Matsumoto Y, Fujiwara T, Honjo Y, Sasaoka N, Tsuchida T, Nagao S
Department of Neurological Surgery, Kagawa Medical School, Japan.
J Surg Oncol. 1993 Jun;53(2):97-103. doi: 10.1002/jso.2930530210.
Camptothecin-11 (CPT-11) is a new derivative of camptothecin, a plant alkaloid antitumor agent. Previous studies indicated that antitumor activity of CPT-11 was mediated through interaction of the drugs with its target enzyme, DNA topoisomerase I (topo I). In this study, we studied the relation between sensitivity to CPT-11 and topo I activity of glioma cells. Furthermore, we established CPT-11 resistant cell lines in order to elucidate the potential mechanisms of drug resistance. A clear correlation between the sensitivities to CPT-11 and topo I activities in surgical glioma specimens was demonstrated. Activities of topo I in the CPT-11-sensitive group (IC50 values for CPT-11; < 50 micrograms/ml) tended to be higher than those in the CPT-11-resistant group (IC50 values, > or = 50). Topo I activity may serve as a novel marker to predict the sensitivity of gliomas to topo inhibitors. CPT-11-resistant cell lines (T98G/CPT-11 and C6), respectively, exhibit a 5.4- and 7.3-fold increase in resistance to CPT-11. No differences in topo I activity and intracellular accumulation of CPT-11 were observed between the parent and CPT-11-resistant lines. On the other hand, topo I from T98G/CPT-11 and C6-CPT-11 cells was at least 4- and 2-fold resistant to the inhibitory effect of the CPT-11 on the relaxation activity of topo I, in comparison with their parent lines. This enzymological difference may be responsible for the resistance to CPT-11.
喜树碱-11（CPT-11）是喜树碱的一种新衍生物，喜树碱是一种植物生物碱类抗肿瘤药物。先前的研究表明，CPT-11的抗肿瘤活性是通过药物与其靶酶DNA拓扑异构酶I（拓扑异构酶I）的相互作用介导的。在本研究中，我们研究了胶质瘤细胞对CPT-11的敏感性与拓扑异构酶I活性之间的关系。此外，我们建立了CPT-11耐药细胞系，以阐明耐药的潜在机制。手术切除的胶质瘤标本中对CPT-11的敏感性与拓扑异构酶I活性之间存在明显的相关性。CPT-11敏感组（CPT-11的IC50值；<50微克/毫升）的拓扑异构酶I活性往往高于CPT-11耐药组（IC50值，≥50）。拓扑异构酶I活性可能作为预测胶质瘤对拓扑异构酶抑制剂敏感性的新标志物。CPT-11耐药细胞系（T98G/CPT-11和C6）对CPT-11的耐药性分别增加了5.4倍和7.3倍。在亲本细胞系和CPT-11耐药细胞系之间，未观察到拓扑异构酶I活性和CPT-11细胞内蓄积的差异。另一方面，与它们的亲本细胞系相比，来自T98G/CPT-11和C6-CPT-11细胞的拓扑异构酶I对CPT-11对拓扑异构酶I松弛活性的抑制作用的耐药性至少分别高4倍和2倍。这种酶学差异可能是对CPT-11耐药的原因。
