喜樹堿是特異性拓?fù)洚悩?gòu)酶I抑制劑，其衍生物伊立替康和拓?fù)涮婵狄褟V泛用于多種實(shí)體瘤的治療,，但均面臨多藥耐藥,、活性受血漿白蛋白等影響的不利因素。吉咪替康是中國科學(xué)院上海藥物研究所自主研發(fā)的新型9位取代的脂溶性喜樹堿衍生物,，研究發(fā)現(xiàn)與伊立替康和拓?fù)涮婵迪啾容^具有明顯的優(yōu)勢,。吉咪替康較SN38（伊立替康的體內(nèi)活性形式）和拓?fù)涮婵稻哂懈鼜?qiáng)的體外抗腫瘤作用，同時(shí)具有抗多藥耐藥特征,，且血漿白蛋白不影響其藥效,。吉咪替康具有與對(duì)照藥物相當(dāng)?shù)耐負(fù)洚悩?gòu)酶I抑制活性，不僅能抑制拓?fù)洚悩?gòu)酶I的催化活性且能穩(wěn)定TopoI/DNA復(fù)合物,。同時(shí)吉咪替康引起強(qiáng)烈的DNA損傷,，造成細(xì)胞的G2-M期阻滯并誘導(dǎo)細(xì)胞凋亡。動(dòng)物實(shí)驗(yàn)顯示,，靜脈注射吉咪替康能夠有效地抑制HCT116,，MDA-MB-435，BEL-7402和A549的裸小鼠人移植瘤的生長,，口服給藥也能有效抑制A549裸小鼠人移植瘤的生長,。綜上，吉咪替康具有優(yōu)于現(xiàn)有同類藥物的特性,，是很有潛力的抗腫瘤候選化合物,。研究論文于2007年被作為封面文章發(fā)表于國際癌癥研究權(quán)威雜志《臨床癌癥研究》（Clinical Cancer Research）上。（來源：中國科學(xué)院上海藥物研究所）
生物谷推薦原始出處：
（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: [email protected] 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: [email protected] .
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.
