Identification of gene expression profiles predicting tumor cell response to L-alanosine
- Publication type:
- Journal article
- Metadata:
-
- Autoren
- T Efferth
- E Gebhart
- DD Ross
- A Sauerbrey
- Autoren-URL
- https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000184879500009&DestLinkType=FullRecord&DestApp=WOS_CPL
- DOI
- 10.1016/S0006-2952(03)00341-1
- Externe Identifier
- Clarivate Analytics Document Solution ID: 713VW
- PubMed Identifier: 12906926
- ISSN
- 0006-2952
- Ausgabe der Veröffentlichung
- 4
- Zeitschrift
- BIOCHEMICAL PHARMACOLOGY
- Schlüsselwörter
- hierarchical cluster analysis
- L-alanosine
- mRNA expression profiling
- multidrug resistance
- p53 tumor suppressor
- Paginierung
- 613 - 621
- Datum der Veröffentlichung
- 2003
- Status
- Published
- Titel
- Identification of gene expression profiles predicting tumor cell response to L-alanosine
- Sub types
- Article
- Ausgabe der Zeitschrift
- 66
Data source: Web of Science (Lite)
- Other metadata sources:
-
- Autoren
- Thomas Efferth
- Erich Gebhart
- Douglas D Ross
- Axel Sauerbrey
- DOI
- 10.1016/s0006-2952(03)00341-1
- ISSN
- 0006-2952
- Ausgabe der Veröffentlichung
- 4
- Zeitschrift
- Biochemical Pharmacology
- Sprache
- en
- Paginierung
- 613 - 621
- Datum der Veröffentlichung
- 2003
- Status
- Published
- Herausgeber
- Elsevier BV
- Herausgeber URL
- http://dx.doi.org/10.1016/s0006-2952(03)00341-1
- Datum der Datenerfassung
- 2024
- Titel
- Identification of gene expression profiles predicting tumor cell response to l-alanosine
- Ausgabe der Zeitschrift
- 66
Data source: Crossref
- Abstract
- The methylthioadenosine phosphorylase (MTAP) gene gained considerable interest as therapeutic target for tumors with the 9p21 deletion. This gene maps to 9p21 and loss of this chromosomal region in tumors offers an unique opportunity for chemoselective treatment, since MTAP is an important salvage enzyme for the formation of adenine that is needed for DNA synthesis. L-Alanosine, an antibiotic from Streptomyces alanosinicus, blocks the common de novo purine biosynthesis pathway and, thereby, inhibits tumor cells with MTAP deficiency. Normal cells escape the detrimental effects of L-alanosine due to their proficiency in the MTAP salvage pathway. The present analysis was undertaken to gain insights into the molecular architecture of tumor cells that determines the response to L-alanosine apart from the MTAP gene. Analysis of cell doubling times and IC(50) values for L-alanosine showed that slowly growing cell lines were more resistant to L-alanosine than rapidly growing ones. Mining the database of the National Cancer Institute (N.C.I.), for the mRNA expression of 9706 genes in 60 cell lines by means of Kendall's tau-test, false discovery rate calculation, and hierarchical cluster analysis pointed to 11 genes or expressed sequence tags whose mRNA expression correlated with the IC(50) values for L-alanosine. Furthermore, we tested L-alanosine for cross-resistance in multidrug-resistant cell lines which overexpress selectively either the P-glycoprotein/MDR1 (CEM/ADR5000), MRP1 (HL-60/AR), or BCRP (MDA-MB-231-BCRP) genes. None of the multidrug-resistant cell lines was cross-resistant to L-alanosine indicating that L-alanosine may be suitable to treat multidrug-resistant, refractory tumors in the clinic. Finally, the IC(50) values for L-alanosine of the 60 cell lines were correlated to the p53 mutational status and expression of p53 downstream genes. We found that p53 mutated cell lines were more resistant to L-alanosine than p53 wild type cell lines.
- Addresses
- Center for Molecular Biology of the University of Heidelberg (ZMBH), Im Neuenheimer Feld 282, 69120 Heidelberg, Germany. thomas.efferth@web.de
- Autoren
- Thomas Efferth
- Thomas Efferth
- Erich Gebhart
- Douglas D Ross
- Axel Sauerbrey
- DOI
- 10.1016/s0006-2952(03)00341-1
- eISSN
- 1873-2968
- Externe Identifier
- PubMed Identifier: 12906926
- Open access
- false
- ISSN
- 0006-2952
- Ausgabe der Veröffentlichung
- 4
- Zeitschrift
- Biochemical pharmacology
- Schlüsselwörter
- HL-60 Cells
- Humans
- Alanine
- Antibiotics, Antineoplastic
- Cluster Analysis
- Gene Expression Profiling
- Drug Resistance, Multiple
- Cell Division
- Tumor Suppressor Protein p53
- Sprache
- eng
- Medium
- Paginierung
- 613 - 621
- Datum der Veröffentlichung
- 2003
- Status
- Published
- Datum der Datenerfassung
- 2003
- Titel
- Identification of gene expression profiles predicting tumor cell response to L-alanosine.
- Sub types
- Journal Article
- Ausgabe der Zeitschrift
- 66
Data source: Europe PubMed Central
- Abstract
- The methylthioadenosine phosphorylase (MTAP) gene gained considerable interest as therapeutic target for tumors with the 9p21 deletion. This gene maps to 9p21 and loss of this chromosomal region in tumors offers an unique opportunity for chemoselective treatment, since MTAP is an important salvage enzyme for the formation of adenine that is needed for DNA synthesis. L-Alanosine, an antibiotic from Streptomyces alanosinicus, blocks the common de novo purine biosynthesis pathway and, thereby, inhibits tumor cells with MTAP deficiency. Normal cells escape the detrimental effects of L-alanosine due to their proficiency in the MTAP salvage pathway. The present analysis was undertaken to gain insights into the molecular architecture of tumor cells that determines the response to L-alanosine apart from the MTAP gene. Analysis of cell doubling times and IC(50) values for L-alanosine showed that slowly growing cell lines were more resistant to L-alanosine than rapidly growing ones. Mining the database of the National Cancer Institute (N.C.I.), for the mRNA expression of 9706 genes in 60 cell lines by means of Kendall's tau-test, false discovery rate calculation, and hierarchical cluster analysis pointed to 11 genes or expressed sequence tags whose mRNA expression correlated with the IC(50) values for L-alanosine. Furthermore, we tested L-alanosine for cross-resistance in multidrug-resistant cell lines which overexpress selectively either the P-glycoprotein/MDR1 (CEM/ADR5000), MRP1 (HL-60/AR), or BCRP (MDA-MB-231-BCRP) genes. None of the multidrug-resistant cell lines was cross-resistant to L-alanosine indicating that L-alanosine may be suitable to treat multidrug-resistant, refractory tumors in the clinic. Finally, the IC(50) values for L-alanosine of the 60 cell lines were correlated to the p53 mutational status and expression of p53 downstream genes. We found that p53 mutated cell lines were more resistant to L-alanosine than p53 wild type cell lines.
- Autoren
- Thomas Efferth
- Erich Gebhart
- Douglas D Ross
- Axel Sauerbrey
- Autoren-URL
- https://www.ncbi.nlm.nih.gov/pubmed/12906926
- DOI
- 10.1016/s0006-2952(03)00341-1
- ISSN
- 0006-2952
- Ausgabe der Veröffentlichung
- 4
- Zeitschrift
- Biochem Pharmacol
- Schlüsselwörter
- Alanine
- Antibiotics, Antineoplastic
- Cell Division
- Cluster Analysis
- Drug Resistance, Multiple
- Gene Expression Profiling
- HL-60 Cells
- Humans
- Tumor Suppressor Protein p53
- Sprache
- eng
- Country
- England
- Paginierung
- 613 - 621
- PII
- S0006295203003411
- Datum der Veröffentlichung
- 2003
- Status
- Published
- Datum, an dem der Datensatz öffentlich gemacht wurde
- 2003
- Titel
- Identification of gene expression profiles predicting tumor cell response to L-alanosine.
- Sub types
- Journal Article
- Ausgabe der Zeitschrift
- 66
Data source: PubMed
- Beziehungen:
- Property of