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The highly lipophilic DNA topoisomerase I inhibitor DB-67 displays elevated lactone levels in human blood and potent anticancer activity

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

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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.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Bom, D
Curran, DPcurran@pitt.eduCURRAN
Zhang, J
Zimmer, SG
Bevins, R
Kruszewski, S
Howe, JN
Bingcang, A
Latus, LJ
Burke, TG
Date: 6 July 2001
Date Type: Publication
Journal or Publication Title: Journal of Controlled Release
Volume: 74
Number: 1-3
Page Range: 325 - 333
DOI or Unique Handle: 10.1016/s0168-3659(01)00343-1
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Refereed: Yes
ISSN: 0168-3659
MeSH Headings: Anisotropy; Antineoplastic Agents, Phytogenic--chemistry; Antineoplastic Agents, Phytogenic--pharmacology; Camptothecin--analogs & derivatives; Camptothecin--chemistry; Camptothecin--pharmacology; Camptothecin--therapeutic use; Chemistry, Physical; Chromatography, High Pressure Liquid; Drug Screening Assays, Antitumor; Enzyme Inhibitors--chemistry; Enzyme Inhibitors--pharmacology; Humans; Lactones--blood; Lipid Bilayers; Organosilicon Compounds--chemistry; Organosilicon Compounds--pharmacology; Physicochemical Phenomena; Spectrometry, Fluorescence; Topoisomerase I Inhibitors; Tumor Cells, Cultured
PubMed ID: 11489514
Date Deposited: 13 Feb 2014 19:24
Last Modified: 22 Jun 2021 13:56


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