D. Bom et al., The highly lipophilic DNA topoisomerase I inhibitor DB-67 displays elevated lactone levels in human blood and potent anticancer activity, J CONTR REL, 74(1-3), 2001, pp. 325-333
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.