| Inhibition of proliferation of small intestinal and bronchopulmonary neuroendocrine cell lines by using peptide analogs targeting receptors. | |
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MedLine Citation:
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PMID: 18224665 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND: Currently, no consistently effective therapy is available to inhibit cell proliferation or metastasis of neuroendocrine tumor (NET) disease. The effects of 4 novel peptides were analyzed: a targeted cytotoxic analog of luteinizing hormone-releasing hormone (LH-RH) analog (AN-152), a targeted cytotoxic analog of somatostatin (AN-238), and 2 antagonists of growth hormone-releasing hormone (GH-RH) on 3 NET (carcinoid) cell lines that expressed respective peptide receptors. METHODS: The effects of the compounds were evaluated on cell proliferation in vitro using MTT uptake and Ki67 expression, apoptosis (caspase 3 expression and activity), and cell cycle parameters (DNA distribution). RESULTS: Proliferation of the LH-RH receptor-expressing lung NET, NCI-H720 line, was inhibited 2-fold by AN-152 containing doxorubicin compared with the chemotherapy alone (IC50 of 9.1 nM vs 24 nM). This was associated with a reduction in Ki67 transcript and an increase in both caspase 3 mRNA levels and activity. Proliferation of the GH-RH receptor expressing lung NET, NCI-H727 line, was inhibited by both GH-RH antagonists, the effects being mediated through changes in Ki67 expression, but not in caspase 3-mediated apoptosis. The small intestinal NET, KRJ-I line, was 8x more sensitive to inhibition by AN-238 than to 2-pyrolino-doxorubicin, reflected by increased caspase 3 transcript as well as activity. AN-238-mediated growth inhibition culminated in complete G1 arrest. CONCLUSIONS: The data demonstrate GH-RH antagonists or peptide-linked antineoplastic agents such as AN-152 and AN-238 are effective inhibitors of NET proliferation in vitro. Because peptide receptors such as those for GH-RH, LH-RH, and SST subtypes are commonly expressed by NETs, the development of antineoplastic agents targeted to specific tumor receptors may provide a more efficacious strategy than systemic chemotherapeutic agents currently in use. |
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Authors:
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Mark Kidd; Andrew V Schally; Roswitha Pfragner; Maximillian V Malfertheiner; Irvin M Modlin |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Cancer Volume: 112 ISSN: 0008-543X ISO Abbreviation: Cancer Publication Date: 2008 Mar |
Date Detail:
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Created Date: 2008-03-10 Completed Date: 2008-05-08 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0374236 Medline TA: Cancer Country: United States |
Other Details:
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Languages: eng Pagination: 1404-14 Citation Subset: AIM; IM |
Copyright Information:
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Copyright (c) 2008 American Cancer Society. |
Affiliation:
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Gastrointestinal Pathobiology Research Group, Yale University School of Medicine, New Haven, Connecticut 06520-8062, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Apoptosis
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drug effects Bronchial Neoplasms / drug therapy*, metabolism, pathology Carcinoid Tumor / drug therapy*, metabolism, pathology Caspase 3 / metabolism Cell Cycle / drug effects Cell Proliferation / drug effects* Cytotoxins / pharmacology Doxorubicin / analogs & derivatives, pharmacology Flow Cytometry Gonadotropin-Releasing Hormone / analogs & derivatives, antagonists & inhibitors, pharmacology Growth Hormone-Releasing Hormone / antagonists & inhibitors* Humans Intestinal Neoplasms / drug therapy*, metabolism, pathology Intestine, Small / drug effects, metabolism, pathology Ki-67 Antigen / genetics, metabolism Lung Neoplasms / drug therapy*, metabolism, pathology Pyrroles / pharmacology RNA, Messenger / genetics, metabolism Receptors, LHRH / antagonists & inhibitors Receptors, Somatostatin / antagonists & inhibitors Reverse Transcriptase Polymerase Chain Reaction Tumor Cells, Cultured |
| Grant Support | |
ID/Acronym/Agency:
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R01-CA1185285/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/AN 238; 0/Cytotoxins; 0/Ki-67 Antigen; 0/Pyrroles; 0/RNA, Messenger; 0/Receptors, LHRH; 0/Receptors, Somatostatin; 149665-71-4/T 107; 23214-92-8/Doxorubicin; 33515-09-2/Gonadotropin-Releasing Hormone; 9034-39-3/Growth Hormone-Releasing Hormone; EC 3.4.22.-/Caspase 3 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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