Bando T, Fujimura M, Kasahara K, Matsuda T
Third Department of Internal Medicine, School of Medicine, Kanazawa University, Japan.
Anticancer Res. 1998 Mar-Apr;18(2A):1079-84.
cis-Diamminedichloroplatinum(II) (CDDP) is a key anticancer agent. It has been reported that intracellular accumulation of CDDP is an important step as a determinant for resistance to CDDP, which may be modulated by Na+, K(+)-ATPase activity. In this study, the significance of membrane Na+, K(+)-ATPase activity and the role of thromboxane (TX) receptors were evaluated using human lung cancer cell lines. In the non-small-cell lung cancer (NSCLC) cell line, EBC-1, sensitivity to CDDP was improved by treatment with two different selective thromboxane receptor antagonists, calcium 5(z)-[1R,2S,3S,4S-7-[3-phenylsulfonylaminobicyclo [2.2.1]hept-2-yl]-5-heptenoate hydrate (S-1452), and (3R)-3-(4-fluorophenyl sulfonamido)-1,2,3,4-tetrahydro-9-carbazolepropanoic acid (BAYu3405). Na+, K(+)-ATPase was activated and intracellular accumulation of CDDP increased with treatment in EBC-1. In the small-cell lung cancer (SCLC) cell lines, SBC-1, sensitivity to CDDP and Na+, K(+)-ATPase activity did not change significantly, and intracellular accumulation of CDDP was not modulated. These results suggest the importance of the TX receptors as determinants of the sensitivity to CDDP in NSCLC cell lines. However, Na+, K(+)-ATPase activity and the role of TX receptors may not be so significant in the resistance mechanisms to CDDP in SCLC cell lines. In EBC-1 cells, the specific binding of S-145 was evident, but not in SBC-1 cells. The difference in TX receptors in NSCLC and SCLC cell lines may be one of the reasons for the variety of the antitumor effects of CDDP in chemotherapy for lung cancer.
顺二氯二氨合铂（II）（CDDP）是一种关键的抗癌药物。据报道，CDDP在细胞内的积累是决定其耐药性的重要步骤，这可能受Na +、K（+）-ATP酶活性调节。在本研究中，利用人肺癌细胞系评估了膜Na +、K（+）-ATP酶活性的意义以及血栓素（TX）受体的作用。在非小细胞肺癌（NSCLC）细胞系EBC-1中，用两种不同的选择性血栓素受体拮抗剂——5（z）-钙-[1R，2S，3S，4S-7-[3-苯基磺酰氨基双环[2.2.1]庚-2-基]-5-庚烯酸水合物（S-1452）和（3R）-3-（4-氟苯基磺酰胺基）-1，2，3，4-四氢-9-咔唑丙酸（BAYu3405）处理后，对CDDP的敏感性提高。在EBC-1中，处理后Na +、K（+）-ATP酶被激活，CDDP在细胞内的积累增加。在小细胞肺癌（SCLC）细胞系SBC-1中，对CDDP的敏感性和Na +、K（+）-ATP酶活性没有明显变化，CDDP在细胞内的积累也未受到调节。这些结果表明TX受体作为NSCLC细胞系中CDDP敏感性决定因素的重要性。然而，Na +、K（+）-ATP酶活性和TX受体的作用在SCLC细胞系对CDDP的耐药机制中可能不那么重要。在EBC-1细胞中，S-145有明显的特异性结合，但在SBC-1细胞中没有。NSCLC和SCLC细胞系中TX受体的差异可能是CDDP在肺癌化疗中抗肿瘤效果多样的原因之一。
