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Improved antitumor activity and tumor targeting of NH(2)-terminal-specific PEGylated tumor necrosis factor-related apoptosis-inducing ligand.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is considered an attractive anticancer agent due to its tumor cell-specific cytotoxicity. However, its low stability, solubility, unexpected side effects, and weak pharmacokinetic profiles restrict its successful clinical application. T... Full description

Journal Title: Molecular cancer therapeutics June 2010, Vol.9(6), pp.1719-1729
Main Author: Chae, Su Young
Other Authors: Kim, Tae Hyung , Park, Kyeongsoon , Jin, Cheng-Hao , Son, Sohee , Lee, Seulki , Youn, Yu Seok , Kim, Kwangmeyung , Jo, Dong-Gyu , Kwon, Ick Chan , Chen, Xiaoyuan , Lee, Kang Choon
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1538-8514 ; DOI: 10.1158/1535-7163.MCT-09-1076
Link: http://search.proquest.com/docview/733285986/?pq-origsite=primo
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title: Improved antitumor activity and tumor targeting of NH(2)-terminal-specific PEGylated tumor necrosis factor-related apoptosis-inducing ligand.
format: Article
creator:
  • Chae, Su Young
  • Kim, Tae Hyung
  • Park, Kyeongsoon
  • Jin, Cheng-Hao
  • Son, Sohee
  • Lee, Seulki
  • Youn, Yu Seok
  • Kim, Kwangmeyung
  • Jo, Dong-Gyu
  • Kwon, Ick Chan
  • Chen, Xiaoyuan
  • Lee, Kang Choon
subjects:
  • Animals–Drug Therapy
  • Cell Line, Tumor–Pathology
  • Humans–Chemistry
  • Male–Therapeutic Use
  • Mice–Chemistry
  • Molecular Imaging–Therapeutic Use
  • Neoplasms–Chemistry
  • Polyethylene Glycols–Pharmacokinetics
  • Rats–Pharmacology
  • Rats, Sprague-Dawley–Therapeutic Use
  • Receptors, Tumor Necrosis Factor, Type I–Drug Effects
  • Tnf-Related Apoptosis-Inducing Ligand–Drug Effects
  • Tissue Distribution–Drug Effects
  • Xenograft Model Antitumor Assays–Drug Effects
  • Pegylated Tumor Necrosis Factor Alpha Receptor 1
  • Receptors, Tumor Necrosis Factor, Type I
  • Tnf-Related Apoptosis-Inducing Ligand
  • Polyethylene Glycols
ispartof: Molecular cancer therapeutics, June 2010, Vol.9(6), pp.1719-1729
description: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is considered an attractive anticancer agent due to its tumor cell-specific cytotoxicity. However, its low stability, solubility, unexpected side effects, and weak pharmacokinetic profiles restrict its successful clinical application. To develop efficient TRAIL-based anticancer biotherapeutics, a new version of trimeric TRAIL was constructed by incorporating trimer-forming zipper sequences (HZ-TRAIL), and then NH(2)-terminal-specific PEGylation was done to produce PEGylated TRAIL (PEG-HZ-TRAIL). The biological, physicochemical, and pharmaceutical characteristics of PEG-HZ-TRAIL were then investigated using various in vitro and in vivo experiments, including a cell-based cytotoxicity test, a solubility test, pharmacokinetic analysis, and antitumor efficacy evaluations. Although slight activity loss occurred after PEGylation, PEG-HZ-TRAIL showed excellent tumor cell-specific cytotoxic effects via apoptotic pathways with negligible normal cell toxicity. The stability and pharmacokinetic problems of HZ-TRAIL were successfully overcome by PEGylation. Furthermore, in vivo antitumor tests revealed that PEG-HZ-TRAIL treatment enhanced therapeutic potentials compared with HZ-TRAIL in tumor xenograft animal models, and these enhancements were attributed to its better pharmacokinetic properties and tumor-targeting performance. These findings show that PEG-HZ-TRAIL administration provides an effective antitumor treatment, which exhibits superior tumor targeting and better inhibits tumor growth, and suggest that PEG-HZ-TRAIL should be considered a potential candidate for antitumor biotherapy.
language: eng
source:
identifier: E-ISSN: 1538-8514 ; DOI: 10.1158/1535-7163.MCT-09-1076
fulltext: fulltext
issn:
  • 15388514
  • 1538-8514
url: Link


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titleImproved antitumor activity and tumor targeting of NH(2)-terminal-specific PEGylated tumor necrosis factor-related apoptosis-inducing ligand.
creatorChae, Su Young ; Kim, Tae Hyung ; Park, Kyeongsoon ; Jin, Cheng-Hao ; Son, Sohee ; Lee, Seulki ; Youn, Yu Seok ; Kim, Kwangmeyung ; Jo, Dong-Gyu ; Kwon, Ick Chan ; Chen, Xiaoyuan ; Lee, Kang Choon
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identifierE-ISSN: 1538-8514 ; DOI: 10.1158/1535-7163.MCT-09-1076
subjectAnimals–Drug Therapy ; Cell Line, Tumor–Pathology ; Humans–Chemistry ; Male–Therapeutic Use ; Mice–Chemistry ; Molecular Imaging–Therapeutic Use ; Neoplasms–Chemistry ; Polyethylene Glycols–Pharmacokinetics ; Rats–Pharmacology ; Rats, Sprague-Dawley–Therapeutic Use ; Receptors, Tumor Necrosis Factor, Type I–Drug Effects ; Tnf-Related Apoptosis-Inducing Ligand–Drug Effects ; Tissue Distribution–Drug Effects ; Xenograft Model Antitumor Assays–Drug Effects ; Pegylated Tumor Necrosis Factor Alpha Receptor 1 ; Receptors, Tumor Necrosis Factor, Type I ; Tnf-Related Apoptosis-Inducing Ligand ; Polyethylene Glycols
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descriptionTumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is considered an attractive anticancer agent due to its tumor cell-specific cytotoxicity. However, its low stability, solubility, unexpected side effects, and weak pharmacokinetic profiles restrict its successful clinical application. To develop efficient TRAIL-based anticancer biotherapeutics, a new version of trimeric TRAIL was constructed by incorporating trimer-forming zipper sequences (HZ-TRAIL), and then NH(2)-terminal-specific PEGylation was done to produce PEGylated TRAIL (PEG-HZ-TRAIL). The biological, physicochemical, and pharmaceutical characteristics of PEG-HZ-TRAIL were then investigated using various in vitro and in vivo experiments, including a cell-based cytotoxicity test, a solubility test, pharmacokinetic analysis, and antitumor efficacy evaluations. Although slight activity loss occurred after PEGylation, PEG-HZ-TRAIL showed excellent tumor cell-specific cytotoxic effects via apoptotic pathways with negligible normal cell toxicity. The stability and pharmacokinetic problems of HZ-TRAIL were successfully overcome by PEGylation. Furthermore, in vivo antitumor tests revealed that PEG-HZ-TRAIL treatment enhanced therapeutic potentials compared with HZ-TRAIL in tumor xenograft animal models, and these enhancements were attributed to its better pharmacokinetic properties and tumor-targeting performance. These findings show that PEG-HZ-TRAIL administration provides an effective antitumor treatment, which exhibits superior tumor targeting and better inhibits tumor growth, and suggest that PEG-HZ-TRAIL should be considered a potential candidate for antitumor biotherapy.
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titleImproved antitumor activity and tumor targeting of NH(2)-terminal-specific PEGylated tumor necrosis factor-related apoptosis-inducing ligand.
authorChae, Su Young ; Kim, Tae Hyung ; Park, Kyeongsoon ; Jin, Cheng-Hao ; Son, Sohee ; Lee, Seulki ; Youn, Yu Seok ; Kim, Kwangmeyung ; Jo, Dong-Gyu ; Kwon, Ick Chan ; Chen, Xiaoyuan ; Lee, Kang Choon
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