Nakatsu S, Kondo S, Kondo Y, Yin D, Peterson J W, Kaakaji R, Morimura T, Kikuchi H, Takeuchi J, Barnett G H
Department of Neurosurgery, Faculty of Medicine, Kyoto University, Japan.
Cancer Chemother Pharmacol. 1997;39(5):417-23. doi: 10.1007/s002800050592.
The overexpression of the multidrug resistance (mdr1) gene and its product, P-glycoprotein (P-gp), is thought to limit the successful chemotherapy of human tumors. Recent studies demonstrate that SN-38, a metabolite of the camptothecin (CPT) derivative CPT-11, has antitumor effects on several tumors, but the mechanisms responsible for its cytotoxicity remain unclear. We therefore determined whether SN-38 has cytotoxic effects on MDR human glioblastoma GB-1 cells and non-MDR human glioblastoma U87-MG cells. Furthermore, we determined what role SN-38 plays in the induction of cytotoxicity in these tumor cells. In this study, we demonstrated that SN-38 had significantly stronger antitumor effects on GB-1 and U-87MG cells than did CPT (P < 0.01 and P < 0.05, respectively). In addition, findings obtained using a DNA fragmentation assay, Hoechst 33258 staining, in situ end-labeling and cell cycle analysis demonstrated that SN-38 induced apoptosis in these tumors. Our results suggest that SN-38 has a stronger antitumor effect on malignant glioma cells regardless of MDR expression than does CPT, and therefore can be considered a new chemotherapeutic agent potentially effective in the treatment of human primary or recurrent malignant gliomas resistant to chemotherapy.
多药耐药（mdr1）基因及其产物P-糖蛋白（P-gp）的过表达被认为会限制人类肿瘤化疗的成功。最近的研究表明，喜树碱（CPT）衍生物CPT-11的代谢产物SN-38对多种肿瘤具有抗肿瘤作用，但其细胞毒性的机制仍不清楚。因此，我们确定SN-38对多药耐药的人胶质母细胞瘤GB-1细胞和非多药耐药的人胶质母细胞瘤U87-MG细胞是否具有细胞毒性作用。此外，我们还确定了SN-38在这些肿瘤细胞诱导细胞毒性中所起的作用。在本研究中，我们证明SN-38对GB-1和U-87MG细胞的抗肿瘤作用明显强于CPT（分别为P < 0.01和P < 0.05）。此外，使用DNA片段化分析、Hoechst 332,58染色、原位末端标记和细胞周期分析获得的结果表明，SN-38可诱导这些肿瘤细胞凋亡。我们的结果表明，无论多药耐药表达如何，SN-38对恶性胶质瘤细胞的抗肿瘤作用都比CPT更强，因此可被视为一种新的化疗药物，可能对治疗对化疗耐药的人类原发性或复发性恶性胶质瘤有效。
