L-Type Amino Acid Transporter-1 Overexpression and Melphalan Sensitivity in Barrett's Adenocarcinoma

Lin, Jules; Raoof, Duna; Thomas, Dafydd G.; Greenson, Joel K.; Giordano, Thomas J.; Robinson, G. A.; Bourner, Maureen; Bauer, Christopher T.; Orringer, Mark B.; Beer, David G.

doi:10.1016/s1476-5586(04)80054-x

Cited by 58 publications

(51 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Tissue slices were incubated with BPA 1 hour after exposure and removal of tyrosine (25), 10 minutes after BCH (without removal; refs. 24,26), and simultaneously with phenylalanine for the time periods shown in Fig. 5, after which they were washed and analyzed for boron content.…”

Section: Resultsmentioning

confidence: 99%

“…Up-regulation of LAT-1 thus seems to be a common feature of tumor cells and of interest in targeting treatments dependent on LAT-1 function, such as transported cytotoxic drugs (e.g., melphalan; ref. 26) or enhancement of BNCT by increased uptake of boron using BPA. Clinical evidence of the role of LAT-1 has been implied by Langen and colleagues and Kuwert and colleagues in studies (14,15) that showed increased tracer (IMT) concentration in progressively more active tumors, suggesting a link between tracer uptake (L-amino acid handling) and proliferative activity and, at the same time, calling into question the use of the LAT-1/ BPA system for BNCT treatment of malignant tumors where the proliferation rate in vivo has been shown to be low (16,17).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

l-Amino Acid Transporter-1 and Boronophenylalanine-Based Boron Neutron Capture Therapy of Human Brain Tumors

2009

View full text Add to dashboard Cite

The system L-amino acid transporter-1 (LAT-1) imports pboronophenylalanine (BPA) into cells and may play a major role in the effectiveness of BPA-based boron neutron capture therapy. The functional status of LAT-1 and its relationship to cell proliferation were simultaneously examined in the same section of human tumor material using a dual-labeling technique. The uptake of BPA (boron inductively coupled plasma mass spectrometry) was profiled in the presence of agonists and antagonists in fresh tumor explants. The number of LAT-1-expressing cells (mean F SD) was three times higher than that of proliferating cell nuclear antigen (PCNA)-expressing cells (71.5 F 17.02% versus 23.8 F 16.5%; P < 0.0001; n = 38 glioblastoma and metastatic tumors). There was no correlation between PCNA cells and the number of LAT-1/ PCNA double-stained cells, and not all PCNA-expressing cells coexpressed LAT-1. Boron uptake reached 30 F 15 Mg/g of wet weight of tissue by 4 hours both in tumor and brain around tumor tissue containing tumor cells compared with time 0 (P < 0.005; n = 4 glioblastoma tumors). This uptake was inhibited by both phenylalanine and 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid. These LAT-1 data indicate that BPA-based boron neutron capture therapy might affect up to 70% of tumor cells, representing a three times higher proportion of tumor cells than their cell cycle status might suggest. Cells expressing PCNA, but not LAT-1, will require a different therapeutic strategy. [Cancer Res 2009;69(5):2126-32]

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

l-Amino Acid Transporter-1 and Boronophenylalanine-Based Boron Neutron Capture Therapy of Human Brain Tumors

2009

View full text Add to dashboard Cite

show abstract

“…In view of the evaluation of LAT1 substrates and inhibitors as potential anticancer drugs (36)(37)(38), 18 F-L-FEHTP is a candidate PET tracer for staging tumors according to their LAT1 expression and activity and therefore their susceptibility to LAT1-targeted drugs. In addition, the in vivo efficiency of LAT1 inhibitors may be monitored directly by PET.…”

Section: Discussionmentioning

confidence: 99%

5-(2-¹⁸F-Fluoroethoxy)-l-Tryptophan as a Substrate of System L Transport for Tumor Imaging by PET

Krämer¹,

Mu²,

Müller³

et al. 2012

J Nucl Med

View full text Add to dashboard Cite

Large neutral L-amino acids are substrates of system L amino acid transporters. The level of one of these, LAT1, is increased in many tumors. Aromatic L-amino acids may also be substrates of aromatic L-amino acid decarboxylase (AADC), the level of which is enhanced in endocrine tumors. Increased amino acid uptake and subsequent decarboxylation result in the intracellular accumulation of the amino acid and its decarboxylation product. 18 F-and 11 C-labeled neutral aromatic amino acids, such as L-3,4-dihydroxy-6-18 F-fluorophenylalanine ( 18 F-FDOPA) and 5-hydroxy-L-[b-11 C]tryptophan, are thus successfully used in PET to image endocrine tumors. However, 5-hydroxy-L-[b-11 C]tryptophan has a relatively short physical half-life (20 min). In this work, we evaluated the in vitro and in vivo characteristics of the 18 F-labeled tryptophan analog 5-(2-18 F-fluoroethoxy)-L-tryptophan ( 18 F-L-FEHTP) as a PET probe for tumor imaging. Methods: 18 F-L-FEHTP was synthesized by no-carrier-added 18 F fluorination of 5-hydroxy-L-tryptophan. In vitro cell uptake and efflux of 18 F-L-FEHTP and 18 F-FDOPA were studied with NCI-H69 endocrine small cell lung cancer cells, PC-3 pseudoendocrine prostate cancer cells, and MDA-MB-231 exocrine breast cancer cells. Small-animal PET was performed with the respective xenograft-bearing mice. Tissues were analyzed for potential metabolites. Results: 18 F-L-FEHTP specific activity and radiochemical purity were 50-150 GBq/mmol and greater than 95%, respectively. In vitro cell uptake of 18 F-L-FEHTP was between 48% and 113% of added radioactivity per milligram of protein within 60 min at 37°C and was blocked by greater than 95% in all tested cell lines by the LAT1/2 inhibitor 2-amino-2-norboranecarboxylic acid. 18 F-FDOPA uptake ranged from 26% to 53%/mg. PET studies revealed similar xenograft-to-reference tissue ratios for 18 F-L-FEHTP and 18 F-FDOPA at 30-45 min after injection. In contrast to the 18 F-FDOPA PET results, pretreatment with the AADC inhibitor S-carbidopa did not affect the 18 F-L-FEHTP PET results. No decarboxylation products of 18 F-L-FEHTP were detected in the xenograft homogenates. Conclusion: 18 F-L-FEHTP accumulates in endocrine and nonendocrine tumor models via LAT1 transport but is not decarboxylated by AADC. 18 F-L-FEHTP may thus serve as a PET probe for tumor imaging and quantification of tumor LAT1 activity. These findings are of interest in view of the ongoing evaluation of LAT1 substrates and inhibitors for cancer therapy.

show abstract

“…Analysis of mRNA Using Oligonucleotide Arrays-For correlation of protein and RNA gene expression patterns, a range of non-dysplastic and dysplastic Barrett samples and esophageal adenocarcinomas were examined by high density oligonucleotide microarrays as described previously (11,12). We compared mRNA expression of 46 samples, including nine Barrett metaplasia, seven samples with a mixture of Barrett metaplasia and low grade dysplasia, eight low grade dysplasia, seven high grade dysplasia, and 15 esophageal adenocarcinomas.…”

Section: Methodsmentioning

confidence: 99%

Comparative Proteomics Analysis of Barrett Metaplasia and Esophageal Adenocarcinoma Using Two-dimensional Liquid Mass Mapping

Zhao

Chang

et al. 2007

Molecular & Cellular Proteomics

Self Cite

View full text Add to dashboard Cite

Esophageal adenocarcinoma, currently the seventh leading cause of cancer-related death, has been associated with the presence of Barrett metaplasia. The malignant potential of Barrett metaplasia is evidenced by ultimate progression of this condition to invasive adenocarcinoma. We utilized liquid phase separation of proteins with chromatofocusing in the first dimension and nonporous reverse phase HPLC in the second dimension followed by ESI-TOF mass spectrometry to identify proteins differentially expressed in six Barrett metaplasia samples as compared with six esophageal adenocarcinoma samples; all six Barrett samples were obtained from the identical six patients from whom we obtained the esophageal adenocarcinoma tissue. Approximately 300 protein bands were detected by mass mappings, and 38 differentially expressed proteins were identified by LC-MS/MS. The false positive rates of the peptide identifications were evaluated by reversed database searching. Among the proteins that were identified, Rho GDP dissociation inhibitor 2, ␣-enolase, Lamin A/C, and nucleoside-diphosphate kinase A were demonstrated to be up-regulated in both mRNA and protein expression in esophageal adenocarcinomas relative to Barrett metaplasia. Candidate proteins were examined at the mRNA level using high density oligonucleotide microarrays. The cellular expression patterns were verified in both esophageal adenocarcinomas and in Barrett metaplasia by immunohistochemistry. These differentially expressed proteins may have utility as useful candidate markers of esophageal adenocarcinoma. Molecular & Cellular Proteomics 6:987-999, 2007.Esophageal adenocarcinoma is increasing rapidly in Western countries and is currently the seventh leading cause of cancer-related death (1). Esophageal adenocarcinoma has been associated with the presence of Barrett metaplasia, a condition in which the normal squamous epithelium of the esophagus is replaced by columnar epithelium. The malignant potential of this condition is evidenced by the progression of Barrett metaplasia to low grade dysplasia, high grade dysplasia, and ultimately to invasive adenocarcinoma. The risk of developing adenocarcinoma is 30 -125 times higher in people who have Barrett metaplasia than people who do not. The prognosis of patients with esophageal adenocarcinoma remains poor with overall 5-year survival rates of only 5-15% (1). Unfortunately patients often present with regionally advanced disease (2). Given the poor prognosis associated with esophageal adenocarcinoma, it is imperative to improve our understanding of the tumorigenesis and the factors associated with increased risk. It is possible that therapeutic targets or protein markers can be identified that will ultimately facilitate improved patient survival.Proteomics technologies have been used for the identification of candidate markers for early cancer detection (3). The global analysis of protein expression complements genomics analyses. For example, proteomics analysis may provide further insight into post-translational mod...

show abstract

L-Type Amino Acid Transporter-1 Overexpression and Melphalan Sensitivity in Barrett's Adenocarcinoma

Cited by 58 publications

References 38 publications

l-Amino Acid Transporter-1 and Boronophenylalanine-Based Boron Neutron Capture Therapy of Human Brain Tumors

l-Amino Acid Transporter-1 and Boronophenylalanine-Based Boron Neutron Capture Therapy of Human Brain Tumors

5-(2-¹⁸F-Fluoroethoxy)-l-Tryptophan as a Substrate of System L Transport for Tumor Imaging by PET

Comparative Proteomics Analysis of Barrett Metaplasia and Esophageal Adenocarcinoma Using Two-dimensional Liquid Mass Mapping

Contact Info

Product

Resources

About

L-Type Amino Acid Transporter-1 Overexpression and Melphalan Sensitivity in Barrett's Adenocarcinoma

Cited by 58 publications

References 38 publications

l-Amino Acid Transporter-1 and Boronophenylalanine-Based Boron Neutron Capture Therapy of Human Brain Tumors

l-Amino Acid Transporter-1 and Boronophenylalanine-Based Boron Neutron Capture Therapy of Human Brain Tumors

5-(2-18F-Fluoroethoxy)-l-Tryptophan as a Substrate of System L Transport for Tumor Imaging by PET

Comparative Proteomics Analysis of Barrett Metaplasia and Esophageal Adenocarcinoma Using Two-dimensional Liquid Mass Mapping

Contact Info

Product

Resources

About

5-(2-¹⁸F-Fluoroethoxy)-l-Tryptophan as a Substrate of System L Transport for Tumor Imaging by PET