The Experts below are selected from a list of 17217 Experts worldwide ranked by ideXlab platform
Thomas G Burke - One of the best experts on this subject based on the ideXlab platform.
-
marked interspecies variations concerning the interactions of camptothecin with serum albumins a frequency domain fluorescence spectroscopic study
Biochemistry, 1994Co-Authors: Thomas G BurkeAbstract:Camptothecin, an anticancer agent reknown for its novel mechanism of action and outstanding murine in vivo activity, has to date displayed only modest therapeutic utility against human cancers. The drug contains an Delta-Lactone Ring moiety which, at pH7.4, hydrolyzes to yield a biologically inactive carboxylate form. Comparison of drug stability in both plasma and purified serum albumin samples revealed that Ring opening occurred to a much greater extent in human samples versus those of other species. Multifrequency phase-modulation spectroscopic analyses of the intrinsic fluorescence emissions of the two drug forms revealed a physical explanation for the extensive Ring opening observed in the presence of human serum albumin (HSA): the protein exhibited a marked 200-fold binding preference for the carboxylate (K = 1.2 x 10(6) M-1) relative to the lactone (K approximately 5.5 x 10(3) M-1). Serum albumins from other species were found to bind camptothecin carboxylate not nearly as tightly as HSA. Due to the unique capacity of human albumin to bind camptothecin carboxylate, resulting in extensive conversion of the drug to its biologically inactive form, it appears that the success of the agent in eradicating cancer in animal models may be inherently more difficult to duplicate in man.
-
the structural basis of camptothecin interactions with human serum albumin impact on drug stability
Journal of Medicinal Chemistry, 1994Co-Authors: Thomas G Burke, Zihou MiAbstract:: The intense intrinsic fluorescence emissions from several clinically relevant camptothecin drugs have been exploited in order to study the structural basis of drug binding to human serum albumin. Both HPLC and time-resolved fluorescence spectroscopic methodologies were employed to characterize the associations of camptothecins with HSA in phosphate-buffered saline (pH 7.4) at 37 degrees C. The alpha-hydroxy Delta-Lactone Ring moiety of camptothecin (C), 10-hydroxycamptothecin (HC), 10,11-(methylenedioxy)camptothecin (MC) and 9-chloro-10,11-(methylenedioxy)camptothecin (CMC) was in each case observed to hydrolyze more rapidly and completely in the presence of HSA than in the protein's absence. Binding isotherms constructed by the method of fluorescence lifetime titration showed that HSA bound preferentially the carboxylate forms of C, HC, MC, and CMC over their lactone forms, thereby providing an explanation for the shift to the right in the lactone-carboxylate equilibrium observed for each compound upon HSA addition. In marked contrast, three analogues (SN-38, CPT-11, and topotecan) all displayed enhanced stabilities in the presence of HSA. While the lifetimes of CPT-11, topotecan, and the carboxylate forms of both drugs were insensitive to the addition of HSA, the lifetimes of both SN-38 and its carboxylate form did titrate upon HSA addition. Analysis of binding isotherms constructed for the albumin interactions of SN-38 and its carboxylate form demonstrated a higher overall association constant for the lactone form [640 (M amino acid (aa) residues)-1] relative to the carboxylate form [150 (M aa)-1]. Our studies indicate that specific modifications at the 7- and 9-positions of the quinoline nucleus, such as those contained in CPT-11, topotecan, and SN-38, enhance drug stability in the presence of HSA. In the case of SN-38, the enhanced stability was shown to be due to preferential associations between the drug's lactone form and the blood protein.
Zihou Mi - One of the best experts on this subject based on the ideXlab platform.
-
the structural basis of camptothecin interactions with human serum albumin impact on drug stability
Journal of Medicinal Chemistry, 1994Co-Authors: Thomas G Burke, Zihou MiAbstract:: The intense intrinsic fluorescence emissions from several clinically relevant camptothecin drugs have been exploited in order to study the structural basis of drug binding to human serum albumin. Both HPLC and time-resolved fluorescence spectroscopic methodologies were employed to characterize the associations of camptothecins with HSA in phosphate-buffered saline (pH 7.4) at 37 degrees C. The alpha-hydroxy Delta-Lactone Ring moiety of camptothecin (C), 10-hydroxycamptothecin (HC), 10,11-(methylenedioxy)camptothecin (MC) and 9-chloro-10,11-(methylenedioxy)camptothecin (CMC) was in each case observed to hydrolyze more rapidly and completely in the presence of HSA than in the protein's absence. Binding isotherms constructed by the method of fluorescence lifetime titration showed that HSA bound preferentially the carboxylate forms of C, HC, MC, and CMC over their lactone forms, thereby providing an explanation for the shift to the right in the lactone-carboxylate equilibrium observed for each compound upon HSA addition. In marked contrast, three analogues (SN-38, CPT-11, and topotecan) all displayed enhanced stabilities in the presence of HSA. While the lifetimes of CPT-11, topotecan, and the carboxylate forms of both drugs were insensitive to the addition of HSA, the lifetimes of both SN-38 and its carboxylate form did titrate upon HSA addition. Analysis of binding isotherms constructed for the albumin interactions of SN-38 and its carboxylate form demonstrated a higher overall association constant for the lactone form [640 (M amino acid (aa) residues)-1] relative to the carboxylate form [150 (M aa)-1]. Our studies indicate that specific modifications at the 7- and 9-positions of the quinoline nucleus, such as those contained in CPT-11, topotecan, and SN-38, enhance drug stability in the presence of HSA. In the case of SN-38, the enhanced stability was shown to be due to preferential associations between the drug's lactone form and the blood protein.