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

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Abstract

The system L-amino acid transporter-1 (LAT-1) imports p-boronophenylalanine (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 +/- SD) was three times higher than that of proliferating cell nuclear antigen (PCNA)expressing cells (71.5 +/- 17.02% versus 23.8 +/- 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 +/- 15 mu g/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]

Details

Original languageEnglish
Pages (from-to)2126-2132
Number of pages7
JournalCancer Research
Volume69
Issue number5
Publication statusPublished - 1 Mar 2009