THE EFFECT OF L-AMINO-ACID OXIDASE ON ACTIVITY OF MELPHALAN AGAINST AN INTRACRANIAL XENOGRAFT

We have previously shown that diet restriction-induced depletion of la rge neutral amino acids (LNAAs) in murine plasma to 46% of control sig nificantly enhances intracranial delivery of melphalan without enhanci ng delivery to other organs. Studies have now been conducted to determ ine whether more substantial LNAA depletion could further enhance intr acranial delivery of melphalan. Treatment with L-amino acid oxidase (L OX) significantly depleted murine plasma LNAAs: phenylalanine, leucine , and tyrosine(> 95%); methionine (83%); isoleucine (70%); and valine (46%). Experiments evaluating the intracellular uptake of melphalan an d high-pressure liquid chromatography quantitation of melphalan metabo lites revealed, however, that melphalan is rapidly degraded in the pre sence of LOX, and that the timing of the administration of melphalan f ollowing the use of LOX to deplete LNAAs is crucial. Conditions were f ound under which LOX-mediated degradation of melphalan was minimized a nd LNAA depletion was maximized, resulting in a potentiation of the an titumor effect of melphalan on human glioma xenografts in nude mice. S uch potentiation could not be obtained using diet restriction alone.