Topotecan is a topoisomerase I inhibitor that acts as a Topo I poison. Topotecan specifically targets the topoisomerase I–DNA cleavage complex, acting after DNA cleavage and inhibiting the re-ligation step. Topotecan can cross the blood–brain barrier and exhibits cytotoxicity against a variety of tumor cell types, showing significant activity in the treatment of brain tumors[1].
In vitro, Topotecan (0.02-40μM; 12-48h) dose- and time-dependently inhibited the proliferation of U251, U87, GSCs-U251, and GSCs-U87 cells, with IC₅₀ values at 24h of 2.73±0.25, 2.95±0.23, 5.46±0.41, and 5.95±0.24μM, respectively[1]. Topotecan (3μM; 24h) significantly upregulated p21 protein levels and induced cell cycle arrest at the G0/G1 and S phases in U251, U87, GSCs-U251, and GSCs-U87 cells[1]. Topotecan (0.1-1000ng/mL; 72h) caused a dose-dependent reduction in the viability of HUVECs, with an IC₅₀ of 4.87ng/mL[2]. Among neuroblastoma cell lines, the IC50 values of Topotecan on SH-SY5Y, BE(2)-c and SK-N-BE(2) were 5.3ng/mL, 45.6ng/mL and 65.0ng/mL, respectively. Among sarcoma cell lines, the IC50 values of Topotecan on RH30, RD, and KHOS cell lines were 7.4ng/mL, 7.5ng/mL, and 4.9ng/mL, respectively[2].
In vivo, Topotecan (1mg/kg/d; p.o.; 56d) significantly improved the survival of nonobese diabetic/severe combined immune deficient (NOD/SCID) mice bearing SK-N-BE (2)[2]. In IGROV-1 tumour-bearing mice, Topotecan (10mg/kg) given intraperitoneally every 4 days for four occasions markedly increased survival time over control mice[3].
References:
[1] Zhang FL, Wang P, Liu YH, et al. Topoisomerase I inhibitors, shikonin and topotecan, inhibit growth and induce apoptosis of glioma cells and glioma stem cells. PLoS One. 2013;8(11):e81815.
[2] Kumar S, Mokhtari RB, Sheikh R, et al. Metronomic oral topotecan with pazopanib is an active antiangiogenic regimen in mouse models of aggressive pediatric solid tumor. Clin Cancer Res. 2011;17(17):5656-5667.
[3] Pratesi G, Tortoreto M, Corti C, Giardini R, Zunino F. Successful local regional therapy with topotecan of intraperitoneally growing human ovarian carcinoma xenografts. Br J Cancer. 1995;71(3):525-528.
Topotecan是一种毒药类的拓扑异构酶I抑制剂。Topotecan特异性靶向拓扑异构酶I-DNA切割复合体，在DNA切割后起作用并抑制再重组。Topotecan可以穿过血脑屏障，对多种肿瘤细胞表现出细胞毒性，在脑肿瘤治疗中显示出显著的活性[1]。
体外实验中，Topotecan（0.02-40μM；12-48h）以剂量和时间依赖方式抑制U251，U87，GSCs-U251和GSCs-U87细胞的增殖，处理24小时的IC₅₀值分别为2.73±0.25，2.95±0.23，5.46±0.41和5.95±0.24μM[1]。Topotecan（3μM；24h）显著上调U251，U87，GSCs-U251和GSCs-U87细胞中p21蛋白水平，并诱导细胞周期阻滞于G0/G1期和S期[1]。Topotecan（0.1-1000ng/mL；72h）以剂量依赖方式降低HUVECs细胞的活力，其IC₅₀值为4.87ng/mL[2]。在神经母细胞瘤细胞系中，Topotecan对SH-SY5Y，BE(2)-c和SK-N-BE(2)的IC50值分别为5.3ng/mL，45.6ng/mL和65.0ng/mL。在肉瘤细胞系中，Topotecan对RH30、RD和KHOS细胞系的IC50值分别为7.4ng/mL，7.5ng/mL和4.9ng/mL[2]。
体内实验中，Topotecan（1mg/kg/天；口服；连续56天）显著提高了携带SK-N-BE(2)肿瘤的NOD/SCID小鼠的生存率[2]。在IGROV-1荷瘤小鼠中，10mg/kg的Topotecan腹腔内每4天给药一次，共4次，小鼠生存时间明显增加[3]。