Chimmitecan, a novel 9-substituted camptothecin, with improved anticancer pharmacologic profiles in vitro and in vivo.
Abstract | PURPOSE: 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: 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.
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Authors | Min Huang, Heyong Gao, Yi Chen, Hong Zhu, Yujun Cai, Xiongwen Zhang, Zehong Miao, Hualiang Jiang, Jian Zhang, Hongwu Shen, Liping Lin, Wei Lu, Jian Ding |
Journal | Clinical cancer research : an official journal of the American Association for Cancer Research
(Clin Cancer Res)
Vol. 13
Issue 4
Pg. 1298-307
(Feb 15 2007)
ISSN: 1078-0432 [Print] United States |
PMID | 17287296
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Irinotecan
- Topotecan
- chimmitecan
- DNA Topoisomerases, Type I
- Camptothecin
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Topics |
- Animals
- Apoptosis
(drug effects)
- Camptothecin
(analogs & derivatives, pharmacokinetics, pharmacology)
- Cell Line, Tumor
- DNA Damage
- DNA Topoisomerases, Type I
(chemistry, metabolism)
- Drug Screening Assays, Antitumor
- Female
- HL-60 Cells
- Humans
- Irinotecan
- Mice
- Mice, Inbred BALB C
- Models, Molecular
- Topotecan
(pharmacokinetics, pharmacology)
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