept-2-yl]-5-heptonoate hydrate (S-1452) and +/- -7-(3,5,6,-trimethyl-1,4-benzoquinon-2-yl)-7-phenylhaptanoic acid (AA-2414), on sensitivity to cis-diamminedichloroplatinum (II) (CDDP) in non-small-cell lung cancer cell lines. IC50 values to CDDP using MTT assay were decreased 2.1- and 4.6-fold respectively by treatment with 250 or 500 microM S-1452, for a 2 h simultaneous drug exposure, and those of PC-9/CDDP, a CDDP-resistant cell line, were decreased 3.1- and 6.1-fold. Sensitivity to carboplatin was also enhanced by the treatment with S-1452. IC50 values to CDDP and carboplatin were decreased by treatment with AA-2414 in a dose-dependent manner. Isobologram analysis showed that the combination of CDDP with S-1452 or AA-2414 produced supra-additive or additive effects in each cell line. Neither glutathione content nor glutathione S-transferase activity was changed in either cell line by treatment with 500 microM S-1452. Accumulation of platinum into PC-9 and PC-9/CDDP was increased by the treatment in a dose-dependent manner. Na+, K+-ATPase activity of PC-9 and PC-9/CDDP was enhanced by the treatment of S-1452 in a dose-dependent manner. These data show that the TXA2 receptor antagonists may enhance the sensitivity of non-small-cell lung cancer cell lines to platinum agents. Increase in Na+, K+-ATPase activity induced by S-1452 may be the mechanism of its sensitising effect through increase in platinum accumulation.
我们研究了选择性血栓素A2（TXA2）受体拮抗剂，即钙5(Z)-1R, 2S, 3S, 4S-7-[3-苯基磺酰氨基双环[2.2.1]庚-2-基]-5-庚酮酸水合物（S-1452）和±-7-(3,5,6-三甲基-1,4-苯醌-2-基)-7-苯基庚酸（AA-2414），对非小细胞肺癌细胞系中顺二氯二氨铂（II）（CDDP）敏感性的影响。通过MTT法检测，在同时暴露2小时、使用250或500微摩尔S-1452处理后，对CDDP的半数抑制浓度（IC50）值分别降低了2.1倍和4.6倍，而对于CDDP耐药细胞系PC-9/CDDP，其IC50值分别降低了3.1倍和6.1倍。用S-1452处理也增强了对卡铂的敏感性。用AA-2414处理后，对CDDP和卡铂的IC50值呈剂量依赖性降低。等效线图分析表明，CDDP与S-1452或AA-2414联合使用在每个细胞系中产生了超相加或相加效应。用500微摩尔S-1452处理后，两种细胞系中的谷胱甘肽含量和谷胱甘肽S-转移酶活性均未改变。S-1452处理使铂在PC-9和PC-9/CDDP中的蓄积呈剂量依赖性增加。S-1452处理使PC-9和PC-9/CDDP的钠钾ATP酶活性呈剂量依赖性增强。这些数据表明，TXA2受体拮抗剂可能增强非小细胞肺癌细胞系对铂类药物的敏感性。S-1452诱导的钠钾ATP酶活性增加可能是其通过增加铂蓄积产生增敏作用的机制。
