The highly lipophilic DNA topoisomerase I inhibitor DB-67 displays elevated lactone levels in human blood and potent anticancer activity
| Autor: | David Bom, Thomas G. Burke, Robert L. Bevins, J. N. Howe, Stefan Kruszewski, Lori J. Latus, Stephen G. Zimmer, AL Bingcang, Junhong Zhang, Dennis P. Curran |
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| Rok vydání: | 2001 |
| Předmět: |
Chemical Phenomena
Stereochemistry Lipid Bilayers Pharmaceutical Science Lactones In vivo Tumor Cells Cultured medicine Humans Organosilicon Compounds Enzyme Inhibitors Cytotoxicity Lipid bilayer Chromatography High Pressure Liquid chemistry.chemical_classification Liposome Chemistry Physical Human serum albumin Antineoplastic Agents Phytogenic Spectrometry Fluorescence chemistry Anisotropy Camptothecin Drug Screening Assays Antitumor Topoisomerase I Inhibitors Pharmacophore Lactone medicine.drug |
| Zdroj: | Journal of Controlled Release. 74:325-333 |
| ISSN: | 0168-3659 |
| Popis: | 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 K(DLPC) value observed for camptothecin (K(DLPC) 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 microM and 0.3 mM, respectively, the lactone form of DB-67 persisted in liposome suspension after 3 h of incubation at 37 degrees 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. |
| Databáze: | OpenAIRE |
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