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

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

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)719-728
Number of pages10
JournalCancer Chemotherapy and Pharmacology
Volume75
Issue number4
DOIs
StatePublished - Jan 1 2015

Fingerprint

Orosomucoid
Lactones
Stabilization
Camptothecin
Glycoproteins
Hydrolysis
Serum Albumin
Acids
Topotecan
cositecan
Immobilized Proteins
Plasma (human)
Antineoplastic Agents
Blood Proteins

All Science Journal Classification (ASJC) codes

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

Cite this

Yao, S., Petluru, P., Parker, A., Ding, D., Chen, X., Huang, Q., ... Hausheer, F. (2015). Stabilization of the Karenitecin® lactone by alpha-1 acid glycoprotein. Cancer Chemotherapy and Pharmacology, 75(4), 719-728. https://doi.org/10.1007/s00280-015-2686-y

Stabilization of the Karenitecin® lactone by alpha-1 acid glycoprotein. / Yao, Shijie; Petluru, Pavankumar; Parker, Aulma; Ding, Daoyuan; Chen, Xinghai; Huang, Qiuli; Kochat, Harry; Hausheer, Frederick.

In: Cancer Chemotherapy and Pharmacology, Vol. 75, No. 4, 01.01.2015, p. 719-728.

Research output: Contribution to journalArticle

Yao, S, Petluru, P, Parker, A, Ding, D, Chen, X, Huang, Q, Kochat, H & Hausheer, F 2015, 'Stabilization of the Karenitecin® lactone by alpha-1 acid glycoprotein', Cancer Chemotherapy and Pharmacology, vol. 75, no. 4, pp. 719-728. https://doi.org/10.1007/s00280-015-2686-y
Yao, Shijie ; Petluru, Pavankumar ; Parker, Aulma ; Ding, Daoyuan ; Chen, Xinghai ; Huang, Qiuli ; Kochat, Harry ; Hausheer, Frederick. / Stabilization of the Karenitecin® lactone by alpha-1 acid glycoprotein. In: Cancer Chemotherapy and Pharmacology. 2015 ; Vol. 75, No. 4. pp. 719-728.
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