Growth hormone excess and the development of growth hormone receptor antagonists.

2.50
Hdl Handle:
http://hdl.handle.net/10541/65700
Title:
Growth hormone excess and the development of growth hormone receptor antagonists.
Authors:
Higham, Claire E; Trainer, Peter J
Abstract:
In 1990, a single amino acid substitution in the growth hormone (GH) gene at position 119 was found to transform the consequent protein from an agonist to an antagonist at the growth hormone receptor (GHR). Further amino acid substitutions plus prolongation of the half-life of the protein by pegylation resulted in the first clinically effective GHR antagonist, pegvisomant. Following extensive clinical trials, this medication has emerged as the most efficacious therapy for treatment-resistant acromegaly. Subsequent advances in our understanding of GH-GHR interactions and downstream GH signalling pathways suggest that pegvisomant binds to preformed GHR dimers and prevents rotational changes within the receptor-GH complex necessary for intracellular signalling to occur. This article reviews the discovery of pegvisomant, from initial experimental data to successful licensing of the drug for treatment-resistant acromegaly, and discusses its other potential therapeutic uses in diseases with abnormalities in the GH-IGF-I axis.
Affiliation:
Department of Endocrinology, Christie Hospital, Manchester M20 4BX, UK.
Citation:
Growth hormone excess and the development of growth hormone receptor antagonists. 2008, 93 (11):1157-69 Exp. Physiol.
Journal:
Experimental Physiology
Issue Date:
Nov-2008
URI:
http://hdl.handle.net/10541/65700
DOI:
10.1113/expphysiol.2008.042515
PubMed ID:
18617577
Type:
Article
Language:
en
ISSN:
0958-0670
Appears in Collections:
All Christie Publications ; Endocrinology

Full metadata record

DC FieldValue Language
dc.contributor.authorHigham, Claire E-
dc.contributor.authorTrainer, Peter J-
dc.date.accessioned2009-04-21T16:52:26Z-
dc.date.available2009-04-21T16:52:26Z-
dc.date.issued2008-11-
dc.identifier.citationGrowth hormone excess and the development of growth hormone receptor antagonists. 2008, 93 (11):1157-69 Exp. Physiol.en
dc.identifier.issn0958-0670-
dc.identifier.pmid18617577-
dc.identifier.doi10.1113/expphysiol.2008.042515-
dc.identifier.urihttp://hdl.handle.net/10541/65700-
dc.description.abstractIn 1990, a single amino acid substitution in the growth hormone (GH) gene at position 119 was found to transform the consequent protein from an agonist to an antagonist at the growth hormone receptor (GHR). Further amino acid substitutions plus prolongation of the half-life of the protein by pegylation resulted in the first clinically effective GHR antagonist, pegvisomant. Following extensive clinical trials, this medication has emerged as the most efficacious therapy for treatment-resistant acromegaly. Subsequent advances in our understanding of GH-GHR interactions and downstream GH signalling pathways suggest that pegvisomant binds to preformed GHR dimers and prevents rotational changes within the receptor-GH complex necessary for intracellular signalling to occur. This article reviews the discovery of pegvisomant, from initial experimental data to successful licensing of the drug for treatment-resistant acromegaly, and discusses its other potential therapeutic uses in diseases with abnormalities in the GH-IGF-I axis.en
dc.language.isoenen
dc.subjectGHen
dc.subjectGrowth Hormone Receptoren
dc.subjectTreatment Resistant Acromegalyen
dc.subjectGrowth Hormone Receptor Antagonisten
dc.subject.meshAcromegaly-
dc.subject.meshAnimals-
dc.subject.meshAntineoplastic Agents-
dc.subject.meshCarrier Proteins-
dc.subject.meshHormone Antagonists-
dc.subject.meshHuman Growth Hormone-
dc.subject.meshHumans-
dc.subject.meshHypoglycemic Agents-
dc.subject.meshModels, Molecular-
dc.subject.meshMutation-
dc.subject.meshProtein Binding-
dc.subject.meshProtein Conformation-
dc.subject.meshProtein Multimerization-
dc.subject.meshSignal Transduction-
dc.titleGrowth hormone excess and the development of growth hormone receptor antagonists.en
dc.typeArticleen
dc.contributor.departmentDepartment of Endocrinology, Christie Hospital, Manchester M20 4BX, UK.en
dc.identifier.journalExperimental Physiologyen

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