Metabolic Manipulation of Glioblastoma in Vivo by Retrograde Microdialysis of L-2, 4 Diaminobutyric Acid (DAB)

Abstract

To study the metabolic effects in vivo of L-2, 4 diaminobutyric acid (DAB) administered by retrograde microdialysis in glioblastoma and to evaluate the feasibility of the technique. In 10 patients with glioblastoma, a stereotactic biopsy was performed followed by implantation of microdialysis catheters. One or two catheters were implanted in tumor tissue and two reference catheters were implanted in normal brain tissue and subcutaneous abdominal tissue, respectively. Tumor catheters were perfused with 80 or 120 mmol/l DAB and reference catheters were perfused with a Ringer solution, all with a flow rate of 2.0 µl/min. Treatment was given for at mean 9.1 (5–19) days. The treatment was well tolerated by the patients with the exception of two patients in whom a transient brain edema appeared. No complications related to the technique were encountered. During treatment, an increase in the extracellular amino acids alanine, glycine, glutamate, aspartate, serine, threonine, and taurine was found demonstrating a significant influence on the intracellular pool of free amino acids induced by DAB. No change in glucose metabolism or glycerol was evident. The metabolism in normal brain was unaffected during treatment. Retrograde microdialysis is a feasible method for intracerebral administration of drugs to tumor tissue in patients with glioblastoma. We found it possible to deliver DAB to glioblastoma tumors in fully mobilized patients and to assess the metabolic effects induced by the treatment. The changes in extracellular amino acids were in concordance to what was expected from in vitro studies. Elevation of glutamate and taurine may be regarded as markers for an induced cellular toxicity while the unchanged level of glycerol may indicate no direct effects on phospholipase activity and membrane phospholipid composition. The effects were restricted to the tumor compartment. Although an improved survival could possibly be suspected no dramatic effect on outcome could be detected. However, the series was small and, most probably, the time for treatment was too short.