de Jong S, Zijlstra J G, Mulder N H, de Vries E G
Department of Internal Medicine, University Hospital Groningen, The Netherlands.
Cancer Chemother Pharmacol. 1991;28(6):461-4. doi: 10.1007/BF00685823.
Cells exhibiting decreased topoisomerase II (Topo II) activity are resistant to several drugs that require Topo II as an intermediate. These drugs are cytotoxic due to the formation of a cleavable complex between the drug, Topo II and DNA. Fostriecin belongs to a new class of drugs that inhibit Topo II without inducing the formation of this cleavable complex. We tested fostriecin in three human small-cell lung carcinoma cell lines. GLC4 is the parent line. GLC4/ADR is the P-glycoprotein-negative multidrug-resistant subline, which is resistant to several Topo II inhibitors due to its decreased Topo II activity. GLC4/cDDP is the cisplatin-resistant subline, which displays increased Topo II activity. Topo II activity proved to be 100% in GLC4, 35% in GLC4/ADR and 130% in GLC4/cDDP. The fostriecin concentration causing inhibition of the growth of 50% of the cells (IC50) in the microculture tetrazolium assay following continuous incubation was 11.2, 4.1 and 14.9 microM, respectively. After 1-h incubations, the IC50 was 117.8, 101.3 and 219.8 microM, respectively. Our results indicate a relationship between Topo II activity and fostriecin sensitivity in these closely related cell lines. At least in vitro, fostriecin displayed the capacity to kill cells showing resistance to drugs due to decreased Topo II activity. There was no relationship between this capacity and an increase in the activity of the reduced-folate carrier system, the proposed mechanism for cellular entry of fostriecin, since we found no correlation between the cytotoxicity of fostriecin and that of methotrexate.
拓扑异构酶II（Topo II）活性降低的细胞对几种需要Topo II作为中间体的药物具有抗性。这些药物具有细胞毒性，因为药物、Topo II和DNA之间会形成可裂解复合物。福司曲星属于一类新型药物，可抑制Topo II而不诱导形成这种可裂解复合物。我们在三种人小细胞肺癌细胞系中测试了福司曲星。GLC4是亲本细胞系。GLC4/ADR是P-糖蛋白阴性的多药耐药亚系，由于其Topo II活性降低，对几种Topo II抑制剂具有抗性。GLC4/cDDP是顺铂耐药亚系，其Topo II活性增加。Topo II活性在GLC4中为100%，在GLC4/ADR中为35%，在GLC4/cDDP中为130%。在连续孵育后的微量培养四唑盐试验中，导致50%细胞生长受抑制的福司曲星浓度（IC50）分别为11.2、4.1和14.9微摩尔。孵育1小时后，IC50分别为117.8、101.3和219.8微摩尔。我们的结果表明，在这些密切相关的细胞系中，Topo II活性与福司曲星敏感性之间存在关联。至少在体外，福司曲星显示出杀死因Topo II活性降低而对药物耐药的细胞的能力。这种能力与还原叶酸载体系统活性的增加无关，还原叶酸载体系统是福司曲星进入细胞的推测机制，因为我们发现福司曲星的细胞毒性与甲氨蝶呤的细胞毒性之间没有相关性。
