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01.04.2015 | Original Article

Stabilization of the Karenitecin^® lactone by alpha-1 acid glycoprotein

verfasst von: Shijie Yao, Pavankumar Petluru, Aulma Parker, Daoyuan Ding, Xinghai Chen, Qiuli Huang, Harry Kochat, Frederick Hausheer

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 4/2015

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Abstract

Purpose

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.

Conclusion

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.

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Titel: Stabilization of the Karenitecin ® lactone by alpha-1 acid glycoprotein
verfasst von: Shijie Yao
Pavankumar Petluru
Aulma Parker
Daoyuan Ding
Xinghai Chen
Qiuli Huang
Harry Kochat
Frederick Hausheer
Publikationsdatum: 01.04.2015
Verlag: Springer Berlin Heidelberg
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 4/2015
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-015-2686-y

Springer Medizin

Stabilization of the Karenitecin^® lactone by alpha-1 acid glycoprotein