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Prodrug AST-003 Improves the Therapeutic Index of the Multi-Targeted Tyrosine Kinase Inhibitor Sunitinib

Patients have responded well to the multi-targeted tyrosine kinase inhibitor (TKI) Sunitinib in the clinic. But the severe toxic side effects associated with Sunitinib limit its therapeutic index. To improve the therapeutic index of Sunitinib, a prodrug strategy was employed to modify Sunitinib. The...

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Autores principales: Huang, Qiang, Zhou, Changhua, Chen, Xiao, Dong, Bing, Chen, Siqi, Zhang, Ning, Liu, Yawei, Li, Anrong, Yao, Meicun, Miao, Ji, Li, Qing, Wang, Zhong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4626378/
https://www.ncbi.nlm.nih.gov/pubmed/26513662
http://dx.doi.org/10.1371/journal.pone.0141395
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author Huang, Qiang
Zhou, Changhua
Chen, Xiao
Dong, Bing
Chen, Siqi
Zhang, Ning
Liu, Yawei
Li, Anrong
Yao, Meicun
Miao, Ji
Li, Qing
Wang, Zhong
author_facet Huang, Qiang
Zhou, Changhua
Chen, Xiao
Dong, Bing
Chen, Siqi
Zhang, Ning
Liu, Yawei
Li, Anrong
Yao, Meicun
Miao, Ji
Li, Qing
Wang, Zhong
author_sort Huang, Qiang
collection PubMed
description Patients have responded well to the multi-targeted tyrosine kinase inhibitor (TKI) Sunitinib in the clinic. But the severe toxic side effects associated with Sunitinib limit its therapeutic index. To improve the therapeutic index of Sunitinib, a prodrug strategy was employed to modify Sunitinib. The inactive prodrug AST-003 can be converted to Sunitinib in vitro and in vivo. Compared with Sunitinib, AST-003 has unique biochemical, cellular and pharmacokinetic properties with improved tolerability in mice and yield higher efficacy in tumor xenograft models. This prodrug strategy may constitute a novel paradigm to improve the therapeutic index of Sunitinib and other TKI or anti-angiogenesis drugs in general.
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spelling pubmed-46263782015-11-06 Prodrug AST-003 Improves the Therapeutic Index of the Multi-Targeted Tyrosine Kinase Inhibitor Sunitinib Huang, Qiang Zhou, Changhua Chen, Xiao Dong, Bing Chen, Siqi Zhang, Ning Liu, Yawei Li, Anrong Yao, Meicun Miao, Ji Li, Qing Wang, Zhong PLoS One Research Article Patients have responded well to the multi-targeted tyrosine kinase inhibitor (TKI) Sunitinib in the clinic. But the severe toxic side effects associated with Sunitinib limit its therapeutic index. To improve the therapeutic index of Sunitinib, a prodrug strategy was employed to modify Sunitinib. The inactive prodrug AST-003 can be converted to Sunitinib in vitro and in vivo. Compared with Sunitinib, AST-003 has unique biochemical, cellular and pharmacokinetic properties with improved tolerability in mice and yield higher efficacy in tumor xenograft models. This prodrug strategy may constitute a novel paradigm to improve the therapeutic index of Sunitinib and other TKI or anti-angiogenesis drugs in general. Public Library of Science 2015-10-29 /pmc/articles/PMC4626378/ /pubmed/26513662 http://dx.doi.org/10.1371/journal.pone.0141395 Text en © 2015 Huang et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Huang, Qiang
Zhou, Changhua
Chen, Xiao
Dong, Bing
Chen, Siqi
Zhang, Ning
Liu, Yawei
Li, Anrong
Yao, Meicun
Miao, Ji
Li, Qing
Wang, Zhong
Prodrug AST-003 Improves the Therapeutic Index of the Multi-Targeted Tyrosine Kinase Inhibitor Sunitinib
title Prodrug AST-003 Improves the Therapeutic Index of the Multi-Targeted Tyrosine Kinase Inhibitor Sunitinib
title_full Prodrug AST-003 Improves the Therapeutic Index of the Multi-Targeted Tyrosine Kinase Inhibitor Sunitinib
title_fullStr Prodrug AST-003 Improves the Therapeutic Index of the Multi-Targeted Tyrosine Kinase Inhibitor Sunitinib
title_full_unstemmed Prodrug AST-003 Improves the Therapeutic Index of the Multi-Targeted Tyrosine Kinase Inhibitor Sunitinib
title_short Prodrug AST-003 Improves the Therapeutic Index of the Multi-Targeted Tyrosine Kinase Inhibitor Sunitinib
title_sort prodrug ast-003 improves the therapeutic index of the multi-targeted tyrosine kinase inhibitor sunitinib
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4626378/
https://www.ncbi.nlm.nih.gov/pubmed/26513662
http://dx.doi.org/10.1371/journal.pone.0141395
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