喜树碱是特异性拓扑异构酶I抑制剂，其衍生物伊立替康和拓扑替康已广泛用于多种实体瘤的治疗，但均面临多药耐药、活性受血浆白蛋白等影响的不利因素。吉咪替康是中国科学院上海药物研究所自主研发的新型9位取代的脂溶性喜树碱衍生物，研究发现与伊立替康和拓扑替康相比较具有明显的优势。吉咪替康较SN38（伊立替康的体内活性形式）和拓扑替康具有更强的体外抗肿瘤作用，同时具有抗多药耐药特征，且血浆白蛋白不影响其药效。吉咪替康具有与对照药物相当的拓扑异构酶I抑制活性，不仅能抑制拓扑异构酶I的催化活性且能稳定TopoI/DNA复合物。同时吉咪替康引起强烈的DNA损伤，造成细胞的G2-M期阻滞并诱导细胞凋亡。动物实验显示，静脉注射吉咪替康能够有效地抑制HCT116，MDA-MB-435，BEL-7402和A549的裸小鼠人移植瘤的生长，口服给药也能有效抑制A549裸小鼠人移植瘤的生长。综上，吉咪替康具有优于现有同类药物的特性，是很有潜力的抗肿瘤候选化合物。研究论文于2007年被作为封面文章发表于国际癌症研究权威杂志《临床癌症研究》（Clinical Cancer Research）上。（来源：中国科学院上海药物研究所）
生物谷推荐原始出处：
（Clinical Cancer Research ），13, 1298-1307, February 15, 2007，Wei Lu，Jian Ding
Chimmitecan, a Novel 9-Substituted Camptothecin, with Improved Anticancer Pharmacologic Profiles In vitro and In vivo
Min Huang1, Heyong Gao2, Yi Chen1, Hong Zhu1, Yujun Cai1, Xiongwen Zhang1, Zehong Miao1, Hualiang Jiang3, Jian Zhang3, Hongwu Shen4, Liping Lin1, Wei Lu2 and Jian Ding1
Authors' Affiliations: Divisions of 1 Anti-Tumor Pharmacology and 2 Chemistry, 3 Drug Discovery and Design Center, and 4 Center for Drug Metabolism and Pharmacokinetics Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, PR China
Requests for reprints: Jian Ding, State Key Laboratory of Drug Research, Division of Anti-tumor Pharmacology, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. 555 Zu Chong Zhi Road, Zhangjiang Hi-Tech Park, Shanghai 201203, PR China. Fax: 86-21-50806722; E-mail: jding@mail.shcnc.ac.cn and Wei Lu, State Key Laboratory of Drug Research, Division of Chemistry, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. 555 Zu Chong Zhi Road, Zhangjiang Hi-Tech Park, Shanghai 201203, PR China. E-mail: luwei@mail.shcnc.ac.cn .
Purpose: 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.
Experimental Design: 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.
Results: 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, G2-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.
Conclusions: 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.
