Huang Min, Gao Heyong, Chen Yi, Zhu Hong, Cai Yujun, Zhang Xiongwen, Miao Zehong, Jiang Hualiang, Zhang Jian, Shen Hongwu, Lin Liping, Lu Wei, Ding Jian
Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, PR China.
Clin Cancer Res. 2007 Feb 15;13(4):1298-307. doi: 10.1158/1078-0432.CCR-06-1277. Epub 2007 Feb 7.
This study aimed to evaluate antitumor activities and pharmacologic profiles of chimmitecan, a novel 9-small-alkyl-substituted lipophilic camptothecin, in comparison with irinotecan (CPT-11) and topotecan.
The in vitro cytotoxities of chimmitecan in human tumor cell lines and multidrug resistance (MDR) cells were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and sulforhodamin B assays. DNA relaxation, cleavage assays, and cellular band depletion assay were combined to delineate its effects on topoisomerase I. DNA damage, cell cycle arrest, and apoptosis were assessed using comet assay, flow cytometry, and DNA ladder analysis, respectively. The in vivo antitumor activities were measured in nude mice bearing human tumor xenografts.
Chimmitecan displayed more potent cytotoxicity than SN38 and topotecan. Neither a cross-resistance to chimmitecan in MDR cells nor an influence of human serum albumin in its cytotoxity was observed. Chimmitecan exhibited comparable effects on topoisomerase I compared with the reference drugs, including inhibiting topoisomerase I catalytic activity and trapping and stabilizing covalent topoisomerase I-DNA complexes. Furthermore, nanomolar levels of chimmitecan caused impressive DNA damage, G(2)-M phase arrest, and apoptosis in human leukemia HL60 cells. I.v. administration of chimmitecan inhibited the growth of HCT-116, MDA-MB-435, BEL-7402, and A549 human carcinoma xenografts in nude mice, with greater potency than CPT-11 against the latter two tumors models. Chimmitecan presented potent efficacy in A549 tumor model when given orally.
Chimmitecan is a potent inhibitor of topoisomerase I and displays outstanding activity in vitro and in vivo. The substitution at the 9-position benefits chimmitecan a salient anti-MDR activity, stability in human serum albumin, improved solubility, and oral availability, which might favorably promise its therapeutic potential in clinical settings.
本研究旨在评估新型9-小烷基取代的亲脂性喜树碱——奇米替康与伊立替康（CPT-11）和拓扑替康相比的抗肿瘤活性和药理特性。
通过3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐和磺酰罗丹明B试验评估奇米替康在人肿瘤细胞系和多药耐药（MDR）细胞中的体外细胞毒性。结合DNA松弛、切割试验和细胞条带消耗试验来描述其对拓扑异构酶I的作用。分别使用彗星试验、流式细胞术和DNA梯状分析评估DNA损伤、细胞周期停滞和凋亡。在携带人肿瘤异种移植瘤的裸鼠中测量体内抗肿瘤活性。
奇米替康显示出比SN38和拓扑替康更强的细胞毒性。未观察到MDR细胞对奇米替康的交叉耐药性，也未观察到人类血清白蛋白对其细胞毒性的影响。与参考药物相比，奇米替康对拓扑异构酶I表现出类似的作用，包括抑制拓扑异构酶I催化活性以及捕获和稳定共价拓扑异构酶I-DNA复合物。此外，纳摩尔水平的奇米替康在人白血病HL60细胞中引起显著的DNA损伤、G(2)-M期停滞和凋亡。静脉注射奇米替康可抑制裸鼠中HCT-116、MDA-MB-435、BEL-7402和A549人癌异种移植瘤的生长，对后两种肿瘤模型的效力比CPT-11更强。口服奇米替康在A549肿瘤模型中表现出强效。
奇米替康是一种有效的拓扑异构酶I抑制剂，在体外和体内均表现出出色的活性。9位取代使奇米替康具有显著的抗MDR活性、在人类血清白蛋白中的稳定性、改善的溶解性和口服可用性，这可能预示着其在临床环境中的治疗潜力。
