Ping Yueh-Hsin, Lee Hsin-Chen, Lee Jen-Yi, Wu Pin-Ho, Ho Li-Kang, Chi Chin-Wen, Lu Ming-Fong, Wang Jane-Jen
Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan.
Oncol Rep. 2006 May;15(5):1273-9.
10-Hydroxycamptothecin (10-HCPT), an indole alkaloid isolated from a Chinese tree, Camptotheca acuminate, inhibits the activity of topoisomerase I and has a broad spectrum of anticancer activity in vitro and in vivo. However, its use has been limited due to its water-insolubility and toxicity with i.v. administration. The purpose of this study was to investigate the efficacy, toxicity and proper dosage of 10-HCPT as a single agent by oral administration in the treatment of human colon cancer. 10-HCPT significantly repressed the proliferation of Colo 205 cells at a relatively low concentration (5-20 nM). Flow cytometry analysis and western blot and apoptosis assays demonstrated that low-dose 10-HCPT arrested Colo 205 cells in the G2 phase of the cell cycle and triggered apoptosis through a caspase-3-dependent pathway. Moreover, following oral administration at doses of 2.5-7.5 mg/kg/2 days, significant suppression of tumor growth by 10-HCPT was observed in mouse xenografts. No acute toxicity was observed after an oral challenge of 10-HCPT in BALB/c-nude mice every 2 days. The results of this study suggest that a relatively low dose of 10-HCPT (p.o.) is able to inhibit the growth of colon cancer, facilitating the development of a new protocol of human trials with this anticancer drug.
10-羟基喜树碱（10-HCPT）是从中国树木喜树中分离出的一种吲哚生物碱，它能抑制拓扑异构酶I的活性，在体外和体内均具有广泛的抗癌活性。然而，由于其水溶性差以及静脉给药的毒性，其应用受到了限制。本研究的目的是探讨口服10-HCPT作为单一药物治疗人类结肠癌的疗效、毒性和合适剂量。10-HCPT在相对较低的浓度（5-20 nM）下就能显著抑制Colo 205细胞的增殖。流式细胞术分析、蛋白质印迹法和凋亡检测表明，低剂量的10-HCPT使Colo 205细胞停滞在细胞周期的G2期，并通过半胱天冬酶-3依赖性途径触发凋亡。此外，以2.�-7.5 mg/kg/2天的剂量口服给药后，在小鼠异种移植瘤中观察到10-HCPT对肿瘤生长有显著抑制作用。每2天对BALB/c裸鼠口服10-HCPT后未观察到急性毒性。本研究结果表明，相对低剂量的10-HCPT（口服）能够抑制结肠癌的生长，有助于开发使用这种抗癌药物的新的人体试验方案。
