Treatment of malignant glioma by a new therapeutic principle

Summary

L- 2,4 diaminobutyric acid (DAB) is a non-physiological, cationic amino acid transported into cells by System A with potent antitumour activity in vitro against human glioma cells. This activity was the result of the pronounced concentrated uptake of DAB in glioma cells to the extent that a cellular lysis could occur due to osmotic reasons. We describe the treatment of 3 patients with inoperable malignant glioma by direct and continuous administration of DAB in tumour tissue employing a microdialysis technique.

One to three microdialysis probes were implanted in the tumour tissue through small dural incisions in 3 patients with inoperable malignant glioma. Micropumps charged with 3 ml a day of a Trisbuffered 0.125 M DAB solution made isotonic at pH 7.55 were adapted to the input channel of the probe and a sampling tube to the output for continuous flowing into tumour tissue. The patients were treated in this way for a total of 14–21 days without side effects assignable to DAB. Massive tumour necrosis occurred as judged by comparison of computed tomography performed before and after DAB treatment. The yield of the dialysis procedure with regard to DAB was estimated to be 40–50%. The dialysate concentration of arginine (a cationic amino acid considered to be transported mainly by system A) was high and increased nearly 4-fold from day 3 to day 6 of treatment. DAB administered in this way into malignant brain tumour tissue was well tolerated and showed promising antitumour activity in the 3 patients with inoperable malignant glioma. High and increasing concentrations of arginine in the dialysate during treatment indicated a displacement of this amino acid from the intracellular space of malignant tumour cells most probably as a consequence of huge intracellular accumulation of DAB preceding cellular lysis.