Lee J H, Lee J M, Kim J K, Ahn S K, Lee S J, Kim M Y, Jew S S, Park J G, Hong C I
Chong Kun Dang Research Institute, Chong Kun Dang Corp., Seoul, Korea.
Arch Pharm Res. 1998 Oct;21(5):581-90. doi: 10.1007/BF02975379.
We developed a novel water-soluble camptothecin analogue, CKD602, and evaluated the inhibition of topoisomerase I and the antitumor activities against mammalian tumor cells and human tumor xenografts. CKD602 was a nanomolar inhibitor of the topoisomerase I enzyme in the cleavable complex assay. CKD602 was found to be 3 times and slightly more potent than topotecan and camptothecin as inhibitors of topoisomerase, respectively. In tumor cell cytotoxicity, CKD602 was more potent than topotecan in 14 out of 26 human cancer cell lines tested, while it was comparable to camptothecin. CKD602 was tested for the in vivo antitumor activity against the human tumor xenograft models. CKD602 was able to induce regression of established HT-29, WIDR and CX-1 colon tumors, LX-1 lung tumor, MX-1 breast tumor and SKOV-3 ovarian tumor as much as 80, 94, 76, 67, 87% and 88%, respectively, with comparable body weight changes to those of topotecan. Also the therapeutic margin (R/Emax: maximum tolerance dose/ED58) of CKD602 was significantly higher than that of topotecan by 4 times. Efficacy was determined at the maximal tolerated dose levels using schedule dependent i.p. administration in mice bearing L1210 leukemia. On a Q4dx4 (every 4 day for 4 doses) schedule, the maximum tolerated dose (MTD) was 25 mg/kg per administration, which caused great weight loss and lethality in < 5% tumor bearing mouse. This schedule brought significant increase in life span (ILS), 212%, with 33% of long-term survivals. The ex vivo antitumor activity of CKD602 was compared with that of topotecan and the mean antitumor index (ATI) values recorded for CKD602 were significantly higher than that noted for topotecan. From these results, CKD602 warrants further clinical investigations as a potent inhibitor of topoisomerase I.
我们研发了一种新型水溶性喜树碱类似物CKD602，并评估了其对拓扑异构酶I的抑制作用以及对哺乳动物肿瘤细胞和人肿瘤异种移植模型的抗肿瘤活性。在可裂解复合物测定中，CKD602是拓扑异构酶I酶的纳摩尔级抑制剂。发现CKD602作为拓扑异构酶抑制剂分别比拓扑替康和喜树碱强3倍且稍强一些。在肿瘤细胞细胞毒性方面，在测试的26种人类癌细胞系中的14种中，CKD602比拓扑替康更具活性，而与喜树碱相当。对CKD602针对人肿瘤异种移植模型的体内抗肿瘤活性进行了测试。CKD602能够使已建立的HT - 29、WIDR和CX - 1结肠肿瘤、LX - 1肺肿瘤、MX - 1乳腺肿瘤和SKOV - 3卵巢肿瘤分别消退80%、94%、76%、67%、87%和88%，体重变化与拓扑替康相当。此外，CKD602的治疗指数（R/Emax：最大耐受剂量/ED58）比拓扑替康显著高4倍。在携带L1210白血病的小鼠中，使用依给药方案而定的腹腔注射，在最大耐受剂量水平测定疗效。按照Q4dx4（每4天给药4次）方案，最大耐受剂量（MTD）为每次25 mg/kg，这在<5%的荷瘤小鼠中导致了严重体重减轻和致死率。该方案使生存期显著延长（ILS）212%，长期生存率为33%。将CKD602的体外抗肿瘤活性与拓扑替康进行了比较，记录的CKD602的平均抗肿瘤指数（ATI）值显著高于拓扑替康。基于这些结果，CKD602作为一种有效的拓扑异构酶I抑制剂值得进一步进行临床研究。
