Locoregional Apo2L/TRAIL eradicates intracranial human malignant glioma xenografts in athymic mice in the absence of neurotoxicity

Glioblastoma multiforme is a lethal neoplasm refractory to radiochemotherap y, Although glioma cells undergo apoptosis when exposed to the death ligand , CD95 (Fas/APO-1) ligand, the therapeutic use of CD95L is considered impos sible because of lethal side effects. Here, we report that the locoregional application of Apoa ligand (Apo2L) exerts strong antitumor activity on pre established intracranially growing human U87MG glioma xenografts in athymic mice. Two repetitive intratumoral injections of 2 mu g Apo2L resulted in l ong-term survival of mice (>100 days), whereas the median survival of mock- treated mice was 36 days. The assessment of tumor volumes at 21 and 35 days after inoculation showed complete eradication of glioma xenografts in Apo2 L-treated mice. Histology and TUNEL assay confirmed the induction of apopto sis by Apo2L in glioma cells in vivo. Importantly, the intracerebral inject ion of Apo2L does not result in acute or delayed neurotoxicity. We propose that a phase 1 trial of intralesional Apo2L therapy for human glioblastoma multiforme is warranted. (C) 1999 Academic Press.