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) i s 25- to 50-times more lipophilic than camptothecin and readily incorporate s into lipid bilayers. Using the method of fluorescence anisotropy titratio n, 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 D LPC value observed for camptothecin (K-DLPC value of 110 M-1). Using HPLC m ethods, we demonstrated that the presence of liposomal membranes readily st abilize the lactone form of DB-67. At drug and lipid concentrations of 10 m uM and 0.3 mM, respectively, the lactone form of DB-67 persisted in liposom e suspension after 3 h of incubation at 37 degreesC. Thus an advantage of a liposomal formulation of DB-67 is that the presence of lipid bilayers assi sts with stabilizing the key pharmacophore of the agent. The highly lipophi lic character of DB-67, in combination with its 10-hydroxy moiety (which fu nctions 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. Ch em, 43 (2000) 3970], Potent cytotoxicities against a broad range of cancer cells were observed for DB-67, indicating that DB-67 is of comparable poten cy to camptothecin. The impressive human blood stability and cytotoxicity p rofiles for DB-67 indicate it is an excellent candidate for comprehensive i n vivo pharmacological and efficacy studies. Based on these promising attri butes, DB-67 is currently being developed under the NCI RAID program. Due t o its potent anti-topoisomerase I activity and its intrinsic blood stabilit y, DB-67 appears as an attractive novel camptothecin for clinical developme nt. (C) 2001 Elsevier Science BM All rights reserved.