title: Silatecan DB-67 is a novel DNA topoisomerase I-targeted radiation sensitizer.
abstract: The silatecan 7-tert-butyldimethylsilyl-10-hydroxy-camptothecin (DB-67) represents a new generation of camptothecin derivatives that exhibits a potent in vitro DNA topoisomerase I (TOP1)-mediated DNA-damaging activity, improved blood stability, and holds significant promise for the treatment of human cancers. In this study, we characterize the role of TOP1 in mediating the radiosensitization activity of DB-67. As examined by clonogenic survival assay, DB-67 exhibited potent radiosensitization activity at a concentration 10-fold lower than camptothecin in the human glioma D54-MG and T-98G cells, which harbor wild-type and mutant p53, respectively. Analyzed by the single-hit multitarget model, DB-67 induced radiosensitization by obliterating the "shoulder" of the radiation survival curve in the D54-MG cells. The in vivo targeting of TOP1 by DB-67 was investigated by immunoblot analysis. In a dose-dependent manner, DB-67 specifically stimulates covalent linking of TOP1 to chromosomal DNA at concentrations 10-fold lower than camptothecin in the D54-MG cells. The potency of in vivo targeting of TOP1 by DB-67 correlates well with its cytotoxicity and radiosensitization activity. Furthermore, DB-67 exhibited substantially less cytotoxicity and radiosensitization activity in the TOP1 mutant Chinese hamster lung fibroblast DC3F/C-10 cells than in their parental DC3F cells. Together, our data show that DB-67 exhibits potent cytotoxicity and radiosensitization activity by targeting TOP1 in mammalian cells and has great potential for being developed to treat human cancers.
authors.affiliation: Department of Radiation Oncology, University of California Davis Medical Center, Sacramento, CA 95817, USA. aychen@ucdavis.edu
authors.forename: Allan Y
authors.initials: AY
authors.lastname: Chen
authors.forename: Shyh-Jen
authors.initials: SJ
authors.lastname: Shih
authors.forename: Liza N
authors.initials: LN
authors.lastname: Garriques
authors.forename: Mace L
authors.initials: ML
authors.lastname: Rothenberg
authors.forename: Michael
authors.initials: M
authors.lastname: Hsiao
authors.forename: Dennis P
authors.initials: DP
authors.lastname: Curran
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006224:Cricetinae; D004247:DNA / Q000378:metabolism; D004264:DNA Topoisomerases, Type I / Q000235:genetics / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005910:Glioma / Q000201:enzymology; D006801:Humans; D009154:Mutation / Q000235:genetics; D017646:Organosilicon Compounds / Q000494:pharmacology*; D011836:Radiation Tolerance / Q000187:drug effects; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D059004:Topoisomerase I Inhibitors; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D017646:Organosilicon Compounds; D011838:Radiation-Sensitizing Agents; D059004:Topoisomerase I Inhibitors; D016159:Tumor Suppressor Protein p53; C415575:7-tert-butyldimethylsilyl-10-hydroxycamptothecin; D004247:DNA; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II; D002166:Camptothecin