title: Stabilization of the Karenitecin® lactone by alpha-1 acid glycoprotein.
abstract: OBJECTIVE
  Camptothecins contain a lactone ring that is necessary for antitumor activity, and hydrolysis of the lactone ring yields an inactive carboxylate species. Human serum albumin (HSA) and alpha-1 acid glycoprotein (AGP) are clinically significant plasma proteins thought to have important roles in camptothecin lactone stability. Herein, we examined the effect(s) of HSA and AGP on the lactone stability of Karenitecin, a novel, highly lipophilic camptothecin analog, currently at the phase 3 clinical testing stage.
  
  
  METHODS
  An AGP-immobilized protein column was used to develop HPLC methods to evaluate the effect(s) of physiologically relevant HSA and AGP concentrations on the lactone/carboxylate ratio and hydrolysis kinetics of Karenitecin, camptothecin (CPT), and topotecan (TPT).
  
  
  RESULTS
  Physiologically relevant concentrations of HSA and AGP substantially slowed Karenitecin lactone hydrolysis. AGP was notably more effective at protecting the Karenitecin lactone from hydrolysis than HSA was in promoting hydrolysis. Additionally, AGP reversed the hydrolysis of partially hydrolyzed Karenitecin lactone. In contrast, HSA and AGP had minimal effects on hydrolysis of the TPT lactone, while the AGP/HSA solutions dramatically accelerated hydrolysis of the CPT lactone.
  
  
  CONCLUSIONS
  AGP strongly enhances the lactone stability of Karenitecin. Since Karenitecin is highly protein-bound in human plasma and exhibits greater lactone stability, relative to other camptothecins, in patient plasma samples, this newly identified role of AGP in promoting lactone stability may have important implications for the design of more effective anticancer agents within the Karentecin™ and camptothecin classes.
authors: BioNumerik Pharmaceuticals, Inc., 8122 Datapoint Drive, Suite 1250, San Antonio, TX, 78229, USA.
authors: Shijie
authors: S
authors: Yao
authors: Pavankumar
authors: P
authors: Petluru
authors: Aulma
authors: A
authors: Parker
authors: Daoyuan
authors: D
authors: Ding
authors: Xinghai
authors: X
authors: Chen
authors: Qiuli
authors: Q
authors: Huang
authors: Harry
authors: H
authors: Kochat
authors: Frederick
authors: F
authors: Hausheer
mesh_terms: D000970:Antineoplastic Agents / Q000097:blood / Q000737:chemistry*; D001665:Binding Sites; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D004355:Drug Stability; D006801:Humans; D006868:Hydrolysis; D007700:Kinetics; D007783:Lactones / Q000737:chemistry*; D015394:Molecular Structure; D009961:Orosomucoid / Q000737:chemistry*; D011485:Protein Binding; D012709:Serum Albumin / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D007783:Lactones; D009961:Orosomucoid; D012709:Serum Albumin; C406143:cositecan; D002166:Camptothecin