Topotecan HCl is a topoisomerase I inhibitor that acts as a Topo I poison. Topotecan HCl specifically targets the topoisomerase I–DNA cleavage complex, acting after DNA cleavage and inhibiting the re-ligation step. Topotecan HCl 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 HCl (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 HCl (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 HCl (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 HCl 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 HCl on RH30, RD, and KHOS cell lines were 7.4ng/mL, 7.5ng/mL, and 4.9ng/mL, respectively[2].
In vivo, Topotecan HCl (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 HCl (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 HCl, 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 HCl 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 HCl of intraperitoneally growing human ovarian carcinoma xenografts. Br J Cancer. 1995;71(3):525-528.
Topotecan HCl是一种毒药类的拓扑异构酶I抑制剂。Topotecan HCl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 HCl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 HCl（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 HCl（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 HCl（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 HCl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 HCl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 HCl（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 HCl腹腔内每4天给药一次，共4次，小鼠生存时间明显增加[3]。