Urasaki Y, Takebayashi Y, Pommier Y
Laboratory of Molecular Pharmacology, Division of Baisic Sciences, National Cancer Institute, NIH, Bethesda, Maryland 20892-4255, USA.
Cancer Res. 2000 Dec 1;60(23):6577-80.
Homocamptothecin (hCPT), which differs from camptothecin (CPT) by the presence of an additional methylene group in the E-ring, was evaluated in CPT-resistant cell lines. Topoisomerase I (top1)-deficient leukemia P388/CPT45 cells were highly resistant to hCPT, which demonstrates that top1 is the primary target of hCPT. Three CPT-resistant cell lines with top1 point mutations (Chinese hamster lung fibroblast DC3F/C10, human prostate carcinoma DU-145/RC1, and human leukemia CEM/C2) and their top1 enzymes were cross-resistant to hCPT. The antiproliferative activity of hCPT was greater than that of CPT in both parental and CPT-resistant cell lines, particularly in the prostate cell lines. The top1 cleavage complexes formed in the presence of hCPT appear to be more stable than those induced by CPT. Together, these data indicate that hCPT is a specific top1 inhibitor, which shares a common binding site with CPT in the topl-DNA cleavage complexes. Because of its potency, hCPT might overcome resistance to CPT in some cancer cells.
高喜树碱（hCPT）与喜树碱（CPT）的区别在于E环中存在一个额外的亚甲基，它在耐CPT细胞系中进行了评估。拓扑异构酶I（top1）缺陷的白血病P388/CPT45细胞对hCPT具有高度抗性，这表明top1是hCPT的主要靶点。三种具有top1点突变的耐CPT细胞系（中国仓鼠肺成纤维细胞DC3F/C10、人前列腺癌DU-145/RC1和人白血病CEM/C2）及其top1酶对hCPT具有交叉抗性。在亲本细胞系和耐CPT细胞系中，hCPT的抗增殖活性均大于CPT，尤其是在前列腺细胞系中。在hCPT存在下形成的top1切割复合物似乎比CPT诱导的复合物更稳定。总之，这些数据表明hCPT是一种特异性的top1抑制剂，它在top1-DNA切割复合物中与CPT共享一个共同的结合位点。由于其效力，hCPT可能克服某些癌细胞对CPT的抗性。
