Chimmitecan, a novel 9-substituted camptothecin, with improved anticancer pharmacologic profiles in vitro and in vivo.
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.
Huang
Min
M
Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, PR China.
Gao
Heyong
H
Chen
Yi
Y
Zhu
Hong
H
Cai
Yujun
Y
Zhang
Xiongwen
X
Miao
Zehong
Z
Jiang
Hualiang
H
Zhang
Jian
J
Shen
Hongwu
H
Lin
Liping
L
Lu
Wei
W
Ding
Jian
J
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*
D000077146:Irinotecan; D019772:Topotecan; C521106:chimmitecan; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin