Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 2 de 2
Filter
Add more filters










Database
Language
Publication year range
1.
Leuk Lymphoma ; 53(8): 1501-8, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22239668

ABSTRACT

The retinoid X receptor (RXR)-agonist bexarotene and the histone deacetylase inhibitor (HDACI) vorinostat are each established monotherapies for cutaneous T-cell lymphomas (CTCLs). We investigated the combination of HDACI and retinoic acid receptor (RAR)/RXR agonists in vitro and in a phase I, multicenter, open-label, two-part dose-escalation study. The combination of bexarotene with a HDACI in vitro leads to cooperative activation of gene transcription and reduction of cell viability in human tumor cell lines. The primary clinical objective was to determine the maximum tolerated dose (MTD) of bexarotene plus vorinostat in 23 patients with CTCLs. The MTD for part I was established at vorinostat 200 mg/day plus bexarotene 300 mg/m(2)/day. The MTD for part II was not reached. Four patients had an objective response and seven patients experienced pruritus relief. We conclude that concomitant administration of vorinostat and bexarotene is feasible only if lower doses of each drug are administered relative to the product label monotherapy doses.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Histone Deacetylase Inhibitors/pharmacology , Hydroxamic Acids/administration & dosage , Lymphoma, T-Cell, Cutaneous/drug therapy , Receptors, Retinoic Acid/metabolism , Retinoid X Receptors/metabolism , Tetrahydronaphthalenes/administration & dosage , Adult , Aged , Bexarotene , Cell Line, Tumor , Cell Survival , Female , Humans , In Vitro Techniques , Male , Middle Aged , Transcription, Genetic , Vorinostat
2.
Biochemistry ; 44(27): 9430-40, 2005 Jul 12.
Article in English | MEDLINE | ID: mdl-15996097

ABSTRACT

The type 1 insulin-like growth factor receptor (IGF-1R) is often overexpressed on tumor cells and is believed to play an important role in anchorage-independent proliferation. Additionally, cell culture studies have indicated that IGF-1R confers increased resistance to apoptosis caused by radiation or chemotherapeutic agents. Thus, inhibitors of the intracellular kinase domain of this receptor may have utility for the clinical treatment of cancer. As part of an effort to develop clinically useful inhibitors of IGF-1R kinase, a novel class of pyrrole-5-carboxaldehyde compounds was investigated. The compounds exhibited selectivity against the closely related insulin receptor kinase intrinsically and in cell-based assays. The inhibitors formed a reversible, covalent adduct at the kinase active site, and treatment of such adducts with sodium borohydride irreversibly inactivated the enzyme. Analysis of a tryptic digest of a covalently modified IGF-1R kinase fragment revealed that the active site Lys1003 had been reductively alkylated with the aldehyde inhibitor. Reductive alkylation of the insulin receptor kinase with one of these inhibitors led to a similarly inactivated enzyme which was examined by X-ray crystallography. The crystal structure confirmed the modification of the active site lysine side chain and revealed details of the key interactions between the inhibitor and enzyme.


Subject(s)
Aldehydes/chemistry , Protein Kinase Inhibitors/chemistry , Pyrroles/chemistry , Receptor, IGF Type 1/antagonists & inhibitors , Receptor, Insulin/antagonists & inhibitors , Receptor, Insulin/chemistry , Aldehydes/metabolism , Amino Acid Sequence , Binding Sites , Borohydrides/chemistry , Cell Line , Crystallography, X-Ray , Enzyme Activation , Humans , Molecular Sequence Data , Peptide Fragments/antagonists & inhibitors , Peptide Fragments/chemistry , Peptide Fragments/metabolism , Phosphorylation , Protein Kinase Inhibitors/metabolism , Protein Structure, Tertiary , Pyrroles/metabolism , Receptor, Insulin/metabolism , Schiff Bases/chemistry , Structure-Activity Relationship
SELECTION OF CITATIONS
SEARCH DETAIL
...