l-amino acid transporter-1 and boronophenylalanine-based boron neutron capture therapy of human brain tumors

Abstract

The system L-amino acid transporter-1 (LAT-I) imports p-boronophenylalanine (BFA) into cells and may play a major role in the effectiveness of BFA-based boron neutron capture therapy. The functional status of LAT-I 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 expiants. 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-I/ PCNA double-stained cells, and not all FCNA-expressing cells coexpressed LAT-I. Boron uptake reached 30 ± 15 iig/g of wet weight of tissue by 4 hours both in tumor d brain around tumor tissue containing tumor cells compared with time 0 (P < 0.005; M = 4 glioblastoma tumors). This uptake was inhibited by both phenylalanine and 2-minobicyclo-(2,2,l)-heptane-2-carboxylic acid. These LAT-I 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-I, will require a different therapeutic strategy. © 2009 American Association for Cancer Research.