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Targeted Chemotherapy Using a Cytotoxic Somatostatin Conjugate to Inhibit Tumor Growth and Metastasis in Nude Mice
The major problems of traditional chemotherapy are non-selectivity and non-specificity, resulting in severe toxic side effects. Peptides are a new-generation of drug-delivery vector to increase efficacy of this therapy and avoid the resulting damage. The cytotoxic somatostatin (SST) conjugate JF-10-...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Libertas Academica
2008
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3161630/ https://www.ncbi.nlm.nih.gov/pubmed/21892324 |
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author | Sun, Li-Chun Mackey, L. Vienna Luo, Jing Fuselier, Joseph A. Coy, David H. |
author_facet | Sun, Li-Chun Mackey, L. Vienna Luo, Jing Fuselier, Joseph A. Coy, David H. |
author_sort | Sun, Li-Chun |
collection | PubMed |
description | The major problems of traditional chemotherapy are non-selectivity and non-specificity, resulting in severe toxic side effects. Peptides are a new-generation of drug-delivery vector to increase efficacy of this therapy and avoid the resulting damage. The cytotoxic somatostatin (SST) conjugate JF-10-81 was developed by coupling camptothecin (CPT) to the N-terminus of a SST analog (JF-07-69) using an activated carbamate linker. This conjugate selectively targets somatostatin receptor subtype 2 (SSTR2) and also retains high binding affinity and rapid internalization as well as anti-proliferative activity towards various tumor cells. JF-10-81 was tested for its inhibitory activity against the growth of human tumors which included neuroblastoma (IMR32), pancreatic cancer (CFPAC-1), leukemia (MOLT-4), pancreatic carcinoid (BON) and prostate cancer (PC-3). Both SSTR2 mRNAs and proteins were detected in all these tumor cell lines. The conjugate displayed potent in vivo inhibitory activity, although some of the potency measured in in vitro experiments was lost. JF-10-81 was found to significantly inhibit growth of these SSTR-positive tumors, resulting in 87% tumor reduction in neuroblastoma IMR32 and 97% in leukemia MOLT-4 bearing animals, even inducing regression of CFPAC-1 tumors. SSTR-overexpressing BON tumors were unfortunately relatively CPT-insensitive in vitro, however, JF-10-81 again exhibited in vivo potency presumably by specifically increasing CPT concentrations inside the tumor cells so that the inhibition rate for JF-10-81 was 85%. Also, JF-10-81 was used to treat highly invasive PC-3 tumors where s.c. injections inhibited both tumor growth (almost 60% reduction) and tumor metastasis (over 70%). This conjugate demonstrated its broad and excellent anti-tumor activity by targeting SSTR2-specific tumor tissues, supporting that short peptides and their analogs may be applied as ideal drug-delivery carriers to improve the traditional chemotherapy. |
format | Online Article Text |
id | pubmed-3161630 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2008 |
publisher | Libertas Academica |
record_format | MEDLINE/PubMed |
spelling | pubmed-31616302011-09-02 Targeted Chemotherapy Using a Cytotoxic Somatostatin Conjugate to Inhibit Tumor Growth and Metastasis in Nude Mice Sun, Li-Chun Mackey, L. Vienna Luo, Jing Fuselier, Joseph A. Coy, David H. Clin Med Oncol Original Research The major problems of traditional chemotherapy are non-selectivity and non-specificity, resulting in severe toxic side effects. Peptides are a new-generation of drug-delivery vector to increase efficacy of this therapy and avoid the resulting damage. The cytotoxic somatostatin (SST) conjugate JF-10-81 was developed by coupling camptothecin (CPT) to the N-terminus of a SST analog (JF-07-69) using an activated carbamate linker. This conjugate selectively targets somatostatin receptor subtype 2 (SSTR2) and also retains high binding affinity and rapid internalization as well as anti-proliferative activity towards various tumor cells. JF-10-81 was tested for its inhibitory activity against the growth of human tumors which included neuroblastoma (IMR32), pancreatic cancer (CFPAC-1), leukemia (MOLT-4), pancreatic carcinoid (BON) and prostate cancer (PC-3). Both SSTR2 mRNAs and proteins were detected in all these tumor cell lines. The conjugate displayed potent in vivo inhibitory activity, although some of the potency measured in in vitro experiments was lost. JF-10-81 was found to significantly inhibit growth of these SSTR-positive tumors, resulting in 87% tumor reduction in neuroblastoma IMR32 and 97% in leukemia MOLT-4 bearing animals, even inducing regression of CFPAC-1 tumors. SSTR-overexpressing BON tumors were unfortunately relatively CPT-insensitive in vitro, however, JF-10-81 again exhibited in vivo potency presumably by specifically increasing CPT concentrations inside the tumor cells so that the inhibition rate for JF-10-81 was 85%. Also, JF-10-81 was used to treat highly invasive PC-3 tumors where s.c. injections inhibited both tumor growth (almost 60% reduction) and tumor metastasis (over 70%). This conjugate demonstrated its broad and excellent anti-tumor activity by targeting SSTR2-specific tumor tissues, supporting that short peptides and their analogs may be applied as ideal drug-delivery carriers to improve the traditional chemotherapy. Libertas Academica 2008-08-19 /pmc/articles/PMC3161630/ /pubmed/21892324 Text en © 2008 the author(s), publisher and licensee Libertas Academica Ltd. http://creativecommons.org/licenses/by/3.0 This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license http://creativecommons.org/licenses/by/3.0/). |
spellingShingle | Original Research Sun, Li-Chun Mackey, L. Vienna Luo, Jing Fuselier, Joseph A. Coy, David H. Targeted Chemotherapy Using a Cytotoxic Somatostatin Conjugate to Inhibit Tumor Growth and Metastasis in Nude Mice |
title | Targeted Chemotherapy Using a Cytotoxic Somatostatin Conjugate to Inhibit Tumor Growth and Metastasis in Nude Mice |
title_full | Targeted Chemotherapy Using a Cytotoxic Somatostatin Conjugate to Inhibit Tumor Growth and Metastasis in Nude Mice |
title_fullStr | Targeted Chemotherapy Using a Cytotoxic Somatostatin Conjugate to Inhibit Tumor Growth and Metastasis in Nude Mice |
title_full_unstemmed | Targeted Chemotherapy Using a Cytotoxic Somatostatin Conjugate to Inhibit Tumor Growth and Metastasis in Nude Mice |
title_short | Targeted Chemotherapy Using a Cytotoxic Somatostatin Conjugate to Inhibit Tumor Growth and Metastasis in Nude Mice |
title_sort | targeted chemotherapy using a cytotoxic somatostatin conjugate to inhibit tumor growth and metastasis in nude mice |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3161630/ https://www.ncbi.nlm.nih.gov/pubmed/21892324 |
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