Abstract 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.