<> "The repository administrator has not yet configured an RDF license."^^ . <> . . . "The highly lipophilic DNA topoisomerase I inhibitor DB-67 displays elevated lactone levels in human blood and potent anticancer activity"^^ . "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."^^ . "2001-07-06" . . "74" . "1-3" . . "Journal of Controlled Release"^^ . . . "01683659" . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . "JN"^^ . "Howe"^^ . "JN Howe"^^ . . "J"^^ . "Zhang"^^ . "J Zhang"^^ . . "SG"^^ . "Zimmer"^^ . "SG Zimmer"^^ . . "S"^^ . "Kruszewski"^^ . "S Kruszewski"^^ . . "DP"^^ . "Curran"^^ . "DP Curran"^^ . . "R"^^ . "Bevins"^^ . "R Bevins"^^ . . "A"^^ . "Bingcang"^^ . "A Bingcang"^^ . . "LJ"^^ . "Latus"^^ . "LJ Latus"^^ . . "TG"^^ . "Burke"^^ . "TG Burke"^^ . . "D"^^ . "Bom"^^ . "D Bom"^^ . . . . . . "The highly lipophilic DNA topoisomerase I inhibitor DB-67 displays elevated lactone levels in human blood and potent anticancer activity (Plain Text)"^^ . . . "licence.txt"^^ . . . "The highly lipophilic DNA topoisomerase I inhibitor DB-67 displays elevated lactone levels in human blood and potent anticancer activity (Other)"^^ . . . . . . "indexcodes.txt"^^ . . "HTML Summary of #20521 \n\nThe highly lipophilic DNA topoisomerase I inhibitor DB-67 displays elevated lactone levels in human blood and potent anticancer activity\n\n" . "text/html" . .