Melphalan, a nitrogen mustard derivative of the neutral amino acid l-phenylalanine, was transported across the rat blood-brain barrier by the large (l-system) neutral amino acid transporter in tumor-bearing brain, but no evidence for blood-brain barrier transport by the alanine-serine-cysteine system carrier was obtained in the present study. The ability of melphalan to inhibit phenylalanine uptake was compared in rats implanted with two experimental CNS tumors: the C-6 glioma (a model of primary brain tumors) and Walker carcinoma (a model of metastatic brain tumors). The melphalan concentration which caused 50% inhibition of blood-brain barrier (BBB) phenylalanine uptake (Ki) was 0.49 ± 0.18 mm in the Walker tumor, compared with 0.46 ± 0.19 mm in the contralateral control brain. In the ipsilateral hemisphere (Ki = 0.59 ± 0.25 mm) and contralateral hemisphere (Ki = 0.45 ± 0.19 mm), drug entry was also via the neutral amino acid transporter. In C-6 gliomas (Ki = 0.77 ± 0.20 mm) and contralateral control brain (Ki = 0.84 ± 0.29 mm), melphalan also inhibited BBB phenylalanine transport. A major finding was that, at melphalan concentrations greater than 1.0 mm, BBB permeability of radiolabeled indium (chelated to EDTA) increased in proportion to melphalan concentration. In the contralateral hemisphere of rats implanted with C-6 gliomas, brain extractions of indium-EDTA measured 3 to 4% in the absence of drug, 5 to 6% at 2.5 mm melphalan, and 9 to 10% at 5 mm melphalan. A similar phenomenon was observed in the nontumoral brain regions of rats implanted with Walker carcinoma cells. In normal (nonimplanted) rats, melphalan's inhibition (Ki = 0.29 mm) of phenylalanine and tryptophan (Ki = 0.20 mm) uptake was confirmed, and brain extraction of sucrose (a nonspecific marker which does not penetrate the intact BBB) was observed to increase in proportion to melphalan concentration. We conclude that melphalan not only enters the brain via the neutral amino acid transporter, but at higher concentrations (>1 mm) may open the blood-brain barrier in a nonspecific manner.

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Supported by NIH Grant NS 25554, NSF IN-8900173, the Auckland Medical Research Foundation (New Zealand), the Medical Research Council (New Zealand), and the US Veterans Administration.

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