eprintid: 20521 rev_number: 26 userid: 1418 dir: disk0/00/02/05/21 datestamp: 2014-02-13 19:24:31 lastmod: 2021-06-13 01:55:25 status_changed: 2014-02-13 19:24:31 type: article metadata_visibility: show item_issues_count: 0 eprint_status: archive creators_name: Bom, D creators_name: Curran, DP creators_name: Zhang, J creators_name: Zimmer, SG creators_name: Bevins, R creators_name: Kruszewski, S creators_name: Howe, JN creators_name: Bingcang, A creators_name: Latus, LJ creators_name: Burke, TG creators_email: creators_email: curran@pitt.edu creators_email: creators_email: creators_email: creators_email: creators_email: creators_email: creators_email: creators_email: creators_id: creators_id: CURRAN creators_id: creators_id: creators_id: creators_id: creators_id: creators_id: creators_id: creators_id: title: The highly lipophilic DNA topoisomerase I inhibitor DB-67 displays elevated lactone levels in human blood and potent anticancer activity ispublished: pub divisions: sch_as_chemistry full_text_status: public abstract: The novel silatecan 7-t-butyldimethylsilyl-10-hydroxycamptothecin (DB-67) is 25- to 50-times more lipophilic than camptothecin and readily incorporates into lipid bilayers. Using the method of fluorescence anisotropy titration, we determined that DB-67 bound to small unilamellar vesicles composed of dilaurylphosphatidylcholine (DLPC) with an association constant (K value) of 5000 M-1. This association constant is significantly higher than the KDLPC value observed for camptothecin (KDLPC value of 110 M-1). Using HPLC methods, we demonstrated that the presence of liposomal membranes readily stabilize the lactone form of DB-67. At drug and lipid concentrations of 10 μM and 0.3 mM, respectively, the lactone form of DB-67 persisted in liposome suspension after 3 h of incubation at 37°C. Thus an advantage of a liposomal formulation of DB-67 is that the presence of lipid bilayers assists with stabilizing the key pharmacophore of the agent. The highly lipophilic character of DB-67, in combination with its 10-hydroxy moiety (which functions to enhance lactone stability in the presence of human serum albumin), results in DB-67 having superior stability in human blood with a percent lactone at equilibrium value of 30 [Cancer Res. 59 (1999) 4898; J. Med. Chem. 43 (2000) 3970]. Potent cytotoxicities against a broad range of cancer cells were observed for DB-67, indicating that DB-67 is of comparable potency to camptothecin. The impressive human blood stability and cytotoxicity profiles for DB-67 indicate it is an excellent candidate for comprehensive in vivo pharmacological and efficacy studies. Based on these promising attributes, DB-67 is currently being developed under the NCI RAID program. Due to its potent anti-topoisomerase I activity and its intrinsic blood stability, DB-67 appears as an attractive novel camptothecin for clinical development. © 2001 Elsevier Science B.V. All rights reserved. date: 2001-07-06 date_type: published publication: Journal of Controlled Release volume: 74 number: 1-3 pagerange: 325 - 333 refereed: TRUE issn: 0168-3659 id_number: 10.1016/S0168-3659(01)00343-1 pmid: 11489514 mesh_headings: Anisotropy mesh_headings: Antineoplastic Agents, Phytogenic--chemistry mesh_headings: Antineoplastic Agents, Phytogenic--pharmacology mesh_headings: Camptothecin--analogs & derivatives mesh_headings: Camptothecin--chemistry mesh_headings: Camptothecin--pharmacology mesh_headings: Camptothecin--therapeutic use mesh_headings: Chemistry, Physical mesh_headings: Chromatography, High Pressure Liquid mesh_headings: Drug Screening Assays, Antitumor mesh_headings: Enzyme Inhibitors--chemistry mesh_headings: Enzyme Inhibitors--pharmacology mesh_headings: Humans mesh_headings: Lactones--blood mesh_headings: Lipid Bilayers mesh_headings: Organosilicon Compounds--chemistry mesh_headings: Organosilicon Compounds--pharmacology mesh_headings: Physicochemical Phenomena mesh_headings: Spectrometry, Fluorescence mesh_headings: Topoisomerase I Inhibitors mesh_headings: Tumor Cells, Cultured chemical_names: Antineoplastic Agents, Phytogenic chemical_names: Enzyme Inhibitors chemical_names: Lactones chemical_names: Lipid Bilayers chemical_names: Organosilicon Compounds chemical_names: Topoisomerase I Inhibitors chemical_names: 7-tert-butyldimethylsilyl-10-hydroxycamptothecin chemical_names: Camptothecin citation: Bom, D and Curran, DP and Zhang, J and Zimmer, SG and Bevins, R and Kruszewski, S and Howe, JN and Bingcang, A and Latus, LJ and Burke, TG (2001) The highly lipophilic DNA topoisomerase I inhibitor DB-67 displays elevated lactone levels in human blood and potent anticancer activity. Journal of Controlled Release, 74 (1-3). 325 - 333. ISSN 0168-3659 document_url: http://d-scholarship-dev.library.pitt.edu/20521/1/licence.txt