Kanzawa F, Nishio K, Ishida T, Fukuda M, Kurokawa H, Fukumoto H, Nomoto Y, Fukuoka K, Bojanowski K, Saijo N
Pharmacology Division, National Cancer Center Research Institute, Tokyo, Japan.
Br J Cancer. 1997;76(5):571-81. doi: 10.1038/bjc.1997.428.
Drug resistance is one of the problems severely limiting chemotherapy in cancer patients. Thus, it is very important to develop new drugs that are effective against drug-resistant tumour cells. The novel anti-tumour agent NK109 has been developed from benzo[c]phenanthridine derivatives by Nippon Kayaku (Tokyo, Japan). We have confirmed that NK109 shows anti-tumour effects against a number of human tumour cell lines by inhibiting DNA topoisomerase II activity through the stabilization of the cleavable complex. Further, its efficacy against several drug-resistant tumour cell lines was also shown. NK109 showed potent anti-tumour activity against doxorubicin-resistant human tumour cell lines that have a typical multidrug resistance phenotype caused by P-glycoprotein. NK109 was not pumped extracellularly by P-glycoprotein and, consequently, NK109 accumulated in resistant cells. Cisplatin-resistant human tumour cell lines, which demonstrated decreased cisplatin accumulation, were sensitive to NK109. NK109 non-cross-resistance was confirmed using xenografts of tumour cells that were resistant to cisplatin in SCID mice. Furthermore, etoposide-resistant cells, with decreased topoisomerase II activity, were markedly sensitive to NK109 when compared with their parent cells, suggesting the possibility that the cytotoxic mechanism of NK109 differs from that of etoposide. In conclusion, NK109 is a very promising new anti-tumour drug for clinical use, because the efficacy of NK109 is not susceptible to several known molecular alterations that are associated with drug resistance. A clinical study of this compound is now in progress in Japan.
耐药性是严重限制癌症患者化疗的问题之一。因此，开发对耐药肿瘤细胞有效的新药非常重要。新型抗肿瘤药物NK109由日本日本化药公司（东京）从苯并[c]菲啶衍生物开发而来。我们已经证实，NK109通过稳定可裂解复合物来抑制DNA拓扑异构酶II活性，从而对多种人类肿瘤细胞系显示出抗肿瘤作用。此外，还显示了其对几种耐药肿瘤细胞系的疗效。NK109对具有由P-糖蛋白引起的典型多药耐药表型的阿霉素耐药人类肿瘤细胞系显示出强大的抗肿瘤活性。NK109不会被P-糖蛋白泵出细胞外，因此，NK109在耐药细胞中积累。顺铂耐药的人类肿瘤细胞系，其顺铂积累减少，对NK109敏感。使用SCID小鼠中对顺铂耐药的肿瘤细胞异种移植物证实了NK109的非交叉耐药性。此外，与亲本细胞相比，拓扑异构酶II活性降低的依托泊苷耐药细胞对NK109明显敏感，这表明NK109的细胞毒性机制可能与依托泊苷不同。总之，NK109是一种非常有前途的临床应用新型抗肿瘤药物，因为NK109的疗效不易受到与耐药性相关的几种已知分子改变的影响。目前日本正在对该化合物进行临床研究。
