L-AMINO-ACID OXIDASE (LOX) MODULATION OF MELPHALAN ACTIVITY AGAINST INTRACRANIAL GLIOMA

These studies evaluated the efficacy of sequential pretreatment with L -amino acid oxidase (LOX) and LOX antiserum in the modulation of melph alan activity against intracranial glioma in athymic nude mice. LOX pr oduced statistically significant (P < 0.01) depletion of the large neu tral amino acids isoleucine, leucine, methionine, phenylalanine, tyros ine, and valine in murine plasma at doses of 100 and 200 mu g administ ered intravenously. Polyclonal anti-LOX antibody was successfully prod uced in mice, rabbits, and goats subsequent to immunization with LOX. Staphylococcal protein A-purified rabbit anti-LOX serum inhibited appr oximately 50% of LOX activity in vitro relative to control samples. Th is antiserum was used in vivo to inactivate LOX after it had depleted the large neutral amino acids, thereby preventing LOX-mediated catabol ism of melphalan. Inoculation of three mice with rabbit anti-LOX serum after the treatment with LOX (100 mu g) reduced LOX activity by 100%, 89%, and 100% at 6 h compared with reductions of 80%, 59%, and 52% ov er the same period in animals receiving LOX alone. In three separate s tudies using groups of eight to ten mice bearing intracranial human gl ioma xenografts, pretreatment with LOX followed by anti-LOX serum incr eased the antitumor activity of melphalan as compared with treatments with melphalan plus LOX, melphalan plus anti-LOX serum, or melphalan a lone.