Chimmitecan, a novel 9-substituted camptothecin, with improved anticancer pharmacologic profiles in vitro and in vivo
文献类型：期刊论文
| 作者 | Huang, Min ; Gao, Heyong; Chen, Yi; Zhu, Hong; Cai, Yujun; Zhang, Xiongwen; Miao, Zehong; Jiang, Hualiang; Zhang, Jian; Shen, Hongwu
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| 刊名 | CLINICAL CANCER RESEARCH
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| 出版日期 | 2007-02-15 |
| 卷号 | 13期号:4页码:1298-1307 |
| ISSN号 | 1078-0432 |
| DOI | 10.1158/1078-0432.CCR-06-1277 |
| 文献子类 | Article |
| 英文摘要 | 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-diphenyl-tetrazolium 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, 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. 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. |
| WOS关键词 | DNA TOPOISOMERASE-I ; POTENT ANTITUMOR-ACTIVITY ; HUMAN SERUM-ALBUMIN ; MULTIDRUG-RESISTANCE ; COMET ASSAY ; HUMAN BLOOD ; CURRENT PERSPECTIVES ; DRUG ; DERIVATIVES ; STABILITY |
| WOS研究方向 | Oncology |
| 语种 | 英语 |
| WOS记录号 | WOS:000244501100031 |
| 出版者 | AMER ASSOC CANCER RESEARCH |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/273326]  |
| 专题 | 药理学第一研究室 中科院受体结构与功能重点实验室 新药研究国家重点实验室 |
| 通讯作者 | Ding, Jian |
| 作者单位 | 1.Chinese Acad Sci, Div Chem, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 2.Chinese Acad Sci, Div Drug Discovery & Design Ctr, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Biol Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol,State Key Lab Drug Res, Shanghai 201203, Peoples R China 4.Chinese Acad Sci, Ctr Drug Metab & Pharmacokinet Res, Shanghai Inst Mat Med, Div Antitumor Pharmacol,State Key Lab Drug Res, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Huang, Min,Gao, Heyong,Chen, Yi,et al. Chimmitecan, a novel 9-substituted camptothecin, with improved anticancer pharmacologic profiles in vitro and in vivo[J]. CLINICAL CANCER RESEARCH,2007,13(4):1298-1307. |
| APA | Huang, Min.,Gao, Heyong.,Chen, Yi.,Zhu, Hong.,Cai, Yujun.,...&Ding, Jian.(2007).Chimmitecan, a novel 9-substituted camptothecin, with improved anticancer pharmacologic profiles in vitro and in vivo.CLINICAL CANCER RESEARCH,13(4),1298-1307. |
| MLA | Huang, Min,et al."Chimmitecan, a novel 9-substituted camptothecin, with improved anticancer pharmacologic profiles in vitro and in vivo".CLINICAL CANCER RESEARCH 13.4(2007):1298-1307. |
入库方式： OAI收割
来源：上海药物研究所
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