Experimental Study to Understand Nonspecific Protoporphyrin IX Fluorescence in Brain Tissues Near Tumors After 5-Aminolevulinic Acid Administration

Objective: (PpIX) fluorescence induced by 5-aminolevulinic acid (5-ALA), which appears in various tumors including malignant gliomas, is a good navigator for tumor resection. However, some non-neoplastic tissue also shows a weak PpIX fluorescence. The origin of non-neoplastic PpIX is still unknown, and three hypotheses on its origins can be proposed: tumor cell-derived PpIX followed by dispersal via bulk flow, direct PpIX production by normal brain or gliotic brain tissue, or PpIX produced in other organs leaking from the tumor vessels. We investigated the possibility of these three origins experimentally. Methods:In vitro, we exposed various cultured glioma and meningioma cell lines to different conditions of 5-ALA. After this, the degree of fluorescence of the culture medium and cells was each quantitatively measured and analyzed by means of photometrical assay. We administered 5-ALA directly into the normal brains of rats by using convection-enhanced delivery technique, and we also administered 5-ALA or PpIX systemically after blood-brain barrier (BBB) disruption. Results: As a result of our in vitro study using cell lines, we found fluorescence of extracellular PpIX in the culture medium. As a result of rat study, we found PpIX fluorescence of the extracted normal brain after systemic administration of 5-ALA with BBB disruption. However, no PpIX fluorescence was observed when we administered PpIX. Conclusions: It was demonstrated that PpIX was quickly excreted by tumor cells out to the extracellular space, and that even normal brain tissue can produce PpIX in the presence of 5-ALA.