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

  title={Stabilization of the Karenitecin{\textregistered} lactone by alpha-1 acid glycoprotein},
  author={S. Yao and Pavankumar N. Petluru and Aulma R. Parker and Daoyuan Ding and Xinghai Chen and Qiuli Huang and Harry Kochat and Frederick H. Hausheer},
  journal={Cancer Chemotherapy and Pharmacology},
PurposeCamptothecins 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… Expand
Carboxylate Forms of Camptothecins -CPT, SN22 and Karenitecin ® Bind Specifically to Site II (Diazepam site) of Human Serum Albumin
Camptothecins are an important class of anti-cancer agents and under physiological conditions exist in equilibrium between the lactone and carboxylate forms. The lactone form of camptothecins isExpand
Evaluation of potential cytochrome p450 and plasma protein binding drug interactions for the class of camptothecins
The camptothecin agents have the potential for 3A4, 2C9, and 2C8 drug interactions that should be monitored prospectively to avoid toxicity and slight variations in plasma AAG and Alb concentration could result in large variations in free drug exposure and potentially contribute to increased toxicity. Expand
Silicon‐containing analogs of camptothecin as anticancer agents
7‐tert‐Butyldimethylsilyl‐10‐hydroxy‐camptothecin (DB‐67 or AR‐67) has enhanced lipophilicity and demonstrates a antitumor activity superior to its carbon analog, and results of clinical trials appear promising. Expand
Dual Stimuli-Responsive Polymer Prodrugs Quantitatively Loaded by Nanoparticles for Enhanced Cellular Internalization and Triggered Drug Release.
The responsive polymer prodrug encapsulation strategy represents an effective method to overcome the disadvantages of common hydrophobic drug encapsulation approaches by amphiphilic block copolymer micelles and simultaneously endows the nanoparticles with responsive drug release behaviors as well as enhanced cellular internalization and tumor penetration capability. Expand
Overcoming platinum resistance in ovarian cancer treatment: from clinical practice to emerging chemical therapies
Results from clinical trials that tested cytotoxic drugs and target strategies for the treatment of platinum resistant (PR) recurrent ovarian cancer (ROC) with particular attention to Phase III and ongoing trials are summarized. Expand
Enantio-, Regio- and Chemoselective Copper-Catalyzed 1,2-Hydroborylation of Acylsilanes.
This robust and scalable additive-free catalytic system relies on the use of low copper(II) acetate and diphosphine ligand loadings at room temperature in the presence of a commercially available and bench-stable hydride source. Expand


Reduced albumin binding promotes the stability and activity of topotecan in human blood.
The biophysical factors underlying the markedly improved bloodstream stability and cytotoxic activity of topotecan relative to camptothecin are elucidated. Expand
Differential interactions of camptothecin lactone and carboxylate forms with human blood components.
The findings that HSA denaturation abolishes high-affinity binding indicate that interactions of the carboxylate drug form are specific for the native HSA conformation. Expand
The structural basis of camptothecin interactions with human serum albumin: impact on drug stability.
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  • Chemistry, Medicine
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Study of associations of camptothecins with HSA in phosphate-buffered saline indicates 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. Expand
Evaluation of In Vitro Drug Interactions with Karenitecin, a Novel, Highly Lipophilic Camptothecin Derivative in Phase II Clinical Development
It was concluded that karenitecin has the potential to alter CYP450 3A4 and 2C8 drug‐metabolizing activity and may displace other highly PPB drugs and that slight variations in plasma AAG concentration may result in large variations in free drug exposure. Expand
[Interaction of camptothecin derivatives with human plasma proteins in vitro].
The interactions of camptothecin (CPT) and its derivatives (CPT-11 and SN-38) with human plasma proteins (serum albumin (HSA) and alpha 1-acid glycoprotein (alpha 1-AGP)) were studied mainly by meansExpand
Marked interspecies variations concerning the interactions of camptothecin with serum albumins: a frequency-domain fluorescence spectroscopic study.
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. Expand
The novel silatecan 7-tert-butyldimethylsilyl-10-hydroxycamptothecin displays high lipophilicity, improved human blood stability, and potent anticancer activity.
The impressive blood stability and cytotoxicity profiles for 7-tert-butyldimethylsilyl-10-hydroxycamptothecin strongly suggest that it is an excellent candidate for additional in vivo pharmacological and efficacy studies. Expand
New highly lipophilic camptothecin BNP1350 is an effective drug in experimental human cancer
BNP1350 shows a broad spectrum of activity in experimental human tumors and is a suitable candidate for oral treatment of cancer. Expand
Plasma and cerebrospinal fluid pharmacokinetic study of BNP1350 in nonhuman primates
The ratio of the CSF AUC to the plasma AUC was less than 5% (range 0.4% to 3.0%), similar to other highly protein-bound topoisomerase inhibitors such as 9-aminocamptothecin and SN-38 (the active metabolite of irinotecan). Expand
Phase I and pharmacokinetic study of karenitecin in patients with recurrent malignant gliomas.
The maximum tolerated dose (MTD) of karenitecin in adults with recurrent malignant glioma (MG), to describe the effects of enzyme-inducing antiseizure drugs (EIASDs) on its pharmacokinetics, and to obtain preliminary evidence of activity are conducted. Expand