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-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]

Enhancing effect of ultrasound on boron concentrations in an oral squamous cell carcinoma cell line SAS for boron neutron capture therapy

“…The microdistribution of boron compounds in peripheral tumors was studied using a SCC mouse model, with particular attention given to the quiescent cells, and this cell population was unable to accumulate BPA [9,10]. On the other hand, Detta and Cruickshank [13] stated that BPA-mediated BNCT might alter up to 70% of tumor cells expressing LAT-1, representing a three times higher proportion of tumor cells than their cell cycle status might suggest. In this case, LAT-1-negative cells would survive BNCT and be the cause of recurrence.…”

“…It was also reported that the selective accumulation of amino acids was made possible by specific uptake mechanisms involving the system L family of heterodimeric, sodium-independent, amino acid transporters located at the plasma membrane, in particular L-amino acid transported-1 (LAT-1) [11,12]. Quiescent cells and a lack of LAT-1 expression may be responsible for the failure of BPA-mediated BNCT [13].…”

Boron Carbide Particle as a Boron Compound for Boron Neutron Capture Therapy

“…BPA is expected to be incorporated into tumour cells by specific uptake mechanisms involving LAT-1 [3,4,21,22]. BSH is not actively incorporated into tumour cells, but enters cells by a concentration gradient.…”

“…Each B 4 C particle was encapsulated in a graphitic layer. They were dissolved in phosphate-buffered saline (PBS) and a stock solution was made of B 4 C at a concentration of 1,000 ppm.…”

“…BPA, a derivative of the amino acid phenylalanine, can be incorporated into tumor cells through specific uptake mechanisms involving the L family of heterodimeric, sodium-independent, amino acid transporters located at the plasma membrane, particularly L-amino acid transported -1 (LAT-1) [3,4], while BSH can permeate the blood-brain barrier for tumor cell in the brain. Difficulties have been associated with labeling of quiescent cells at the G0 phase with BPA [5,6].…”