L-amino acid transporter-1 and boronophenylalanine-based boron neutron capture therapy of human brain tumors.
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 mug/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.
Detta
Allah
A
Department of Neurosurgery, Molecular Neurooncology Laboratory, The University of Birmingham, Queen Elizabeth Hospital Neuroscience Centre, Edgbaston, Birmingham, United Kingdom.
Cruickshank
Garth S
GS
D001896:Boron Compounds / Q000493:pharmacokinetics*; D016754:Boron Neutron Capture Therapy / Q000379:methods*; D001932:Brain Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D049109:Cell Proliferation; D006801:Humans; D007150:Immunohistochemistry; D027283:Large Neutral Amino Acid-Transporter 1 / Q000032:analysis / Q000502:physiology*; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis
D001896:Boron Compounds; D027283:Large Neutral Amino Acid-Transporter 1; D018809:Proliferating Cell Nuclear Antigen; D010649:Phenylalanine; C033685:4-boronophenylalanine