title: Chimmitecan, a novel 9-substituted camptothecin, with improved anticancer pharmacologic profiles in vitro and in vivo.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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, 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.
authors.affiliation: Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, PR China.
authors.forename: Min
authors.initials: M
authors.lastname: Huang
authors.forename: Heyong
authors.initials: H
authors.lastname: Gao
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.forename: Hong
authors.initials: H
authors.lastname: Zhu
authors.forename: Yujun
authors.initials: Y
authors.lastname: Cai
authors.forename: Xiongwen
authors.initials: X
authors.lastname: Zhang
authors.forename: Zehong
authors.initials: Z
authors.lastname: Miao
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.forename: Hongwu
authors.initials: H
authors.lastname: Shen
authors.forename: Liping
authors.initials: L
authors.lastname: Lin
authors.forename: Wei
authors.initials: W
authors.lastname: Lu
authors.forename: Jian
authors.initials: J
authors.lastname: Ding
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D004249:DNA Damage; D004264:DNA Topoisomerases, Type I / Q000737:chemistry / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D005260:Female; D018922:HL-60 Cells; D006801:Humans; D000077146:Irinotecan; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D019772:Topotecan / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000077146:Irinotecan; D019772:Topotecan; C521106:chimmitecan; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin